Porphyrin derivative, preparation method thereof and antibacterial application of porphyrin derivative

Abstract

The invention relates to a compound of formula (I), a preparation method thereof and a use thereof for bacteriostasis, wherein the groups in the formula (I) are as defined in the description. The method for preparing the compound as shown in the formula (I) is simple in synthesis process and low in cost, and good yield can be obtained by using the combination of the specific condensation catalyst and the condensing agent. Moreover, the compound as shown in the formula (I) provided by the invention has good targeting and antibacterial capabilities on gram-negative cocci, bacilli or bacilli, and has a treatment effect on oral diseases such as periodontitis, gingivitis, dental plaque, decayed teeth and the like. # imgabs0 # (I).

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and more specifically relates to a porphyrin derivative, a preparation method thereof and a use thereof for inhibiting bacteria, and more specifically to a porphyrin derivative for inhibiting Porphyromonas gingivalis (Porphyromonas gingivalis) in photodynamic therapy. Porphyromonas gingivalis ) and other Gram-negative bacteria. Background Art

[0002] Photodynamic therapy (PDT) is a new type of therapy that uses photosensitizers, light, and oxygen molecules to produce photodynamic reactions, and then selectively targets diseases such as malignant tumors, vascular lesions, and microbial infections. Photosensitizers are the core of PDT. The photosensitizers currently used in clinical practice mainly include Photofrin from the United States, Photogem from Russia, and Photosan from Germany. However, these photosensitizers still have many disadvantages. For example, they are mostly mixed preparations composed of porphyrin derivatives, the active ingredients are unclear, and there are no controllable quality standards. In addition, they can easily cause skin phototoxic effects such as rashes and blisters because they can remain in the skin for several weeks. Patients need to avoid direct sunlight for 1 month or even longer after taking the medicine.

[0003] Periodontitis is a chronic inflammatory disease that is mainly caused by the destruction of periodontal tissues by bacteria in dental plaque. Porphyromonas gingivalis is the main pathogen of periodontitis and gingivitis. It is a Gram-negative coccobacillus that generally exists in the human mouth and intestines. Due to antibiotic resistance, oral diseases caused by periodontitis and dental plaque have not been effectively treated.

[0004] Therefore, it is of great significance to develop photosensitizers targeting Gram-negative bacteria. Summary of the invention

[0005] In view of the state of the prior art, the present invention aims to provide a class of porphyrin derivatives with simple synthesis process and low cost. Such porphyrin derivatives have high biological safety and can be used as photosensitizers in photodynamic therapy. More specifically, they can be used to inhibit Gram-negative cocci, bacilli or coccobacilli. They are porphyrin derivatives with potential clinical application value and can be produced on a large scale.

[0006] The first aspect of the present invention provides a compound of formula (I) (I) in, X - is the acetate ion, q is 2, so that X - Balance the charge of the cations, R +The following formula (II) (II) “ "The wavy line indicates the connection point to the rest of the p is 0 or 1, K is the following formula (II-a) or (II-b), preferably formula (II-a), (II-a) or (II-b), R1 is hydrogen, alkyl, cycloalkyl or heteroarylalkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; preferably hydrogen or heteroarylalkylene; R2 is hydrogen or heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; A + It is the following formula (II-c) or (II-d), preferably formula (II-d), (II-c) or (II-d), n is each independently an integer from 0 to 8; m is 0 or 1, so that the N atom has a positive charge; Q is a heterocyclic or heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further contains one or more heteroatoms selected from O, S and N; R3 are each independently an alkyl group.

[0007] The second aspect of the present invention provides a method for preparing a compound of formula (I), the method comprising: i) in the presence of a condensation catalyst and a condensation agent, allowing protoporphyrin (PPIX) to undergo a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent to obtain an intermediate compound; iii) subjecting the intermediate compound to an alkylation reaction; in, The compound having a reactive hydrogen atom is selected from compounds of the general formula (III) (III) in, H represents a reactive hydrogen atom; p is as defined above; K is as defined above; A is the following formula (III-c) or (III-d), (III-c) or (III-d), n is as defined above; P is as defined above for Q and is electrically neutral; R3 is as defined above.

[0008] The third aspect of the present invention provides a medicament comprising a compound of formula (I).

[0009] The fourth aspect of the present invention provides a non-therapeutic method for inhibiting Gram-negative cocci, bacilli or coccobacilli, which comprises contacting the compound of formula (I) with Gram-negative cocci, bacilli or coccobacilli and irradiating them with an effective inhibitory amount of light of a specific wavelength.

[0010] The fifth aspect of the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating a disease or condition caused by a Gram-negative coccus, bacillus or coccobacillus.

[0011] The sixth aspect of the present invention provides a compound of formula (I) for use in treating a disease or condition caused by a Gram-negative coccus, bacillus or coccobacillus.

[0012] The seventh aspect of the present invention is to provide a method for treating diseases or conditions caused by Gram-negative cocci, bacilli or coccobacilli, which comprises administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof and irradiating a therapeutically effective amount of light of a specific wavelength.

[0013] Technical effects of the present invention: The present invention provides a class of porphyrin derivatives with positive charge, which can be used as photosensitizers in photodynamic therapy. The method for preparing the compound of formula (I) of the present invention has a simple synthesis process and low cost, and a good yield can be obtained by using a combination of a specific condensation catalyst and a condensation agent. In addition, the compound of formula (I) provided by the present invention has good targeting and antibacterial ability against Gram-negative cocci, bacilli or coccobacilli, and has a therapeutic effect in oral diseases such as periodontitis, gingivitis, dental plaque and caries. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 : Inhibitory effect of PPIX, 5-ALA and porphyrin derivatives on Porphyromonas gingivalis (Note: **** indicates compared with PPIX; ^^^^ indicates compared with P-12-02 (* P＜ 0.05, **** indicates P＜ 0.0001, ^^^^ indicates P ＜ 0.0001)); Figure 2 :Targeted fluorescence effect of PPIX and porphyrin derivatives on Porphyromonas gingivalis. DETAILED DESCRIPTION

[0015] Hereinafter, the present invention will be described in more detail.

[0016] Unless otherwise indicated, "compound of formula (I) of the present invention", "compound of formula (I)", "compound of the present invention" and "porphyrin derivative of the present invention" are used synonymously.

[0017] As used herein, the term "comprising" and its synonyms "including" and "containing" mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps.

[0018] The terms "optional", "optional" or "optionally" as used herein mean that the subsequently described event, circumstance or material may or may not appear or exist, and that such description includes instances where the event, circumstance or material appears or exists and instances where the event, circumstance or material does not appear or exist.

[0019] 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.

[0020] As used herein, the term "halogen" refers to, for example, fluorine, chlorine, bromine or iodine.

[0021] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon radical having in each case the specified number of carbon atoms, such as (C1-C8)-alkyl, (C1-C6)-alkyl and (C1-C4)-alkyl, examples of which include, but 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.

[0022] As used herein, the term "alkylene" refers to a hydrocarbon group having two monovalent radical centers derived from an alkyl group by removing a hydrogen atom, which may be a saturated branched alkyl group or a saturated straight chain alkyl group. Suitable examples include, but are not limited to, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 1,2-propylene, 2,2-propylene, 1,4-butylene, 1,3-butylene, 1,2-butylene, 1,5-pentylene, and 1,6-hexylene.

[0023] As used herein, the term "cycloalkyl" refers to a carbocyclic saturated ring system having in each case the specified number of carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In particular, the cycloalkyl has 3 to 6 carbon atoms.

[0024] Unless otherwise defined, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic heterocyclic group of carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur, wherein at least one ring is aromatic. Preferably, the heteroaryl group contains 3, 4, 5, 6, 7 or 8 carbon atoms, which can be attached to the parent molecular moiety through any carbon atom or nitrogen atom contained in the heterocyclic ring. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl, 1,2,3-oxadi ...3-oxadiazolyl, 1,2,4-triazolyl, 1,3,4-triaz oxadiazole, 1,2,4-triazine, 1,3,5-triazine, tetrazolyl, benzofuranyl, benzisofuranyl, benzothiophenyl, benzisothiophenyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 2,1,3-benzoxadiazole, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl, imidazopyridinyl, thienopyrimidinyl, thienopiperidinyl, and the like.

[0025] The term "heteroarylalkylene" refers to a combination of the groups "heteroaryl" and "alkylene" as defined according to the present invention, wherein the group is usually connected to the backbone or the rest through an alkylene group, wherein the definitions of alkylene and heteroaryl are as described above. Examples include, but are not limited to, pyrrolylmethylene, pyrrolylethylene, thienylmethylene, thienylethylene, furanylmethylene, furanylethylene, etc.

[0026] Unless otherwise defined, the term "heterocyclyl" means a saturated or partially saturated monocyclic ring of carbon atoms and at least one heteroatom in the ring. Preferably, the heterocyclyl contains 2, 3, 4, 5 or 6 carbon atoms and 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, which can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained in the heterocyclic ring. If more than one oxygen atom is contained in the ring, they are not directly adjacent. Examples of heterocyclyl include, but are not limited to, aziridine, oxirane; azetidine, oxetane, thietane; tetrahydrofuranyl, 1,3-dioxolane, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl; piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydro Thiopyranyl, dithianyl, morpholinyl, 1,2-oxazepanyl, oxathianyl, thiomorpholinyl; oxepanyl, azepanyl, 1,4-diazepanyl, 1,4-oxazepanyl; dihydrofuranyl, 1,3-dioxolyl, dihydrothiophenyl, pyrrolinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrothiazolyl; pyranyl, thiopyranyl and thiazinyl.

[0027] As used herein, the term "amino protecting group" is a protecting group attached to nitrogen in an intermediate used to prepare a compound of formula (I). The group may be selected from substituted sulfonyl groups, such as mesyl, tosyl or benzenesulfonyl, acyl groups, such as benzoyl, acetyl or tetrahydrofuranone, or carbamate groups, such as tert-butyloxycarbonyl (Boc), or may contain silicon, such as 2-(trimethylsilyl)ethoxymethyl (SEM).

[0028] Compounds obtained from combinations which are contrary to the laws of nature and which a person skilled in the art would therefore exclude based on his / her expert knowledge are not covered herein. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0029] According to one aspect of the present invention, the present invention provides a compound of formula (I) (I) in, X - is a pharmaceutically acceptable counter ion, q is 1 or 2 so that X - Balance the charge of the cations, R + The following formula (II) (II) “ "The wavy line indicates the connection point to the rest of the p is 0 or 1, K is the following formula (II-a) or (II-b), preferably formula (II-a), (II-a) or (II-b), R1 is hydrogen, alkyl, cycloalkyl or heteroarylalkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; preferably hydrogen or heteroarylalkylene; R2 is hydrogen or heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; A + It is the following formula (II-c) or (II-d), preferably formula (II-d), (II-c) or (II-d), n is each independently an integer from 0 to 8; m is 0 or 1, so that the N atom has a positive charge; Q is a heterocyclic or heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further contains one or more heteroatoms selected from O, S and N; R3 are each independently an alkyl group.

[0030] Among them, X - It is a pharmaceutically acceptable counter ion, which may be selected from, for example, carbonate ion, sulfate ion, sulfonate ion, citrate ion, trifluoroacetate ion, halogen ion (such as iodide ion or chloride ion, etc.) and acetate ion, preferably acetate ion.

[0031] The inventors unexpectedly found that, compared with other anions (such as iodide ions, chloride ions and trifluoroacetate ions), the use of acetate ions to form salts is more conducive to optimizing and balancing the solubility, chemical stability, biosafety, ease of preparation and yield of the compound. For example, in terms of solubility, the compounds of the present invention formed by acetate ions have higher solubility than the corresponding compounds formed by iodide ions; in terms of chemical stability, the compounds of the present invention formed by acetate ions have higher chemical stability than the corresponding compounds formed by chloride ions or iodide ions; in terms of ease of preparation and yield, the use of acetate ions to form salts is easier to prepare than the use of trifluoroacetate ions, and the yield is higher; in terms of biosafety, acetate ions have better biocompatibility than iodide ions.

[0032] In the case where Q is a heterocyclic group, the connection site of the Q and the optional alkylene group can be on any ring-forming atom of the heterocyclic group, such as a positively charged N atom, a ring-forming carbon atom or a ring-forming heteroatom. In the case where Q is a heteroaryl group, the connection site of the Q and the optional alkylene group can be on any ring-forming atom other than a positively charged N atom, such as a ring-forming carbon atom.

[0033] In a preferred embodiment of the present invention, wherein in formula (I), R1 is hydrogen, (C1-C8)-alkyl, (C3-C 10 )-cycloalkyl or (C3-C 10 )-heteroaryl-(C1-C8)-alkylene, the heteroarylalkylene containing one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C 10 )-heteroaryl, the heteroaryl containing one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 8; m is 0 or 1, so that the N atom has a positive charge; Q is a (C2-C 10 )-heterocyclic or (C3-C 10 )-heteroaryl, the heterocyclic group optionally further comprising one or more heteroatoms selected from O, S and N; R3 is each independently (C1-C8)-alkyl.

[0034] In a more preferred embodiment of the present invention, wherein in formula (I), R1 is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or (C3-C8)-heteroaryl-(C1-C6)-alkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C8)-heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 6; m is 0 or 1, so that the N atom has a positive charge; Q is a (C2-C7)-heterocyclyl or (C3-C8)-heteroaryl group containing one positively charged N atom, the heterocyclyl group optionally further comprising one or more heteroatoms selected from O, S and N; R3 are each independently (C1-C6)-alkyl.

[0035] In a more preferred embodiment of the present invention, wherein in formula (I), R1 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or (C3-C5)-heteroaryl-(C1-C4)-alkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C5)-heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 4; m is 0 or 1, so that the N atom has a positive charge; Q is a (C3-C5)-heterocyclyl or (C3-C5)-heteroaryl group containing one positively charged N atom, the heterocyclyl group optionally further comprising one or more heteroatoms selected from O, S and N; R3 are each independently (C1-C4)-alkyl.

[0036] In a more preferred embodiment of the present invention, wherein in formula (I), R1 is hydrogen, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or thienylmethylene, thienyl-1,2-ethylene, thienyl-1,1-ethylene, thienyl-1,3-propylene, thienyl-1,2-propylene, thienyl-2,2-propylene, thienyl- 1,4-butylene, thienyl-1,3-butylene, thienyl-1,2-butylene, furanylmethylene, furanyl-1,2-ethylene, furanyl-1,1-ethylene, furanyl-1,3-propylene, furanyl-1,2-propylene, furanyl-2,2-propylene, furanyl-1,4-butylene, furanyl-1,3-butylene or furanyl-1,2-butylene; R2 is hydrogen or thienyl or furyl; n is each independently 0, 1, 2 or 3; m is 0 or 1, so that the N atom has a positive charge; Q is morpholinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyrazinyl, pyrazolyl or pyridinyl containing a positively charged N atom; R3 is each independently methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

[0037] In a more preferred embodiment of the present invention, wherein in formula (I), R1 is hydrogen, methyl, cyclopropyl or thienylmethylene; R2 is hydrogen or thienyl; n is each independently an integer from 0 to 2; m is 0 or 1, so that the N atom has a positive charge; Q is a morpholinyl, piperazinyl, imidazolidinyl or pyridinyl group containing a positively charged N atom; R3 is each independently methyl or ethyl.

[0038] In a more preferred embodiment of the present invention, wherein in formula (I), R + Each is independently selected from the following groups: , , , , , , , , , , and .

[0039] According to another aspect of the present invention, the present invention also provides a method for preparing a compound of formula (I), the method comprising: i) in the presence of a condensation catalyst and a condensation agent, allowing protoporphyrin (PPIX) to undergo a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent to obtain an intermediate compound; iii) subjecting the intermediate compound to an alkylation reaction.

[0040] in, The compound having a reactive hydrogen atom is selected from compounds of the general formula (III) (III) in, H represents a reactive hydrogen atom; p is as defined above; K is as defined above; A is the following formula (III-c) or (III-d), (III-c) or (III-d), n is as defined above; P is as defined above for Q and is electrically neutral; R3 is as defined above.

[0041] Specifically, P has the same structure as Q as defined above, except that P is electrically neutral and has no positive charge. For example, when Q is a morpholinyl group containing a positively charged N atom, P is a morpholinyl group containing a N atom, wherein the N atom has no positive charge.

[0042] Wherein, according to the reaction requirements, the compound having a reactive hydrogen atom may optionally carry an amino protecting group commonly used in amidation reactions known to those skilled in the art, such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), etc. Those skilled in the art can reasonably select according to actual needs. Preferably, the amino protecting group is -Boc (tert-butyloxycarbonyl).

[0043] In a preferred embodiment of the present invention, the compound having a reactive hydrogen atom is selected from tert-butyl 3-aminomethyl-morpholine-4-carbonate, tert-butyl (R)-3-(hydroxymethyl)morpholine-4-carboxylate, tert-butyl 1-tert-butoxycarbonylpiperazine, tert-butyl imidazoline-1-carboxylate, 1-(2-thienyl)-3-(dimethylamino)-1-propanol, N1,N1-dimethyl-N2-(thien-2-ylmethyl)ethane-1,2-diamine, 2-morpholine-N-(thien-2-ylmethyl)ethylamine, 4-hydroxymethylpyridine, N-cyclopropylpyridin-4-amine, N-methyl-N-(4-pyridylmethyl)amine and N,N-diethylethylenediamine.

[0044] The condensation catalyst suitable for the method of the present invention is an organic base catalyst, which is preferably 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.

[0045] The condensing agent suitable for the method of the present invention is a urea cation type condensing agent, which is preferably 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 (TBTU), O-(1, 2-dihydro-2-oxy-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU); or a carbodiimide type condensing agent, which is preferably selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or a carbonyl imidazole type condensing agent, which is preferably selected from N,N-carbonyldiimidazole (CDI); or a mixture of the above condensing agents; the condensing agent is preferably selected from HATU, EDCI, CDI or a mixture thereof, more preferably HATU.

[0046] The polar organic solvent suitable for the method of the present invention is selected from N,N-dimethylformamide, N,N-dimethylacetamide, formamide, dimethyl sulfoxide, acetone, pyridine or a mixture thereof, preferably N,N-dimethylformamide.

[0047] In a preferred embodiment of the present invention, the molar ratio of the condensation catalyst to the condensation agent is (0.7-3):1, preferably (0.8-2.5):1, and more preferably (0.9-2):1.

[0048] In a preferred embodiment of the present invention, the molar ratio of the condensation catalyst to the compound having a reactive hydrogen atom is (0.7-3):1, preferably (0.65-2.5):1, and more preferably (0.7-2):1.

[0049] In a preferred embodiment of the present invention, the content relationship between the protoporphyrin (p), the compound having a reactive hydrogen atom (n) and the condensing agent (q) in moles satisfies the following relationship: 2.5≤q / [np / (n+p)]≤4.5; preferably 2.7≤q / [np / (n+p)]≤4.3; more preferably 2.9≤q / [np / (n+p)]≤4.1.

[0050] In a preferred embodiment of the present invention, the catalyst is DIPEA, and the condensation agent is HATU, wherein the molar ratio of the condensation catalyst to the condensation agent is (0.7-3):1, preferably (0.8-2.5):1, and more preferably (0.9-2):1.

[0051] In a preferred embodiment of the present invention, the molar ratio of the compound having reactive hydrogen atoms to the condensation catalyst is 1:(0.6-3), preferably 1:(0.65-2.5), and more preferably 1:(0.7-2).

[0052] In a preferred embodiment of the present invention, the weight ratio of the polar organic solvent to the total amount of the protoporphyrin, catalyst, condensation agent and compound having reactive hydrogen atoms is 1:(0.06-0.25), preferably 1:(0.065-0.2), more preferably 1:(0.062-0.18).

[0053] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the condensation catalyst is 1:(1.8-8), preferably 1:(1.8-6), more preferably 1:(1.8-4), more preferably 1:(1.9-3).

[0054] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the catalyst is 1:(1.8-8), preferably 1:(1.8-6), more preferably 1:(1.8-4), more preferably 1:(1.9-3).

[0055] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the compound having a reactive hydrogen atom is 1:(2-6), preferably 1:(2.5-5), more preferably 1:(2.5-4.5), more preferably 1:(2.5-3.5).

[0056] The method for preparing the compound of formula (I) of the present invention uses a combination of a specific organic base catalyst and a specific condensing agent in step i), especially a combination of DIPEA and HATU in a specific ratio, which can obtain a high-purity intermediate compound with a good yield through simple post-treatment, thereby further improving the yield of the target product. In step i), too low or too high an amount of the catalyst or condensing agent will have an adverse effect on the intermediate compound. For example, too high or too low an amount of the base will lead to difficulty in post-treatment, an increase in the proportion of by-products, and a low yield of the intermediate compound, thereby further reducing the yield of the target product.

[0057] In the method of the present invention, the reaction time of step i) is 0.5-24 hours, preferably 1-22 hours, more preferably 1-20 hours.

[0058] In one embodiment of the present invention, the method of the present invention further comprises: step ii) removing the amino protecting group of the intermediate compound when the intermediate compound contains an amino protecting group.

[0059] The removal of the amino protecting group can be carried out by conventional methods known to those skilled in the art, for example, using a solution of hydrogen chloride or trifluoroacetic acid in a specific organic solvent (e.g., dioxane, ethyl acetate, methanol or dichloromethane), preferably a solution of hydrogen chloride in dioxane or a solution of trifluoroacetic acid in dichloromethane.

[0060] In the method of the present invention, the alkylation reaction of step iii) can be carried out by conventional means known to those skilled in the art. For example, the intermediate compound is alkylated with a halogenated alkane in the presence of a base by a method known to those skilled in the art or similar to a method known to those skilled in the art. The base can be a carbonate of an alkali metal (such as lithium, sodium or potassium), and the alkylation reaction is preferably carried out at room temperature in a suitable solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide or ethyl acetate.

[0061] In a preferred embodiment of the present invention, the intermediate compound is dissolved in N,N-dimethylformamide, add potassium carbonate, then add methyl iodide or ethyl iodide, stir at room temperature until the reaction is complete, and then purify and freeze-dry to obtain the compound of formula (I).

[0062] In the above method for preparing the compound of the present invention, each step of the method may optionally include other post-treatment steps. The post-treatment steps may include conventional purification steps such as adjusting the pH value, crystallization, extraction, filtration, concentration under reduced pressure, and drying. Each of the above steps can be carried out in a conventional manner known to those skilled in the art. If present, extraction is usually carried out using a mixed solution of dichloromethane and methanol, preferably a mixed solution of dichloromethane / methanol = 10:1 (v / v); drying is usually carried out by freeze drying, vacuum drying, etc., preferably freeze drying.

[0063] In a preferred embodiment of the present invention, the method may further include a purification step by a chromatographic column. The purification may be performed by: a normal phase silica gel column, the silica gel particle size is 30-100 μm, preferably 40-63 μm, the loading is 20-120 g, preferably 40 g, eluted with dichloromethane / methanol (elution gradient 100% / 0% to 90% / 10%, gradient elution time 15 min), or dichloromethane / methanol containing 1% triethylamine (elution gradient 100% / 0% to 90% / 10%, gradient elution time 15 min); or a C18 column, the filler particle size is 20-80 μm, preferably 40-63 μm, the loading is 4-120 g, preferably 40 g, the carbon content is between 10-30%, preferably 17%, eluted with water / acetonitrile containing 5% acetic acid (elution gradient 95% / 5% to 5% / 95%, gradient elution time 20-25 min).

[0064] Unless explicitly stated otherwise, all operations were performed at room temperature; reagents or starting materials used were either commercially available or prepared by methods known to those skilled in the art.

[0065] 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.

[0066] According to another aspect of the present invention, the present invention also provides a medicament comprising the compound of formula (I).

[0067] According to another aspect of the present invention, the present invention also provides a method for inhibiting Gram-negative cocci, bacilli or coccobacilli for therapeutic or non-therapeutic purposes, which comprises contacting a compound of formula (I) with Gram-negative cocci, bacilli or coccobacilli and irradiating with light of a specific wavelength in an effective amount for inhibition. The contact can be carried out in vivo or in vitro, for example, in vitro.

[0068] According to another aspect of the present invention, the present invention also provides the use of the compound of formula (I) in the preparation of a medicament for treating a disease or condition caused by Gram-negative cocci, bacilli or coccobacilli.

[0069] According to another aspect of the present invention, the present invention also provides use of the compound of formula (I) for treating diseases or conditions caused by Gram-negative cocci, bacilli or coccobacilli.

[0070] According to another aspect of the present invention, the present invention also provides a method for treating a disease or condition caused by Gram-negative cocci, bacilli or coccobacilli, which comprises administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof and administering a therapeutically effective amount of light irradiation of a specific wavelength; preferably, wherein the subject is a mammal, more preferably a human.

[0071] In one embodiment of the present invention, the medicament may further comprise one or more other active compounds. The other active compounds are compounds that are also effective in treating diseases or conditions caused by Gram-negative cocci, bacilli or coccobacilli.

[0072] In one embodiment of the invention, the medicine also includes pharmaceutically acceptable carriers, excipients and / or other adjuvants. When pharmaceutically acceptable carriers, excipients and / or other adjuvants are included, the compound of formula (I) of effective dose and one or more pharmaceutically acceptable carriers, excipients and / or other adjuvants are usually combined to form suitable application form or dosage form, and this procedure includes mixing, granulating, compressing or dissolving components by a suitable method. The content of the carrier in the medicine can be 1 to 98 weight %, usually accounting for about 80 weight %. For convenience, other adjuvants such as local anesthetics, preservatives, buffers can be directly dissolved in the carrier.

[0073] In a preferred embodiment of the present invention, the drug comprises 0.01 mg-600 mg, preferably 0.05 mg-450 mg, more preferably 0.1 mg-300 mg, more preferably 0.5 mg-200 mg, more preferably 1 mg-120 mg of the compound of formula (I), for example 0.1 mg-600 mg, 0.5 mg-450 mg, 1.0 mg-300 mg, 5 mg-200 mg, 6 mg-120 mg or 10 mg-120 mg, more specifically for example 0.01 mg, 0.1 mg, 1 mg, 2 mg, 4 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 120 mg, 200 mg, 400 mg or 600 mg.

[0074] Compounds of the present invention or medicine can work systemically and / or locally.For this purpose, they can be administered with suitable routes of administration, for example, by oral, pulmonary, nasal, sublingual, tongue, buccal, rectal, vaginal, dermal, transdermal, conjunctival or ear canal administration, or by subcutaneous, intravenous, intramuscular, intraperitoneal or intracranial injection or infusion, or as implant or stent administration.

[0075] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[0076] The drug of the present invention can be administered in a unit dosage form. The dosage form can be a liquid dosage form, a semisolid preparation and a solid dosage form. The liquid dosage form can be a true solution, a colloid, a microgranule dosage form, a suspension dosage form, etc. The semisolid dosage form can be an ointment, a cream, a paste, a gel, etc. The solid dosage form can be an orodispersible film, a tablet, a capsule, a drop pill, a pill, a powder, a granule, a suppository, a freeze-dried powder injection, a clathrate, an implant, a patch, etc. The compound of the present invention can be incorporated into the dosage form. This can be achieved in a known manner by mixing with a pharmaceutically suitable excipient.

[0077] In one embodiment, the single administration amount of the drug of the present invention is 0.01-100 mg active ingredient / kg body weight, preferably 0.02-80 mg active ingredient / kg body weight, more preferably 0.05-50 mg active ingredient / kg body weight, more preferably 0.08-40 mg active ingredient / kg body weight, particularly preferably 0.1-20 mg active ingredient / kg body weight, more preferably 0.2-10 mg active ingredient / kg body weight, for example 0.2-4 mg active ingredient / kg body weight, 0.2-2 mg active ingredient / kg body weight, 0.8-4 mg active ingredient / kg body weight, 0.4-2 mg active ingredient / kg body weight. In one embodiment, the drug of the present invention is administered at least once a month, for example 1, 2 or 3 times a month. Preferably, the drug of the present invention is administered 2 times a month. Here, the term "active ingredient" refers to the compound of formula (I) in the present invention.

[0078] In one embodiment of the present invention, in the use described in the present invention, the compound of formula (I) is used as a photosensitizer in photodynamic therapy. Photodynamic therapy comprises administering a therapeutically effective amount of the compound of formula (I) to a subject in need thereof and irradiating a therapeutically effective amount of light of a specific wavelength.

[0079] In one embodiment of the present invention, in the use or method of the present invention, the specific wavelength range is 300 nm-800 nm, preferably 400 nm-650 nm, for example, 405 nm, 505 nm, 540 nm, 575 nm or 630 nm, more preferably 405 nm.

[0080] In one embodiment of the present invention, in the antibacterial method or treatment method, the irradiation time of the light irradiation is 1-1200 s, such as 20s, 30s, 60s, 120s, 180s, 240s, 480s, 600s, 720s, 1000s, 1200s, etc. Preferably 2-800s, more preferably 4-600s, more preferably 8-240s, more preferably 10-120 s, more preferably 30-120s.

[0081] In one embodiment of the present invention, in the antibacterial method or treatment method, the light dose of the light irradiation is 1-200 J, preferably 10-120 J, more preferably 10-60 J, more preferably 20 J and 30 J.

[0082] In the antibacterial method or treatment method, the Gram-negative cocci, bacilli or coccobacilli can be selected from Gram-negative bacilli or coccobacilli, such as Gram-negative anaerobic bacilli or coccobacilli, Gram-negative facultative anaerobic coccobacilli, and Gram-negative aerobic bacilli.

[0083] In a preferred embodiment of the present invention, the Gram-negative cocci, bacilli or coccobacilli are Porphyromonas gingivalis ( Porphyromonas gingivalis ), Actinobacillus actinomycetemcomitans ( Actinobacillus actinomycetemcomitans ), Tannerella forsythiae ( Tannerella forsythia ), Prevotella intermedia ( Prevotella intermedia )、Escherichia coli( Escherichia coli ) or Pseudomonas aeruginosa ( Pseudomonas aeruginosa gingivalis); more preferably Porphyromonas gingivalis.

[0084] In a preferred embodiment of the present invention, the disease or condition is selected from one or more of the following: periodontitis, gingivitis, dental plaque and caries; preferably, the periodontitis is chronic periodontitis or aggressive periodontitis; more preferably, the disease or condition is selected from one or more of the following: swollen gums, bleeding gums, gum pain, periodontal pocket formation, alveolar bone resorption and loose teeth.

[0085] Example Detailed synthesis examples of selected compounds of the present invention are given below. However, these examples are merely illustrative and should not be interpreted as limiting the scope of the present invention in any way.

[0086] The NMR peaks reported in the synthetic examples are 1H NMR spectral data were obtained on a Bruker 400MHz or 600MHz NMR spectrometer. The structures of the compounds were also characterized by time-of-flight mass spectrometry (ESI source positive ion, TOF MSES+) and liquid chromatography-mass spectrometry (LC-MS). TOF MS ES+ data were obtained using a Waters instrument (model: XevoG2-XS); LC-MS data were obtained using a Waters instrument (model: SQD2).

[0087] In order to facilitate the understanding of the present invention, some terms of the present invention are explained or defined. Unless otherwise explained or defined, the scientific and technical terms used in conjunction with the present invention will have the meanings commonly understood by those of ordinary skill in the art.

[0088] The corresponding relationship between the compound having a reactive hydrogen atom, the intermediate compound and the compound of formula (I) is shown in Table 1 below, wherein the anion of the compound of formula (I) is an acetate ion, and the " "The wavy line indicates the point of attachment to the rest of Formula (I); the " The wavy line indicates the connection point to the rest of the following formula (IV) (IV).

[0089] Table 1:

[0090] Table 1

[0091] The reagents or instruments used without indicating the manufacturer are all commercially available conventional products commonly used in the art. In the embodiments of the present invention, unless otherwise specified, all operations are carried out at room temperature and normal pressure. Unless otherwise specified, the contents and percentages in the context of this application are based on weight.

[0092]

[0093] A. Synthesis Examples Example 1: Synthesis of P-01 i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 4 mL DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added in sequence. After stirring for 0.5 hour, tert-butyl 3-aminomethyl-morpholine-4-carbonate (114 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to obtain the intermediate P-01-01 (100 mg, yield 59%) in the form of a black powder.

[0094] ii) 100 mg of intermediate P-01-01 was added to 10 mL of 4 mol / L hydrogen chloride dioxane solution, stirred for 4 hours, and then freeze-dried to obtain intermediate P-01-02 (75 mg, yield 95%) in the form of a reddish brown solid.

[0095] iii) 75 mg of the intermediate P-01-02 was dissolved in 6 mL of DMF solution, potassium carbonate (68 mg, 0.49 mmol, 5 equ) was added and stirred for 5 minutes, and then iodomethane (69 mg, 0.49 mmol, 5 equ) was added and stirred for 12 h. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and the obtained pure product was lyophilized to obtain the product P-01 (61 mg, yield 75%) in the form of a reddish brown solid.

[0096] LC-MS (m / z): 408.3 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.39 (s, 1H), 10.30 (s, 2H), 10.28 (s, 1H), 8.65-8.64 (m, 2H), 8.60-8.49 (m, 2H), 6.48 (dd, J= 18.0, 5.2 Hz, 2H), 6.26-6.23 (m, 2H), 4.41-3.78 (m, 4H), 3.78 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H), 3.65 (s, 3H), 3.55-3.50 (m, 4H), 3.50-3.40 (m,4H), 3.19-3.16 (m, 6H), 2.99-2.96 (m, 3H), 2.88-2.84 (m, 5H), 2.81 (s, 6H), 2.76 (s, 6H), -3.81 (s, 2H).

[0097] Example 2: Synthesis of P-02 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, and HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added in sequence. The mixture was stirred for 10 minutes and ( R )-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (230 mg, 1.06 mmol, 3 equ), stirred for 1 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-02-01 (290 mg, yield 85%) was obtained by freeze-drying in the form of a reddish brown solid.

[0098] ii) At 0°C, 290 mg of intermediate P-02-01 was dissolved in 5 mL of 4 mol / L hydrogen chloride-dioxane solution, stirred for 2 h, and then freeze-dried to obtain 218 mg of intermediate P-02-02 in the form of a reddish brown solid with a yield of 95%.

[0099] iii) 218 ​​mg of intermediate P-02-02 was dissolved in 10 mL of DMF, potassium carbonate (118 mg, 0.86 mmol, 3 equ) was added, and after stirring for 5 minutes, iodomethane (80 mg, 0.57 mmol, 2 equ) was added. After stirring for 12 hours, it was purified by reverse phase C18 (water / acetonitrile containing 5% acetic acid (v / v) 95% / 5% to 5% / 95%, 25 min) and lyophilized to obtain the product P-02 (197 mg, yield 84%) as a reddish brown solid.

[0100] LC-MS (m / z): 409.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.15–9.77 (m,4H), 8.40-8.30 (m, 2H), 6.40-6.34 (m, 2H), 6.21-6.16 (m, 2H), 4.32 (s, 5H), 3.80 (s, 12H), 3.62 (s, 4H), 3.60-3.57 (m, 10H), 3.46-3.43 (m, 2H), 3.30-20(m, 4H), 3.11 (s, 6H), 3.09 (s, 6H), 2.917 –2.79 (m, 2H).

[0101] Example 3: Synthesis of P-03 i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added in sequence. After stirring for 10 minutes, 1-tert-butyloxycarbonylpiperazine (99 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to obtain the intermediate P-03-01 (93 mg, yield 58%) in the form of a black powder.

[0102] ii) 93 mg of the intermediate P-03-01 was added to a mixed solution of 3 mL of trifluoroacetic acid and 12 mL of dichloromethane, stirred for 2 h, and then freeze-dried to obtain the intermediate P-03-02 (68 mg, yield 94%) in the form of a reddish brown solid.

[0103] iii) 68 mg of the intermediate P-03-02 was dissolved in 3 mL of DMF solution, potassium carbonate (67 mg, 0.49 mmol, 5 equ) was added and stirred for 5 minutes, and then iodomethane (69 mg, 0.49 mmol, 5 equ) was added and stirred for 12 h. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and the product P-03 (55 mg, yield 76%) was obtained by lyophilization as a reddish brown solid.

[0104] LC-MS (m / z): 378.7 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40-10.27 (m,4H), 8.56 (ddd, J =18.0, 12.0, 8.4 Hz, 2H), 6.49 (dd, J = 17.6, 3.2 Hz, 2H), 6.25(d, J = 11.2 Hz, 2H), 4.37 – 4.33 (m, 4H), 3.81-3.75 (m, 14H), 3.69(s, 3H), 3.66(s, 3H), 3.13(br s, 6H), 3.04 (br s, 6H), 2.86 (s, 12H), -3.83 (s, 2H).

[0105] Example 4: Synthesis of P-04 i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added in sequence. After stirring for 10 minutes, tert-butyl imidazoline-1-carboxylate (92 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to obtain the intermediate P-04-01 (120 mg, yield 77%) in the form of a black powder.

[0106] ii) 120 mg of intermediate P-04-01 was added to 10 mL of 4 mol / L hydrogen chloride dioxane solution, stirred at room temperature for 4 hours, and normal phase thin layer chromatography confirmed that the reaction was complete. The mixture was concentrated under reduced pressure below 40°C to obtain a reddish brown oily liquid, which was lyophilized to obtain intermediate P-04-02 (90 mg, yield 98%) in the form of a reddish brown solid.

[0107] iii) 90 mg of the intermediate P-04-02 was dissolved in 3 mL of DMF solution, potassium carbonate (74 mg, 0.54 mmol, 5 equ) was added and stirred for 5 minutes, and then iodomethane (76 mg, 0.49 mmol, 5 equ) was added and stirred for 12 h. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and the product P-04 (70 mg, yield 69%) was obtained as a reddish brown solid by lyophilization.

[0108] LC-MS (m / z): 378.7 [M] 2+ / 2. 1 H NMR (400 MHz, D2O) δ 9.07-8.83 (m, 3H),8.48-8.40 (m, 1H), 8.19-8.95 (m, 2H), 6.28-6.19 (m, 4H), 4.27-4.09 (m, 6H),3.37-3.28 (m, 16H), 3.08-2.75 (m, 14H), 2.17-1.87 (m, 8H).

[0109] Example 5: Synthesis of P-05 i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added in sequence. After stirring for 10 minutes, tert-butyl imidazoline-1-carboxylate (92 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to obtain the intermediate P-05-01 (120 mg, yield 77%) in the form of a black powder.

[0110] ii) 120 mg of the intermediate P-05-01 was added to 10 mL of 4 mol / L hydrogen chloride dioxane solution, stirred for 4 hours, and then freeze-dried to obtain the intermediate P-05-02 (90 mg, yield 98%) in the form of a reddish brown solid.

[0111] iii) 90 mg of the intermediate P-05-02 was dissolved in 3 mL of DMF solution, potassium carbonate (74 mg, 0.54 mmol, 5 equ) was added and stirred for 5 minutes, and then iodoethane (84 mg, 0.54 mmol, 5 equ) was added and stirred for 12 h. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and the product P-05 (63 mg, yield 60%) was obtained as a reddish brown solid by lyophilization.

[0112] LC-MS (m / z): 392.8 [M] 2+ / 2. 1 H NMR (400 MHz, D2O) δ 9.34 (br s, 1H), 9.05(s, 2H), 8.6-8.41 (m, 1H), 8.33-8.08 (m, 2H), 6.43-6.26 (m, 4H), 4.34-3.95(m, 10H), 3.51-3.29 (m, 16H), 3.03-2.78 (m, 10H), 2.67-2.47 (m, 4H), 0.36 – -0.70 (m, 12H).

[0113] Example 6: Synthesis of P-06 i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added in sequence. After stirring for 10 minutes, 1-(2-thienyl)-3-(dimethylamino)-1-propanol (98 mg, 0.53 mmol, 3 equ) was added and reacted for 15 hours. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol = 10:1 (v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by normal phase silica gel column (dichloromethane / methanol containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min) to obtain intermediate P-06-02 (100 mg, yield 63%).

[0114] iii) 100 mg of the intermediate P-06-02 was dissolved in 10 mL of DMF, potassium carbonate (68 mg, 0.33 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (46 mg, 0.33 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min) and lyophilized to obtain the product P-06 (98 mg, yield 94%) as a reddish brown solid.

[0115] LC-MS (m / z): 463.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 9.86-9.72 (m,4H), 8.25-8.20 (m, 2H), 7.10-7.06 (q, J = 4.8 Hz, 2H), 6.87 (d, J = 3.7 Hz, 2H),6.68-6.65 (m, 2H), 6.36-6.31 (m, 2H), 6.20-6.16 (m, 2H), 5.83-5.78 (m, 2H),4.30 (q, J = 7.2 Hz, 4H), 3.58 (d, J = 6.4 Hz, 6H), 3.46 (d, J = 4.0 Hz, 6H), 3.27-3.21 (m, 4H), 2.46-2.41 (m, 4H), 2.18-2.00 (m, 18H), 1.85-1.70 (m, 4H).

[0116] Example 7: Synthesis of P-07 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added, and after stirring for 10 minutes, N1,N1 -Dimethyl- N2-(Thiophen-2-ylmethyl)ethane-1,2-diamine (195 mg, 1.06 mmol, 3 equ), after stirring for 5 h, the reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-07-02 (289 mg, yield 91%) was obtained by lyophilization in the form of a reddish-brown solid.

[0117] iii) 289 mg of intermediate P-07-02 was dissolved in 10 mL of DMF, potassium carbonate (200 mg, 0.97 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (135 mg, 0.97 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min) and lyophilized to obtain the product P-07 (272 mg, yield 90%) as a reddish brown solid.

[0118] LC-MS (m / z): 462.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.39-10.18 (m,4H), 8.60-8.47 (m, 2H), 7.31-7.28 (m, 2H), 6.85-6.78 (m, 2H), 6.75-6.70 (m,2H), 6.50-6.44 (m, 2H), 6.28-6.20 (m, 2H), 4.74 (d, J = 16.0 Hz, 4H), 4.41-4.37(m, 4H), 3.77-3.74 (m, 6H), 3.70-3.65 (m, 4H), 3.63-3.55 (m, 6H), 3.27 (d, J =7.2 Hz, 4H), 3.02-2.97 (m, 18H), -3.89 (d, J = 8.4 Hz, 2H).

[0119] Example 8: Synthesis of P-08 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added, and after stirring for 10 minutes, 2-morpholine- N -(Thiophen-2-ylmethyl)ethylamine (240 mg, 1.06 mmol, 3 equ), stirred for 3 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-08-02 (299 mg, yield 85%) was obtained by freeze-drying in the form of a reddish brown solid.

[0120] iii) 299 mg of the intermediate P-08-02 was dissolved in 10 mL of DMF, potassium carbonate (189 mg, 0.92 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (128 mg, 0.92 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min) and lyophilized to obtain the product P-08 (283 mg, yield 92%) as a reddish brown solid.

[0121] LC-MS (m / z): 504.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40–10.22 (m,4H), 8.59-8.49 (m, 2H), 7.35–7.21 (m, 2H), 6.91–6.80 (m, 2H), 6.78-6.71 (m,2H), 6.53–6.43 (m, 2H), 6.24 (d, J = 11.6 Hz, 2H), 4.75 (s, 4H), 4.39 (s, 4H), 3.77-3.73 (m, 14H), 3.70 – 3.63 (m, 8H), 3.60 (d, J = 10.4 Hz, 6H), 3.45 (br s,8H), 3.11-3.07 (m, 4H), -3.86 (d, J = 10.4 Hz, 2H).

[0122] Example 9: Synthesis of P-09 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added, and the mixture was stirred for 10 minutes. Then, 4-hydroxymethylpyridine (115 mg, 1.06 mmol, 3 equ) was added and stirred for 3 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min). After evaporating the solvent, the intermediate P-09-02 (227 mg, yield 85%) was obtained as a reddish brown solid by lyophilization.

[0123] iii) 227 mg of intermediate P-09-02 was dissolved in 10 mL of DMF, potassium carbonate (189 mg, 0.92 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (128 mg, 0.92 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid (v / v) 95% / 5% to 5% / 95%, 20 min) and lyophilized to obtain the product P-09 (225 mg, yield 95%) as a reddish brown solid.

[0124] LC-MS (m / z): 387.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.39-10.18 (m,4H), 8.36-8.33 (m, 2H), 8.31-8.27 (m, 4H), 7.66-7.62 (m, 4H), 6.55-6.41 (m,2H), 6.27-6.24 (m, 2H), 5.33-5.31 (m, 4H), 4.33-4.27 (m, 4H), 3.83-3.80 (m,6H), 3.76 (s, 6H), 3.67-3.64 (m, 6H), 3.40-3.34 (m, 4H).

[0125] Example 10: Synthesis of P-10 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added, and after stirring for 10 minutes, N -cyclopropylpyridin-4-amine (142 mg, 1.06 mmol, 3 equ), stirred for 5 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, purified by normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-10-02 (229 mg, yield 80%) was obtained by freeze-drying in the form of a reddish brown solid.

[0126] iii) 229 mg of the intermediate P-10-02 was dissolved in 10 mL of DMF, potassium carbonate (176 mg, 0.86 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (119 mg, 0.86 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 20 min) and lyophilized to obtain the product P-10 (199 mg, yield 84%) as a reddish brown solid.

[0127] LC-MS (m / z): 412.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36-10.31 (m,4H), 8.75 (s, 4H), 8.62-8.35 (m, 2H), 8.02-7.99 (m, 4H), 6.48 (d, J = 18.0 Hz,2H), 6.24 (d, J = 11.6 Hz, 2H), 4.46 (s, 4H), 4.18 (s, 6H), 3.90-3.85 (m, 2H), 3.76 (d, J = 8.0 Hz, 6H), 3.69 (d, J = 8.8 Hz, 6H), 3.38-3.36 (m, 4H), 1.21-1.14(m, 4H), 0.87-0.84 (m, 4H), -3.87 (br s, 2H).

[0128] Example 11: Synthesis of P-11 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (232 mg, 1.8 mmol, 5 equ) were added, and after stirring for 10 minutes, N -methyl- N -(4-pyridylmethyl)amine hydrochloride (169 mg, 1.06 mmol, 3 equ), stirred for 5 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, purified by normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-11-02 (233 mg, yield 84%) was obtained by freeze-drying in the form of a reddish brown solid.

[0129] iii) 233 mg of intermediate P-11-02 was dissolved in 10 mL of DMF, potassium carbonate (189 mg, 0.92 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Methyl iodide (128 mg, 0.92 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid (v / v) 95% / 5% to 5% / 95%, 20 min) and lyophilized to obtain the product P-11 (208 mg, yield 86%) as a reddish brown solid.

[0130] LC-MS (m / z): 400.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.46 – 10.07 (m,4H), 8.79 – 8.52 (m, 2H), 8.59 – 8.40 (m, 4H), 7.91 – 7.58 (m, 4H), 6.47 (d, J = 18.4 Hz, 2H), 6.25 (d, J = 12.0 Hz, 2H), 4.40 – 4.27 (m, 4H), 4.04 (d, J = 8.4Hz, 4H), 3.75 – 3.70 (m, 6H), 3.66 (d, J= 8.0 Hz, 6H), 3.43 (s, 6H), 3.40 (s, 6H), 3.26-3.21 (m, 4H).

[0131] Example 12: Synthesis of P-12 i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added, and after stirring for 10 minutes, N,N -Diethylethylenediamine (122 mg, 1.06 mmol, 3 equ), stirred for 4 h. The reaction solution was poured into 30 mL of water and extracted with a mixed solution of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a normal phase silica gel column (dichloromethane / methanol containing 1% triethylamine (v / v) 100% / 0% to 90% / 10%, 15 min), and after evaporating the solvent, the intermediate P-12-02 (237 mg, yield 87%) was obtained by freeze-drying in the form of a reddish brown solid.

[0132] iii) 237 mg of intermediate P-12-02 was dissolved in 10 mL of DMF, potassium carbonate (193 mg, 0.94 mmol, 3 equ) was added, and the mixture was stirred for 5 minutes. Ethyl iodide (147 mg, 0.94 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was purified by C18 column (water / acetonitrile containing 5% acetic acid (v / v) 95% / 5% to 5% / 95%, 20 min) and lyophilized to obtain the product P-12 (245 mg, yield 96%) as a reddish-brown solid.

[0133] LC-MS (m / z): 408.8 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.46-10.14 (m,4H), 8.61-8.52 (m, 2H), 8.33 (s, 2H), 6.52-6.46 (m, 2H), 6.25 (d, J = 11.6 Hz,2H), 4.39 (br s, 4H), 3.78 (d, J = 6.8 Hz, 6H), 3.67 (d, J = 9.6 Hz, 6H), 3.38(br s, 4H), 3.12 (t,J = 6.8 Hz, 4H), 3.10-3.06 (m, 4H), 2.36 (d, J = 7.6 Hz, 12H), 1.30-1.17 (m, 18H), -3.89 (s, 2H).

[0134] Example 13: Synthesis of P-12-02 Synthesized as in step i) of Example 12.

[0135] LC-MS(m / z): 759.8 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 11.25 (s, 1H), 11.18 (s, 1H), 10.94-10.52 (m, 4H), 8.32-7.99 (m, 2H), 6.57-6.14 (m, 4H), 4.50 (s, 4H), 3.79-3.50 (m, 12H), 3.28 (s, 4H), 3.19-2.95 (m, 12H), 2.84 (s, 4H), 1.26 (s, 12H), -3.65 (m, 4H).

[0136] Comparative Synthesis Example Comparative Example 1: Synthesis of P-02 The method was similar to that of Example 2, except that: i) Using 84 mg (0.65 mmol, 1.81 equ) of DIPEA, intermediate P-02-01 (92 mg, yield 27%) was obtained. ii) Using 92 mg of intermediate P-02-01 and 3 mL of 4 mol / L hydrogen chloride dioxane solution, intermediate P-02-02 (69 mg, yield 95%) was obtained. iii) Using 69 mg of intermediate P-02-02, 5 mL of DMF, 37 mg (0.27 mmol, 3 equ) of potassium carbonate and 25 mg (0.18 mmol, 2 equ) of iodomethane, product P-02 (62 mg, yield 84%) was obtained.

[0137] Comparative Example 2: Synthesis of P-02 The method was similar to that of Example 2, except that: i) Using 348 mg (2.7 mmol, 7.5 equ) of DIPEA, the intermediate P-02-01 (145 mg, 42% yield) was obtained. ii) Using 145 mg of intermediate P-02-01, the intermediate P-02-02 (109 mg, 95% yield) was obtained. iii) Using 109 mg of intermediate P-02-02, 5 mL of DMF, 59 mg (0.43 mmol, 3 equ) of potassium carbonate and 40 mg (0.28 mmol, 2 equ) of iodomethane, the product P-02 (99 mg, 84% yield) was obtained.

[0138] Comparative Example 3: Synthesis of P-07 The method was similar to that of Example 7, except that: i) Using 247 mg (0.65 mmol, 1.8 equ) of HATU, the intermediate P-07-02 (149 mg, 47% yield) was obtained. iii) Using 149 mg of intermediate P-07-02, 70 mg (0.5 mmol, 3 equ) of potassium carbonate and 71 mg (0.5 mmol, 3 equ) of iodomethane, the product P-07 (141 mg, 90% yield) was obtained.

[0139] Comparative Example 4: Synthesis of P-07 The method was similar to that of Example 7, except that: i) Using 479 mg (1.26 mmol, 3.5 equ) of HATU, the intermediate P-07-02 (203 mg, yield 64%) was obtained. iii) Using 203 mg of intermediate P-07-02, 95 mg (0.69 mmol, 3 equ) of potassium carbonate and 98 mg (0.69 mmol, 3 equ) of iodomethane, the product P-07 (192 mg, yield 90%) was obtained.

[0140] Comparative Example 5: Synthesis of P-09 The method was similar to that of Example 9, except that: i) 170 mg (0.89 mmol, 2.5 equ) EDCI and 120 mg (0.89 mmol, 2.5 equ) HOBT were used instead of HATU to obtain intermediate P-09-02 (139 mg, yield 52%). iii) 139 mg intermediate P-09-02, 77 mg (0.56 mmol, 3 equ) potassium carbonate and 79 mg (0.56 mmol, 3 equ) iodomethane were used to obtain product P-09 (138 mg, yield 95%).

[0141] Comparative Example 6: Synthesis of P-09 The method was similar to that of Example 9, except that: i) 286 mg (0.89 mmol, 2.5 equ) of TBTU was used instead of HATU to obtain intermediate P-09-02 (179 mg, yield 67%). iii) 179 mg of intermediate P-09-02, 99 mg (0.72 mmol, 3 equ) of potassium carbonate and 102 mg (0.72 mmol, 3 equ) of iodomethane were used to obtain product P-09 (177 mg, yield 95%).

[0142] Comparative Example 7: Synthesis of P-09 The method was similar to that of Example 9, except that: i) Using 463 mg (0.89 mmol, 2.5 equ) of PyBOP instead of HATU, the intermediate P-09-02 (104 mg, yield 39%) was obtained. iii) Using 104 mg of intermediate P-09-02, 58 mg (0.42 mmol, 3 equ) of potassium carbonate and 60 mg (0.42 mmol, 3 equ) of iodomethane, the product P-09 (103 mg, yield 95%) was obtained.

[0143] Comparative Example 8: Synthesis of P-12 The method was similar to that of Example 12, except that: i) Using 298 mg (0.53 mmol, 1 equ) of protoporphyrin, 338 mg (0.89 mmol, 1.7 equ) of HATU, 115 mg (0.89 mmol, 1.7 equ) of DIPEA and 122 mg (1.06 mmol, 2 equ) of N,N-diethylethylenediamine, the intermediate P-12-02 (123 mg, yield 45%) was obtained. iii) Using 123 mg of intermediate P-12-02, 67 mg (0.486 mmol, 3 equ) of potassium carbonate and 76 mg (0.486 mmol, 3 equ) of iodoethane, the product P-12 (127 mg, yield 96%) was obtained.

[0144] Comparative Example 9: Synthesis of P-12 The method was similar to that of Example 12, except that: i) Using 111 mg (0.20 mmol, 1 equ) protoporphyrin, 338 mg (0.89 mmol, 4.5 equ) HATU, 115 mg (0.89 mmol, 4.5 equ) DIPEA and 122 mg (1.06 mmol, 5.4 equ) N,N-diethylethylenediamine, the intermediate P-12-02 (172 mg, yield 63%) was obtained. iii) Using 172 mg intermediate P-12-02, 94 mg (0.68 mmol, 3 equ) potassium carbonate and 106 mg (0.68 mmol, 3 equ) iodoethane, the product P-12 (178 mg, yield 96%) was obtained.

[0145] Comparative Example 10: Synthesis of P-12-I 237 mg of intermediate P-12-02 was dissolved in 10 mL of DMF, potassium carbonate (193 mg, 0.94 mmol, 3 equ) was added, and stirred for 5 minutes. Ethyl iodide (147 mg, 0.94 mmol, 3 equ) was added and stirred for 12 hours. The reaction solution was slowly dripped into 40 mL of methyl tert-butyl ether, and the precipitated reddish brown crude product was collected. The crude product was washed with 3×10 mL of acetone and dried to obtain the product P-12-I (212 mg, yield 83%) in the form of a reddish brown solid. The cation of the product P-12-I and Cationic phase of P-12 same, The anion is iodide ion.

[0146] The data of the examples and comparative examples of the compounds of the present invention are summarized in Tables 2 and 3 below.

[0147] Table 2: Comparison of condensation agent types between examples and comparative examples.

[0148]

[0149] Table 3: Comparison of reagent dosage data between preparation examples and comparative examples.

[0150] .

[0151] B. Antibacterial Effect Example Experiment 1 1. Materials and Methods 1.1 Information on the drug to be tested Antibacterial test drugs: drugs of Examples 1-12.

[0152] Positive drug 1: Protoporphyrin IX (PPIX).

[0153] Positive drug 2: 5-aminolevulinic acid (ALA).

[0154] 1.2 Main experimental reagent information Table 4: Main experimental reagents

[0155] 1.3 Main instrument and equipment information Table 5: Main instrument information

[0156] 1.4 Test on the killing ability of the compounds of the present invention against Porphyromonas gingivalis Porphyromonas gingivalis (purchased from Beijing Beina Chuanglian Biotechnology Research Institute, batch number BNCC353909) was revived and inoculated into BHI medium and cultured to the logarithmic phase under anaerobic conditions of 10% H2, 10% CO2, and 80% N2; 1 mL of bacterial solution was taken, the OD value was measured, and after centrifugation and discarding the supernatant, a certain amount of BHI medium was added to adjust the bacterial solution concentration to 10 10 CFU / mL (1 OD≈9.52*10 9 CFU / mL).

[0157] Test drug group: add 100 μL bacterial solution, 898 μL BHI medium and 2 μL DMSO solution of the drug to be tested to the centrifuge tubes respectively, shake well (the final concentration of bacterial solution is 10 9 CFU / mL, the final concentration of the test drug was 10 μg / mL, the final concentration of positive drug 1 was 10 μg / mL, and the final concentration of positive drug 2 was 80 μg / mL). After culturing for 4 h under light-proof and anaerobic conditions, the supernatant was centrifuged and discarded, and then resuspended with 1 mL of BHI medium, and the resuspended liquid was added to a 96-well plate, 100 μL of bacterial solution was added to each well, and 4 replicates were set each time. Illumination was performed under a 405 nm laser, the laser output power was 300 mW, the irradiation was 66.67 s, and the light dose was 20 J. After the illumination ended, the culture was continued under anaerobic conditions for 24 h, and then the OD value of each group of bacterial solution at 600 nm was measured and the inhibition rate was calculated.

[0158] Blank illumination group: The above method was followed, except that 100 μL of bacterial solution and 900 μL of BHI culture medium were added to the centrifuge tube.

[0159] The antibacterial rate calculation formula is as follows:

[0160] Among them: OD 阴性 It represents the average OD value of bacterial solution measured in the blank illumination group; OD 待测It represents the average OD value of bacterial solution measured in the test drug group.

[0161] 1.5 Calculation of statistical differences GraphPad Prism8 was used for statistical analysis, and the difference in inhibition rate was compared to evaluate the antibacterial effect. One-way ANOVA was used for multiple group comparisons, and post hoc multiple comparisons were performed, with PPIX as the comparison object. P<0.05 was considered statistically significant, where * indicates P<0.05, ** indicates P<0.001, and **** indicates P<0.0001, representing a significant decrease.

[0162] 2. Results and Discussion The results are as follows Figure 1 As shown in (a) and Table 6, the 12 porphyrin derivatives and PPIX had good antibacterial effects, and the antibacterial effects of most of the 12 porphyrin derivatives were better than those of PPIX, with statistically significant differences (P < 0.0001).

[0163] Table 6: Inhibitory effects of PPIX, 5-ALA and 12 porphyrin derivatives on Porphyromonas gingivalis

[0164] Experiment 2 1. Materials and Methods The experiment was carried out in a similar manner to Experiment 1, except that the drugs to be tested were: Antibacterial test drugs: P-12, P-12-02.

[0165] Positive drug 1: protoporphyrin (PPIX); Positive drug 2: 5-aminolevulinic acid (5-ALA).

[0166] 2. Results and Discussion The results are as follows Figure 1 (b) and Table 7. Compared with PPIX, the antibacterial rates of P-12 and P-12-02 both had significant antibacterial effects, with statistical differences (P<0.05 was considered statistically significant, **** indicates P<0.0001 compared with PPIX). At the same time, the antibacterial effect of P-12 was stronger than that of P-12-02, with statistical differences (P<0.05 was considered statistically significant, ^^^^ indicates P<0.0001 compared with P-12-02).

[0167] Table 7: Inhibitory effects of PPIX, 5-ALA, P-12-02 and P-12 on Porphyromonas gingivalis

[0168] C. Targeting Effect Example 1. Experimental Materials 1.1 Information on the drug to be tested Experimental drugs: P-02, P-06, P-12, P-12-02; Positive drug: protoporphyrin (PPIX).

[0169] 1.2 Main experimental reagent information Table 8: Main experimental reagents

[0170] 1.3 Main instrument and equipment information Table 9: Main instrument information

[0171] 2. Experiment After resuscitation, Porphyromonas gingivalis (purchased from Beijing Beina Chuanglian Biotechnology Research Institute, batch number BNCC353909) was inoculated into BHI medium and cultured to the logarithmic phase under anaerobic conditions of 10% H2, 10% CO2, and 80% N2; an appropriate amount of the above bacterial solution was taken and centrifuged at 10,000×g for 5 minutes at room temperature, the supernatant was discarded, and the solution was washed once with saline. The concentration of the bacterial solution was adjusted to 10 6 bacteria / mL.

[0172] Test group: Take 1 mL of bacterial solution, add 1 μL of DMSO solution of the drug to be tested, and shake well (to make the final concentration of the drug 5ug / mL). After incubating at 37℃ in the dark for 15 minutes, take 10μL of bacterial solution from each group and drop it on the slide.

[0173] Control group: The above method was followed, except that no compound was added.

[0174] The bacteria were observed under a fluorescence microscope and the differences in fluorescence intensity of the compounds among the groups were compared (Ex: 405 nm; Em: 630 nm).

[0175] 3. Results and Discussion The results are as follows Figure 2 As shown in (a), Porphyromonas gingivalis has different degrees of uptake of PpIX, P-06, P-02 and P-12, among which Porphyromonas gingivalis has a stronger uptake of P-06, P-02 and P-12 than PpIX. Figure 2 As shown in (b), the uptake of P-12 by Porphyromonas gingivalis was significantly higher than that of P-12-02. P-12 has a stronger targeting effect on Porphyromonas gingivalis than P-12-02.

[0176] D. Dissolution Effect Example Weigh P-12 and P-12-I (see Table 10 for sample quantity) and operate at 25°C. Add water in small amounts and multiple times, shake vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes. If there are no visible solute particles or droplets, it is considered to be completely dissolved. At this time, record the total amount of water added as the solvent amount.

[0177] Table 10: Solubility of P-12 and P-12-I

[0178] *The approximate solubility of the drug is expressed in the following terms (from the pharmacopoeia): Slightly soluble: refers to the solute 1g (ml) can be dissolved in 30 to less than 100ml of solvent; Very slightly soluble: refers to the solute 1g (ml) can be dissolved in 1000 to less than 10000ml of solvent.

[0179] According to the experimental results, P-12 (the compound of the present invention formed by acetate ion salt) has higher solubility than P-12-I (the corresponding compound formed by iodide ion salt).

Claims

1. Compounds of formula (I) (I)， in, X - is the acetate ion, q is 2, so that X - Balance the charge of the cations, R + The following formula (II) (II), " "The wavy line indicates the connection point to the rest of the p is 0 or 1, K is the following formula (II-a) or (II-b), (II-a)or (II-b), R1 is hydrogen, alkyl, cycloalkyl or heteroarylalkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; A + is the following formula (II-c) or (II-d), (II-c) or (II-d), n is each independently an integer from 0 to 8; m is 0 or 1, so that the N atom has a positive charge; Q is a heterocyclic or heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further contains one or more heteroatoms selected from O, S and N; R3 are each independently alkyl.

2. The compound according to claim 1, wherein K is formula (II-a), R1 is hydrogen or heteroarylalkylene; A + It is formula (II-d).

3. The compound according to claim 1, wherein R1 is hydrogen, (C1-C8)-alkyl, (C3-C 10 )-cycloalkyl or (C3-C 10 )-heteroaryl-(C1-C8)-alkylene, the heteroarylalkylene containing one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C 10 )-heteroaryl, the heteroaryl containing one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 8; m is 0 or 1, so that the N atom has a positive charge; Q is a (C2-C 10 )-heterocyclic or (C3-C 10 )-heteroaryl, the heterocyclic group optionally further comprising one or more heteroatoms selected from O, S and N; R3 is each independently (C1-C8)-alkyl.

4. The compound according to claim 3, wherein R1 is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or (C3-C8)-heteroaryl-(C1-C6)-alkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C8)-heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 6; m is 0 or 1, so that the N atom has a positive charge; Q is a (C2-C7)-heterocyclyl or (C3-C8)-heteroaryl group containing one positively charged N atom, the heterocyclyl group optionally further comprising one or more heteroatoms selected from O, S and N; R3 are each independently (C1-C6)-alkyl.

5. The compound according to claim 4, wherein R1 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or (C3-C5)-heteroaryl-(C1-C4)-alkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or (C3-C5)-heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from O and S; n is each independently an integer from 0 to 4; m is 0 or 1, so that the N atom has a positive charge; Q is a (C3-C5)-heterocyclyl or (C3-C5)-heteroaryl group containing one positively charged N atom, the heterocyclyl group optionally further comprising one or more heteroatoms selected from O, S and N; R3 are each independently (C1-C4)-alkyl.

6. The compound according to claim 5, wherein R1 is hydrogen, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or thienylmethylene, thienyl-1,2-ethylene, thienyl-1,1-ethylene, thienyl-1,3-propylene, thienyl-1,2-propylene, thienyl-2,2-propylene, thienyl- 1,4-butylene, thienyl-1,3-butylene, thienyl-1,2-butylene, furanylmethylene, furanyl-1,2-ethylene, furanyl-1,1-ethylene, furanyl-1,3-propylene, furanyl-1,2-propylene, furanyl-2,2-propylene, furanyl-1,4-butylene, furanyl-1,3-butylene or furanyl-1,2-butylene; R2 is hydrogen or thienyl or furyl; n is each independently 0, 1, 2 or 3; m is 0 or 1, so that the N atom has a positive charge; Q is morpholinyl, piperazinyl, imidazolidinyl, pyrrolyl, pyrazinyl, pyrazolyl or pyridinyl containing a positively charged N atom; R3 is each independently methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

7. The compound according to claim 6, wherein R1 is hydrogen, methyl, cyclopropyl or thienylmethylene; R2 is hydrogen or thienyl; n is each independently an integer from 0 to 2; m is 0 or 1, so that the N atom has a positive charge; Q is a morpholinyl, piperazinyl, imidazolidinyl or pyridinyl group containing a positively charged N atom; R3 is each independently methyl or ethyl.

8. The compound according to claim 7, wherein R + Each is independently selected from the following groups: , , , , , , , , , , and .

9. A method for preparing a compound according to any one of claims 1 to 8, comprising: i) in the presence of a condensation catalyst and a condensation agent, allowing protoporphyrin to undergo a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent to obtain an intermediate compound; iii) subjecting the intermediate compound to an alkylation reaction; in, The compound having a reactive hydrogen atom is selected from compounds of the general formula (III) (III), in, H represents a reactive hydrogen atom; p as defined in any one of claims 1 to 7; K as defined in any one of claims 1 to 7; A is the following formula (III-c) or (III-d), (III-c) or (III-d), n as defined in any one of claims 1 to 7; P is Q as defined in any one of claims 1 to 7 and is electrically neutral; R3 is as defined in any one of claims 1 to 7; Alternatively, the compound having a reactive hydrogen atom is selected from tert-butyl 3-aminomethyl-morpholine-4-carbonate, (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate, tert-butyl 1-tert-butyloxycarbonylpiperazine, tert-butyl imidazoline-1-carboxylate, 1-(2-thienyl)-3-(dimethylamino)-1-propanol, N1,N1-dimethyl-N2-(thien-2-ylmethyl)ethane-1,2-diamine, 2-morpholine-N-(thien-2-ylmethyl)ethylamine, 4-hydroxymethylpyridine, N-cyclopropylpyridine-4-amine, N-methyl-N-(4-pyridylmethyl)amine and N,N-diethylethylenediamine.

10. The method according to claim 9, wherein: The method further comprises: ii) In case the intermediate compound contains an amino protecting group, removing the amino protecting group of the intermediate compound.

11. A medicament comprising a compound of formula (I) as claimed in any one of claims 1 to 8.

12. A method for non-therapeutic inhibition of Gram-negative cocci, bacilli or coccobacilli, comprising contacting the compound of formula (I) according to any one of claims 1 to 8 with Gram-negative cocci, bacilli or coccobacilli and irradiating the gram-negative cocci, bacilli or coccobacilli with an inhibitory effective amount of light of a specific wavelength.

13. Use of a compound of formula (I) as claimed in any one of claims 1 to 8 for the preparation of a medicament for the treatment of a disease or condition caused by a Gram-negative coccus, bacillus or coccobacillus.

14. The method according to claim 12, wherein the Gram-negative cocci, bacilli or coccobacilli are Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Tannerella forsythiae, Prevotella intermedia, Escherichia coli or Pseudomonas aeruginosa, preferably Porphyromonas gingivalis.

15. The use according to claim 13, wherein the Gram-negative cocci, bacilli or coccobacilli are Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Tannerella forsythiae, Prevotella intermedia, Escherichia coli or Pseudomonas aeruginosa, preferably Porphyromonas gingivalis.

16. The use according to claim 13, wherein the disease or condition is selected from one or more of the following: periodontitis, gingivitis, dental plaque and caries.

17. The use according to claim 16, wherein the periodontitis is chronic periodontitis or aggressive periodontitis.

18. The use according to claim 16, wherein the disease or condition is selected from one or more of the following: gingival swelling, gingival bleeding, gingival pain, periodontal pocket formation, alveolar bone resorption and tooth mobility.

19. The use according to claim 13, wherein the compound of formula (I) is used as a photosensitizer in photodynamic therapy.

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