Bis(heterocyclic)-substituted porphyrin derivatives, preparation methods thereof and uses thereof as photosensitizers

Abstract

The present invention relates to a compound of formula (I) or a salt thereof, wherein the group R is as defined in the specification; and also to a method for preparing the compound and its use as a photosensitizer in photodynamic therapy. The biheterocyclic substituted porphyrin derivatives of the present invention have high ROS production, high activity, and good biosafety. The preparation method is simple, low-cost, and can obtain the target product in good yield, making it particularly suitable for industrial production. They can be used as highly effective photosensitizers for photodynamic therapy to treat hyperproliferative diseases such as cancer or precancerous lesions, particularly cervical cancer or precancerous lesions, or to treat oral diseases such as periodontitis, gingivitis, dental plaque, and dental caries caused by Gram-negative anaerobic cocci, such as Porphyromonas gingivalis.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a biheterocyclic substituted porphyrin derivative, a preparation method thereof, and use thereof as a photosensitizer, in particular use thereof as a photosensitizer for treating cancer or precancerous lesions such as cervical cancer or cervical precancerous lesions through photodynamic therapy, or treating oral diseases such as periodontitis, gingivitis, dental plaque and caries caused by Gram-negative anaerobic cocci such as Porphyromonas gingivalis. Background Art

[0002] Photodynamic therapy (PDT) is based on the photochemical reaction of photosensitizers. Under the combined action of light and oxygen, photosensitizers produce cytotoxic reactive oxygen species (ROS), which are used to destroy cell membranes and leak cellular contents, thereby leading to irreversible damage to tumor cells and tissues, achieving the purpose of treating diseases such as cancer and microbial infections.

[0003] 5-Aminolevulinic acid (5-ALA) is a recently developed second-generation photosensitizer. While not inherently photosensitizing, exogenous 5-ALA is selectively absorbed and accumulated by actively proliferating cells, where it is converted into protoporphyrin IX (PPIX). PPIX within cells is a photosensitizer that, upon exposure to red light of a specific wavelength, undergoes a photodynamic reaction, generating reactive oxygen species such as singlet oxygen, which kills actively proliferating cells.

[0004] Periodontitis is a chronic inflammatory disease primarily caused by the destruction of periodontal tissues by bacteria in dental plaque. Porphyromonas gingivalis, a Gram-negative coccobacillus, is the primary pathogenic bacteria that causes periodontitis and gingivitis. Currently, treatment options include metronidazole tablets and amoxicillin capsules. However, frequent use of antibiotics can lead to drug resistance, and some patients may even experience adverse reactions such as allergies. Therefore, safer, less toxic, and non-invasive alternative treatments are needed.

[0005] Cervical cancer is one of the most common tumors of the female reproductive system. Currently, only 5-aminolevulinic acid and 5-aminolevulinic acid hexyl ester (HAL) are used as photosensitizers for photodynamic therapy of cervical precancerous lesions. These are currently in clinical trials. No photosensitizers for the treatment of cervical cancer or precancerous lesions are currently available on the market. Therefore, the development of new photosensitizers is urgently needed to promote the development of this industry.

[0006] In summary, the development of porphyrin photosensitizers with high efficiency in killing cancerous cells and / or antibacterial ability is of great significance. Summary of the Invention

[0007] In view of the state of the prior art, the present invention aims to provide a class of biheterocyclic substituted porphyrin derivatives with high ROS production, easy preparation, low cost, high activity and good biosafety. Such derivatives can be excited under light of different wavelengths and are particularly suitable as photosensitizers for the treatment of hyperproliferative diseases, especially cervical cancer or cervical precancerous lesions, through photodynamic therapy, or for antibacterial treatment of oral diseases such as periodontitis, gingivitis, dental plaque or caries.

[0008] In one aspect, the present invention provides a compound of formula (I) or a salt thereof,

[0009] (I)

[0010] in

[0011] R each independently represents a 3-10 membered heterocyclic group or a 3-14 membered heteroaryl group containing at least one nitrogen atom, said heterocyclic group or heteroaryl group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, (C1-C8)-alkyl, (C1-C8)-alkoxy, (C3-C 10 )-cycloalkyl, (C1-C8)-haloalkyl, carboxyl-(C1-C8)-alkylcarbonyl, di-(C1-C8)-alkylamino or (C6-C 14 )-aryl-(C1-C8)-alkyl,

[0012] wherein the heterocyclic group or heteroaryl group is connected to the carbonyl group in formula (I) through a nitrogen atom,

[0013] With the proviso that compounds wherein each R is independently piperidinyl are excluded.

[0014] On the other hand, the present invention provides a method for preparing the compound of formula (I) as described above, which comprises subjecting protoporphyrin (PPIX) to a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent in the presence of a catalyst and a condensing agent, wherein the compound having a reactive hydrogen atom is selected from the compounds of general formula (II)

[0015] RH (II)

[0016] wherein R is as defined above.

[0017] On the other hand, the present invention also provides use of the compound of formula (I) or a salt thereof as described above in the preparation of a medicament for treating hyperproliferative diseases (particularly cervical cancer or cervical precancerous lesions).

[0018] In addition, the present invention also relates to a method for treating a hyperproliferative disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined above or a salt 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.

[0019] In another aspect, the present invention also provides use of a compound of formula (I) or a salt thereof as described above in the preparation of a medicament for treating a disease or condition caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0020] In addition, the present invention also relates to a method for inhibiting Gram-negative or Gram-positive cocci, bacilli, or coccobacilli for non-therapeutic purposes, comprising contacting a compound of formula (I) or a salt thereof with Gram-negative or Gram-positive cocci, bacilli, or coccobacilli and irradiating the gram-negative or Gram-positive cocci, bacilli, or coccobacilli with an inhibitory effective amount of light of a specific wavelength. The contacting can be performed in vivo or in vitro, for example, in vitro.

[0021] Accordingly, the present invention also relates to a method for treating a disease or condition caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli, which comprises administering a therapeutically effective amount of a compound of formula (I) or a salt thereof as described above 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.

[0022] In another aspect, the present invention also provides a pharmaceutical composition comprising the compound of formula (I) or a salt thereof as described above, optionally further comprising one or more other active compounds.

[0023] In addition, the present invention also relates to a drug kit comprising a therapeutically effective amount of the compound of formula (I) or a salt thereof, or the pharmaceutical composition, and instructions for using the compound as a photosensitizer in photodynamic therapy.

[0024] Surprisingly, the present invention has the following beneficial effects:

[0025] The present invention develops a novel class of bicyclic substituted porphyrin derivatives that can be used as photosensitizers in photodynamic therapy. The compounds of the present invention have high ROS production, high activity, and good biosafety. Their preparation methods are simple, inexpensive, and can produce the target product in good yield, making them particularly suitable for industrial production. They can be used as highly effective photosensitizers for the treatment of hyperproliferative diseases such as cancer or precancerous lesions, particularly cervical cancer or precancerous lesions, through PDT. Their efficacy is significantly superior to that of the drugs 5-ALA and HAL, especially when used in significantly smaller dosages. Furthermore, the compounds of the present invention exhibit excellent inhibitory effects against bacteria such as Porphyromonas gingivalis, and have therapeutic effects in oral diseases such as periodontitis, gingivitis, dental plaque, and dental caries. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The ultraviolet absorption spectrum of the compound of the present invention is shown.

[0027] Figure 2 The singlet oxygen ( 1 O2) production curve.

[0028] Figure 3 The graph shows the inhibition rates of PPIX, 5-ALA and the compound of the present invention on Porphyromonas gingivalis. Compared with PPIX, the compound of the present invention had ***P<0.001 and ****P<0.0001.

[0029] Figure 4 The graph shows the PDT killing effects of PPIX, HAL, 5-ALA and the compound of the present invention at different concentrations on Hela cells under 2 J of 630 nm laser irradiation.

[0030] Figure 5 The weight changes of Hela tumor-bearing mice in each treatment group after administration are shown ( Figure 5 (a)), tumor volume changes ( Figure 5 (b)) and tumor weight at the end point of the experiment ( Figure 5 (c)). Data points represent the mean within the group, and error bars represent the standard error of the group (SEM). Figure 5 In (b), compared with the negative control group, the PPIX-treated group *P<0.05; the 5-ALA-treated group ***P<0.001; the compound of the present invention-treated group ****P<0.0001. DETAILED DESCRIPTION

[0031] The preferred embodiments of the present invention will be described in detail below. It should be noted that the present application is not limited to these embodiments. These embodiments are merely exemplary, and those skilled in the art may make various modifications, additions, and substitutions to the present invention without departing from the scope and spirit of the present invention.

[0032] Unless otherwise specified, "compounds of formula (I) of the present invention", "compounds of formula (I)" and "porphyrin derivatives of the present invention" are used synonymously, and they and their pharmaceutically acceptable salts are sometimes collectively referred to as "compounds of the present invention".

[0033] Unless otherwise stated, the term "comprise" and its synonyms "comprising" and "containing" used herein mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps.

[0034] Unless expressly stated otherwise, the designations of chemical groups are generally to be understood as such that the bond to the skeleton or the remainder of the molecule is via the structural element of the last mentioned chemical group concerned, i.e., for example, in the case of aryl-(C1-C8)-alkyl, via a carbon atom of the alkyl group; in this context, reference is made to a "heterocyclyl or heteroaryl group containing at least one nitrogen atom", which means that the bond of the designated heterocyclyl or heteroaryl group containing a nitrogen atom to the remainder of the skeleton or the molecule is via a nitrogen atom.

[0035] As used herein, the term "optionally" means that the subsequently described event, circumstance or material may or may not occur or exist, and that such description includes instances where said event, circumstance or material occurs or exists and instances where said event, circumstance or material does not occur or exist.

[0036] 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.

[0037] As used herein, the term "halogen" when applied to a radical refers to a fluorine, chlorine, bromine, or iodine atom.

[0038] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon radical having in each case the number of carbon atoms specified, 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.

[0039] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different, such as (C1-C8)-haloalkyl, (C1-C6)-haloalkyl and (C1-C4)-haloalkyl, examples of which include but are not limited to chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl.

[0040] As used herein, the term "cycloalkyl" refers to a carbocyclic saturated ring system having the specified number of carbon atoms in each instance, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. In particular, the cycloalkyl group has 3 to 6 carbon atoms.

[0041] According to the present invention, "alkoxy" denotes a straight-chain or branched alkyl-O- group having in each case the specified number of carbon atoms, such as (C1-C8)-alkoxy, (C1-C6)-alkoxy and (C1-C4)-alkoxy, examples including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0042] As used herein, the term "dialkylamino" means that the two hydrogen atoms on the amino group N are replaced by an alkyl group as described above, such as di-(C1-C8)-alkylamino, di-(C1-C6)-alkylamino and di-(C1-C4)-alkylamino, examples of which include but are not limited to dimethylamino, diethylamino, dipropylamino, etc.

[0043] According to the present invention, unless otherwise defined, "carboxyl" refers to the group HO-C(=O)-; "alkylcarbonyl" (alkyl-C(=O)-) refers to an alkyl group connected to the molecular skeleton or the rest of the molecular skeleton through -C(=O)-, such as (C1-C8)-alkylcarbonyl, (C1-C6)-alkylcarbonyl or (C1-C4)-alkylcarbonyl, wherein the number of carbon atoms refers to the number of carbon atoms of the alkyl group in the alkylcarbonyl group.

[0044] As used herein, the term "carboxyalkylcarbonyl" refers to an alkylcarbonyl group as defined above in which one of the hydrogen atoms is replaced by a carboxyl group as defined above, wherein the group is typically attached to the molecular backbone or the remainder via the carbonyl group in the alkylcarbonyl group, such as carboxyl-(C1-C8)-alkylcarbonyl, carboxyl-(C1-C6)-alkylcarbonyl or carboxyl-(C1-C4)-alkylcarbonyl, examples of which include but are not limited to carboxymethylcarbonyl, carboxyethylcarbonyl, and the like.

[0045] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring system in which all ring members are carbon atoms, for example, preferably having 6 to 14, particularly 6 to 10, ring carbon atoms, and the ring system can be a monocyclic ring or a fused polycyclic ring (such as a bicyclic or tricyclic ring). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In particular, the aryl group refers to phenyl.

[0046] Unless otherwise defined, the term "arylalkyl" means a combination of the groups "aryl" and "alkyl" as defined herein, wherein the group is typically attached to the backbone or remainder of the molecule via the alkyl group. Examples include, but are not limited to, benzyl, phenethyl, or α-methylbenzyl, preferably benzyl.

[0047] Unless otherwise defined, the term "heterocyclyl" refers to a saturated or partially saturated monocyclic or polycyclic ring system of carbon atoms and at least one heteroatom in the ring (e.g., selected from N, O, S, P, B, Si, Se, etc.), which may be unsubstituted or substituted, wherein the bonding site is on a ring atom. Preferably, the heterocyclyl is a heterocycle containing 3 to 10, preferably 3 to 8, more preferably 3 to 6 ring atoms (i.e., 3-10 members, preferably 3-8 members, more preferably 3-6 members), and contains one or more, preferably 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocycle, wherein the heteroatoms are selected from N, O and S, but the two oxygen atoms should not be directly adjacent. If the heterocyclyl is optionally substituted, it may be fused to other carbocyclic or heterocyclic rings. In the case of optionally substituted heterocyclyl, the invention also includes polycyclic ring systems, for example 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[2.2.2]octyl or 1-azabicyclo[2.2.1]heptyl.

[0048] According to the present invention, preferred heterocyclic groups may be, for example, aziridine, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, morpholinyl, 1,2-oxazepanyl, thiazepanyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, oxomorpholinyl, thiomorpholinyl, oxopiperazinyl, oxopyrrolidinyl, dioxopyrrolidinyl, pyrrolinyl, imidazolinyl, tetrahydroimidazole, pyrazolinyl, 1,3-diazacyclopentadienyl, tetrahydropyridinyl.

[0049] Unless otherwise defined, the term "heteroaryl" means a monocyclic, bicyclic or tricyclic heterocyclic radical of carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur, wherein at least one ring is aromatic, which may be unsubstituted or substituted, wherein the bonding site is on a ring atom. Preferably, the heteroaryl contains 3 to 14, preferably 5 to 12, more preferably 5 to 10 ring atoms, and contains one or more, preferably 1 to 4, in particular 1, 2 or 3 heteroatoms selected from N, O and S in the ring, but no two oxygen atoms should be directly adjacent. Examples include 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, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl , 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, benzofuranyl, benzisofuranyl, benzothiophenyl, benzisothiophenyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 2,1,3-benzoxadiazole, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl, imidazopyridinyl, thienopyrimidinyl, thienopiperidinyl, 4-[4-(2-methyl-1-oxo-1-yl)-1-methyl-1-pyridinyl]- ... H -imidazo[4,5-d]thiazole, thieno[2,3-b]pyrrole, carbazole, etc. If the heteroaryl group is optionally substituted, it may be fused to other carbocyclic or heterocyclic rings.

[0050] According to the present invention, the preferred heteroaryl group containing at least one nitrogen atom may be a heterocyclic group formed by condensing the heterocyclic group as defined above with the heteroaryl group as described above, and may be, for example, thienotetrahydropyridine.

[0051] Any recitation of a compound of formula (I) anywhere herein also encompasses any diastereomers or enantiomers of the compound of formula (I), as well as salts thereof, that exist.

[0052] Depending on the nature of the substituents, the compounds of formula (I) described herein may also be in the form of stereoisomers, i.e., optical isomers. The invention provides both the pure stereoisomers and any desired mixtures of these isomers, although generally only the compounds of formula (I) are discussed herein.

[0053] Compounds obtained from combinations that contradict the laws of nature and which a person skilled in the art would therefore exclude based on his / her expert knowledge are not encompassed herein. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0054] In the context of the present invention, reference to a salt of a compound of formula (I) means a pharmaceutically acceptable salt thereof, generally a salt that is considered pharmaceutically safe and suitable for use in pharmaceutical formulations. Unless otherwise expressly stated, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include, but are not limited to, salts of the following acids: for example, hydrochloric acid, trifluoroacetic acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, acetic acid, etc., preferably acetate. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art will recognize a variety of non-toxic pharmaceutically acceptable addition salts.

[0055] As used herein, the term "IC 50 " is called the half-maximal inhibitory concentration, which refers to the drug concentration at which the inhibitory effect of the drug on cell proliferation reaches 50% of the normal cell proliferation level after a specific exposure time in in vitro tests. The stronger the effect of the drug, the higher the IC 50 The smaller.

[0056] As used herein, the term "cancer" includes, but is not limited to, breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, liver cancer, eye cancer, skin cancer, head and neck tumors and distant metastases, and also includes multiple myeloma, lymphoma and sarcoma.

[0057] Unless otherwise clearly defined, "precancerous lesions" herein refer to abnormal cell proliferation with a high potential for canceration, examples of which include but are not limited to cervical precancerous lesions, oral leukoplakia, myelodysplastic diseases, familial intestinal polyps, skin nevi, psoriasis, solar keratosis, etc.

[0058] As used herein, the term "treating" means killing, inhibiting or slowing the growth or increase in size of a hyperproliferative cell mass or group or a tumor or cancerous growth, reducing the number of hyperproliferative cells, or preventing spread to other anatomical sites, as well as methods of reducing the size of a hyperproliferative growth or the number of hyperproliferative cells. However, it should be understood that "treating" does not necessarily mean curing or completely eliminating a hyperproliferative growth.

[0059] As used herein, the term "therapeutically effective amount" or "inhibitory effective amount" or "effective dose" refers to that amount of an active compound or agent that elicits the biological or medicinal response that is being sought or desired by a researcher, physician, or other clinician in a tissue, system, animal, individual, or human.

[0060] As used herein, the term "kit" means any commercial package comprising a container for holding a compound of the invention or a pharmaceutical formulation comprising the same, and optionally further comprising a separate container such as a separate vial or foil package, for example, to hold a reconstituted dissolution matrix. The container may be of any conventional shape or form known in the art and made of pharmaceutically acceptable material.

[0061] Administration and dosage

[0062] The compounds or medicines of the present invention can work systemically and / or locally. For this purpose, they can be administered with a suitable route of administration, for example, by oral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival or ear canal administration, or by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or as implant or stent administration. Specific methods can be, for example, oral, oral mucosal administration, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or input, or by a kind of explanted reservoir medication.

[0063] Preferred routes of administration include oral administration, oral administration, intramuscular injection, topical administration, vaginal administration, rectal administration, intraperitoneal administration, or intravenous administration. Oral administration includes local injection, local application, local irrigation, oral rinse, local controlled / sustained release, and microneedle device administration.

[0064] The drug delivery system of the present invention can be a targeted drug delivery system, a controlled drug delivery system, and a regulated drug delivery system, or it can be a novel delivery system, such as an emulsified drug delivery system, a biomimetic drug delivery system, a living cell delivery system, an exosome drug delivery system, a microneedle drug delivery system, a nanodrug delivery system, or a protein or polypeptide delivery system.

[0065] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[0066] The medicament of the present invention can be administered in a unit dosage form. The dosage form can be a liquid dosage form, a semisolid preparation, or a solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticle dosage forms, suspension dosage forms, etc. Semisolid dosage forms can be ointments, creams, pastes, gels, etc. Solid dosage forms can be orally disintegrating films, tablets, capsules, pellets, pills, powders, granules, suppositories, lyophilized powder injections, inclusion compounds, implants, patches, etc.

[0067] The compounds according to the invention can be incorporated into the aforementioned administration forms. This can be achieved in a known manner by mixing with pharmaceutically suitable carriers, excipients and / or other auxiliaries.

[0068] The single administration dose of the medicament 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, still more preferably 0.08-40 mg active ingredient / kg body weight, particularly preferably 0.1-20 mg active ingredient / kg body weight, further preferably 0.1-15 mg active ingredient / kg body weight, for example 0.1-10 mg active ingredient / kg body weight, 0.1-8 mg active ingredient / kg body weight, most preferably 0.2-6 mg active ingredient / kg body weight.

[0069] In one embodiment, the medicament of the present invention is administered at least once a month, for example 1, 2, 3, 4 or 5 times a month. Preferably, the medicament of the present invention is administered 1, 2 or 3 times a month. Herein, the term "active ingredient" refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof in the present invention.

[0070] plan

[0071] According to one aspect of the present invention, the present invention provides a compound of formula (I) or a salt thereof,

[0072] (I)

[0073] in

[0074] R each independently represents a 3-10 membered heterocyclic group or a 3-14 membered heteroaryl group containing at least one nitrogen atom, said heterocyclic group or heteroaryl group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, (C1-C8)-alkyl, (C1-C8)-alkoxy, (C3-C 10 )-cycloalkyl, (C1-C8)-haloalkyl, carboxyl-(C1-C8)-alkylcarbonyl, di-(C1-C8)-alkylamino or (C6-C 14 )-aryl-(C1-C8)-alkyl,

[0075] wherein the heterocyclic group or heteroaryl group is connected to the carbonyl group in formula (I) through a nitrogen atom,

[0076] With the proviso that compounds wherein each R is independently piperidinyl are excluded.

[0077] In a preferred embodiment, wherein in formula (I),

[0078] R each independently represents a 3-8 membered heterocyclic group or a 5-12 membered heteroaryl group containing at least one nitrogen atom, said heterocyclic group or heteroaryl group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C3-C8)-cycloalkyl, (C1-C6)-haloalkyl, carboxyl-(C1-C6)-alkylcarbonyl, di-(C1-C6)-alkylamino or (C6-C 10 )-aryl-(C1-C6)-alkyl.

[0079] Preferably, the heterocyclic or heteroaryl group containing at least one nitrogen atom contains 1-3 (preferably 1-2) nitrogen atoms, and optionally further contains 1-3 (preferably 1-2, more preferably 1) oxygen atoms and / or 1-3 (preferably 1-2, more preferably 1) sulfur atoms.

[0080] In a more preferred embodiment, wherein in formula (I),

[0081] R each independently represents a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one nitrogen atom, said heterocyclic group or heteroaryl group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl, carboxyl-(C1-C4)-alkylcarbonyl, di-(C1-C4)-alkylamino or phenyl-(C1-C4)-alkyl.

[0082] In a further more preferred embodiment, wherein in formula (I),

[0083] R each independently represents a 3-membered, 5-membered or 6-membered heterocyclic group or a 5-10-membered heteroaryl group containing at least one nitrogen atom, said heterocyclic group or heteroaryl group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl, carboxyl-(C1-C4)-alkylcarbonyl, di-(C1-C4)-alkylamino or phenyl-(C1-C4)-alkyl.

[0084] In a particularly preferred embodiment, wherein in formula (I),

[0085] Each R independently represents an aziridine, imidazolidinyl, pyrrolidinyl, morpholinyl, piperazinyl or 5-10 membered heteroaryl group, which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl (preferably fluoroalkyl), carboxy-(C1-C4)-alkylcarbonyl (preferably carboxymethylcarbonyl), di-(C1-C4)-alkylamino (preferably diethylamino) or phenyl-(C1-C4)-alkyl (preferably benzyl).

[0086] In a very particularly preferred embodiment, in which, in formula (I),

[0087] R each independently represents 2-benzyl-aziridine-1-yl, imidazolidin-1-yl, 3-(carboxymethylcarbonyl)imidazolidin-1-yl, 3-(diethylamino)pyrrolidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-trifluoroethyl-piperazin-1-yl or 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl.

[0088] The definitions of radicals listed above in general terms or in preferred ranges can be combined with one another as desired, ie including combinations between the preferred ranges given.

[0089] Very particular preference is given to the compounds of the formula (I) according to the invention listed in Table 1 below.

[0090] Table 1: Compounds of formula (I), in which R has the meaning given below.

[0091]

[0092] Note:" ” indicates that it is connected to the carbonyl group of the compound of formula (I).

[0093] According to another aspect of the present invention, the present invention provides a method for preparing the compound of formula (I) as described above, the method comprising

[0094]

[0095] In the presence of a catalyst and a condensing agent, protoporphyrin (PPIX) is subjected to a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent, wherein the compound having a reactive hydrogen atom is selected from the compound of formula (II)

[0096] RH (II)

[0097] wherein R is as defined above.

[0098] The catalyst suitable for the method of the present invention is an organic base catalyst, which can be preferably selected from N,N-diisopropylethylamine (DIPEA), N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine (NMM), N-ethylmorpholine, N-methylimidazole (NMI), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 2,6-lutidine or a mixture thereof, more preferably DIPEA.

[0099] The condensing agent suitable for the method of the present invention can be selected from the urea cation type condensing agent, such as O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), borate (TBTU), O-(1,2-dihydro-2-oxy-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU); carbodiimide type condensing agent, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or carbonyl imidazole type condensing agent, such as N,N-carbonyldiimidazole (CDI), preferably selected from HATU, EDCI or CDI, more preferably HATU.

[0100] The polar organic solvent suitable for the method of the present invention may be preferably selected from N,N-dimethylformamide (DMF), N,N-dimethylacetamide, formamide, dimethyl sulfoxide (DMSO), acetone, pyridine or a mixture thereof, more preferably DMF.

[0101] In a preferred embodiment, the compound having a reactive hydrogen atom is selected from morpholine, imidazoline-1-carboxylic acid tert-butyl ester, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1-(2,2,2-trifluoroethyl)piperazine (or its hydrochloride), ( S )-2-benzylaziridine, 1-tert-butoxycarbonylpiperazine, 3-(imidazolidin-1-yl)-3-oxopropionic acid, N,N-diethylpyrrolidin-3-amine.

[0102] In a preferred embodiment of the present invention, the content relationship between protoporphyrin (p), the compound having a reactive hydrogen atom (n) and the condensing agent (q) in terms of moles satisfies the following relationship:

[0103] 2.5≤q / [np / (n+p)]≤4.5;

[0104] Preferred

[0105] 2.7≤q / [np / (n+p)]≤4.3;

[0106] More preferred

[0107] 2.9≤q / [np / (n+p)]≤4.1.

[0108] In the method for preparing the compound of formula (I) of the present invention, the molar ratio of the catalyst to the condensing agent is (0.7-3):1, preferably (0.8-2.5):1, more preferably (0.9-2):1.

[0109] In a preferred embodiment of the present invention, the molar ratio of the compound having reactive hydrogen atoms to the catalyst is 1:(0.6-3), preferably 1:(0.65-2.5), more preferably 1:(0.7-2).

[0110] In the method of the present invention, the condensation reaction time is 0.5-24 hours, preferably 1-22 hours, more preferably 1-20 hours.

[0111] Depending on the reaction requirements, the compound having a reactive hydrogen atom may optionally carry an amino-protecting group commonly used in condensation reactions, such as a tert-butoxycarbonyl group (-Boc). Removal of the amino-protecting group can be performed by conventional methods known to those skilled in the art, for example, using a solution of hydrogen chloride in a specific organic solvent (e.g., dioxane, ethyl acetate, methanol), preferably a solution of hydrogen chloride in dioxane.

[0112] In a preferred embodiment, the method further comprises the step of hydrolyzing the intermediate compound by using a hydrogen chloride dioxane solution; preferably, the compound having a reactive hydrogen atom is tert-butyl imidazoline-1-carboxylate or 1-tert-butyloxycarbonylpiperazine.

[0113] Preferably, the hydrogen chloride concentration of the hydrogen chloride-dioxane solution is 4 mol / L; in the reaction mixed solution, the molar ratio of hydrogen chloride to the intermediate compound is 1:(0.001-0.5), preferably 1:(0.005-0.1), more preferably 1:(0.006-0.06).

[0114] If present, the intermediate compound preferably has the structure shown in Table 2 below.

[0115] Table 2: Intermediate compounds

[0116]

[0117] Note:" ” indicates that it is connected to the carbonyl group of the compound of formula (I).

[0118] The method of the present invention for preparing the compound of formula (I) uses a combination of a specific organic base catalyst and a specific condensing agent, particularly a combination of DIPEA and HATU in a specific ratio, and can obtain a target compound of high purity in good yield through simple post-treatment. Excessive or excessive amounts of the catalyst or condensing agent will adversely affect the target product. For example, excessive or insufficient amounts of the base will make post-treatment difficult, increase the proportion of by-products, and reduce the yield of the target product.

[0119] Optionally, in the above method for preparing the compound of the present invention, the reaction is terminated by adding water, and the amount of water added is 20-70 mL, preferably 30-60 mL.

[0120] In the above-described method for preparing the compounds of the present invention, the method may optionally include additional post-processing steps. Such post-processing steps may include, for example, pH adjustment, crystallization, extraction, filtration, concentration under reduced pressure, and drying, among other conventional purification steps. Each of these steps can be performed in conventional manners known to those skilled in the art. Extraction, if any, is typically performed using a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane / methanol (10 / 1, v / v). Drying is typically performed by freeze drying, infrared drying, vacuum drying, or the like, preferably freeze drying.

[0121] In a preferred embodiment, the method may further comprise a purification step by chromatography. The purification may be performed by using a normal phase silica gel column with a silica gel particle size of 30-100 μm, preferably 40-63 μm, a loading of 20-120 g, preferably 40 g, and elution using dichloromethane / methanol (elution gradient of 100% / 0% to 90% / 10%, gradient elution time of 15 minutes), or dichloromethane / methanol containing 1% triethylamine (elution gradient of 100% / 0% to 90% / 10%, gradient elution time of 15 minutes); or a C18 column with a filler particle size of 20-80 μm, preferably 40-63 μm, a loading of 4-120 g, preferably 40 g, a carbon content of 10-30%, preferably 17%, and elution using water / methanol (elution gradient of 100% / 0% to 50% / 50%, gradient elution time of 20 minutes).

[0122] Unless explicitly stated otherwise, all operations were performed at room temperature; the reagents used were either commercially available or prepared by methods known to those skilled in the art.

[0123] 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.

[0124] According to another aspect of the present invention, the present invention also provides use of the compound of formula (I) or a salt thereof as described above in the preparation of a medicament for treating hyperproliferative diseases (particularly cervical cancer or cervical precancerous lesions).

[0125] In addition, the present invention also relates to a method for treating a hyperproliferative disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined above or a salt 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.

[0126] In a preferred embodiment, the compound of formula (I) or a salt thereof as described above is used as a photosensitizer in photodynamic therapy, in particular for the treatment of hyperproliferative diseases.

[0127] Preferably, the hyperproliferative disease is cancer or a precancerous lesion, and the cancer is preferably selected from bladder cancer, esophageal cancer, bronchial cancer, oral cancer, nasopharyngeal cancer, liver cancer, pancreatic cancer, skin cancer, penile cancer, cervical cancer, vaginal cancer, endometrial cancer, ovarian cancer, colorectal cancer, kidney cancer, urothelial cell carcinoma, thyroid cancer, breast cancer, anal cancer, Kaposi's sarcoma, lung cancer, gastric cancer, bile duct cancer, prostate cancer, melanoma or brain cancer, more preferably cervical cancer; the precancerous lesion is selected from cervical precancerous lesions, oral leukoplakia, myelodysplastic disease, familial intestinal polyps, skin nevus, psoriasis or actinic keratosis, more preferably cervical precancerous lesions.

[0128] According to another aspect of the present invention, the present invention also provides use of the compound of formula (I) or a salt thereof as described above in the preparation of a medicament for treating diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0129] The present invention also relates to a method for inhibiting Gram-negative or Gram-positive cocci, bacilli, or coccobacilli, comprising contacting a compound of formula (I) or a salt thereof with Gram-negative or Gram-positive cocci, bacilli, or coccobacilli and irradiating the gram-negative or Gram-positive cocci, bacilli, or coccobacilli with an inhibitory effective amount of light of a specific wavelength. Preferably, the inhibition is for non-therapeutic purposes. The contacting can be performed in vivo or in vitro, for example, in vitro.

[0130] Accordingly, the present invention also relates to a method for treating a disease or condition caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli, which comprises administering a therapeutically effective amount of a compound of formula (I) or a salt thereof as described above 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.

[0131] In a preferred embodiment, the compound of formula (I) or a salt thereof as described above is used as a photosensitizer in photodynamic therapy, in particular for the treatment of diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0132] Preferably, 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.

[0133] More preferably, the disease or condition is selected from one or more of the following: swollen gums, bleeding gums, painful gums, bad breath, periodontal pocket formation, alveolar bone resorption, and loose teeth.

[0134] The Gram-negative or -positive cocci, bacilli or coccobacilli can be selected from Gram-negative bacilli or coccobacilli, or Gram-positive cocci; for example, Gram-negative anaerobic bacilli or coccobacilli, Gram-negative facultative anaerobic cocci, Gram-negative aerobic bacilli or Gram-positive facultative anaerobic cocci.

[0135] In a preferred embodiment, the Gram-negative or Gram-positive cocci, bacilli or coccobacilli is Porphyromonas gingivalis ( Porphyromonas gingivalis ), Actinobacillus actinomycetemcomitans ( Actinobacillus actinomycetemcomitans ), Tannerella forsythia ( Tannerella forsythia ), Fusobacterium nucleatum ( Fusobacterium nucleatum ), Prevotella intermedia ( Prevotella intermedia ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ) or Staphylococcus aureus ( Staphylococcus aureus gingivalis); more preferably Porphyromonas gingivalis.

[0136] In a preferred embodiment, the compound of formula (I) or a salt thereof is used as a photosensitizer in photodynamic therapy to treat cancer or precancerous lesions, in particular cervical cancer or cervical precancerous lesions, or for treating diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0137] Preferably, the irradiation time of light irradiation is 10-2000 s, preferably 20-1500 s, further preferably 30-1200 s, more preferably 60-900 s; for example, 30 s, 60 s, 120 s, 240 s, 480 s, 600 s, 900 s, 1200 s, 1500 s, 1800 s, etc.

[0138] Preferably, the light dose of light irradiation is 1-300 J, preferably 5-200 J, further preferably 10-200 J, more preferably 20-120 J; for example, 2 J, 10 J, 20 J, 40 J, 60 J, 80 J, 100 J, 120 J, 150 J, 180 J, etc.

[0139] Preferably, the wavelength range of light irradiation is 300 nm-800 nm, preferably 350 nm-700 nm, more preferably 400 nm-650 nm, for example, 405 nm, 505 nm, 540 nm, 575 nm or 630 nm; when used to treat hyperproliferative diseases, it is preferably 630 nm; when used to treat diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli, it is preferably 405 nm.

[0140] Preferably, the light power of the light irradiation is 30-1000 mW, preferably 60-600 mW, more preferably 80-300 mW.

[0141] In the context of the present invention, the term "optical power" refers to the actual optical power at the light irradiation site, which can be measured by an optical power meter.

[0142] In the context of the present invention, the term "light dose" refers to the actual light dose at the light irradiation site, which is obtained by multiplying the light power by the irradiation time.

[0143] According to another aspect of the present invention, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described above or a salt thereof, optionally further comprising one or more other active compounds. The other active compounds are compounds that are generally effective for treating hyperproliferative diseases, or diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0144] In addition, the present invention also relates to a drug kit comprising a therapeutically effective amount of the compound of formula (I) or a salt thereof, or the pharmaceutical composition, and instructions for using the compound as a photosensitizer in photodynamic therapy.

[0145] In a preferred embodiment, the kit comprises a lyophilized formulation of a compound of formula (I) in a therapeutically effective amount; a dissolving matrix (such as water for injection or a gel matrix containing excipients such as a cosolvent) for reconstituting the lyophilized formulation for administration; and instructions for using the compound of formula (I) as a photosensitizer for photodynamic therapy.

[0146] The various components of the kit, such as the compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation comprising the same, a dissolving matrix, other active ingredients for treating cancer or precancerous lesions, other active ingredients for treating diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli, etc., can be packaged in separate containers. Regardless of the number or type of containers, the kit can also include a device for assisting in administering the drug to the patient. The device can be an applicator, an inhaler, a syringe, a pipette, a spoon with a measuring unit, or any other delivery device approved for medical use.

[0147] In a preferred embodiment, the medicament comprises 1 mg-600 mg, preferably 1 mg-400 mg, more preferably 2 mg-300 mg, further preferably 3 mg-200 mg, further preferably 4 mg-100 mg of a compound of formula (I) or a salt thereof, for example 2 mg-500 mg, 2 mg-400 mg, 2 mg-300 mg, 3 mg-240 mg, 5 mg-120 mg or 5 mg-60 mg, more specifically for example 1 mg, 2 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 180 mg, 240 mg, 300 mg, 400 mg or 600 mg.

[0148] In a preferred embodiment, the medicine also includes pharmaceutically acceptable carriers, excipients and / or other adjuvants. When comprising pharmaceutically acceptable carriers, excipients and / or other adjuvants, usually the compound of formula (I) or its salt and one or more pharmaceutically acceptable carriers, excipients and / or other adjuvants of effective dose are combined to make suitable application form or dosage form, and this program includes mixing, granulating, compressing, dissolving or lyophilizing components by a suitable method. The content of carrier in the medicine can be 1 to 98 weight %, usually accounting for approximately 80 weight %. For convenience, other adjuvants such as local anesthetics, preservatives, buffers can be directly dissolved in the carrier.

[0149] Example

[0150] The following are detailed synthesis examples of selected compounds of the present invention. However, these examples are merely illustrative and should not be interpreted as limiting the scope of the present invention in any way.

[0151] The NMR peaks reported in the synthesis examples are 1 H NMR spectral data were obtained on a Bruker 400 MHz or 600 MHz NMR spectrometer, and the signals listed have the following meanings: s = singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiplet, br s = broad singlet. The deuterated solvent used in each case is also specified in the table.

[0152] Liquid chromatography-mass spectrometry (LC-MS) data were obtained using a Waters instrument (model: SQD2); liquid chromatography-tandem mass spectrometry (LC-MS / MS) data were obtained using an AB sciex instrument (model: API4000).

[0153] Unless otherwise specified, the contents and percentages in this application are based on weight. All operations were performed at room temperature and normal pressure. The reagents or instruments used, without manufacturer indicated, were all commercially available conventional products commonly used in the art.

[0154] A. Synthesis Examples

[0155] Example 1: Synthesis of BLDT-1213

[0156] Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 2.5 mL of DMF. HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. The mixture was stirred for 0.5 h, and morpholine (46 mg, 0.53 mmol, 3 equ) was added. After reacting at room temperature for 15 h, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the target compound BLDT-1213 (97 mg, 78% yield) as a black powder.

[0157] LC-MS (m / z): 701.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d6): δ 10.33-10.20 (m,4H), 8.58-8.48 (m, 2H), 6.47 (d, J = 17.6 Hz, 2H), 6.24 (d, J = 11.4 Hz, 2H),4.34-4.30 (m, 4H), 3.76 (s, 3H), 3.74 (s, 3H), 3.64 (s, 3H), 3.62(s, 3H),3.39-3.44 (m, 4H), 3.31-3.21 (m, 12H), 3.01-2.98 (m, 4H), -3.95 (br s, 2H).

[0158] Example 2: Synthesis of BLDT-1214

[0159] Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 4 mL of DMF. HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. The mixture was stirred for 0.5 h, and tert-butyl imidazoline-1-carboxylate (91 mg, 0.53 mmol, 3 equ) was added. After reacting at room temperature for 15 h, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the intermediate BLDT-1214-01 (120 mg, 77% yield) as a black powder.

[0160] 120 mg of the intermediate BLDT-1214-01 was added to 10 mL of a 4 mol / L hydrogen chloride-dioxane solution. After stirring for 4 hours, the mixture was concentrated under reduced pressure and lyophilized to obtain the target compound BLDT-1214 (90 mg, 98% yield) as a reddish-brown solid.

[0161] LC-MS (m / z): 671.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 10.23-10.05 (m, 4H), 8.33-8.26 (m, 2H), 6.38 (d, J = 16.8 Hz, 2H), 6.21 (d, J= 11.2 Hz, 2H), 4.46-4.42 (m, 4H), 4.29-4.26 (m, 2H), 3.98 (s, 2H), 3.72 (br s, 6H), 3.64 (s, 3H), 3.63 (s, 3H), 3.25-3.20 (m, 6H), 2.92-2.88 (m, 2H), 2.70-2.59 (m, 4H), -3.74-(-3.80) (m, 2H).

[0162] Example 3: Synthesis of BLDT-1216

[0163] Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF. HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. The mixture was stirred for 0.5 h, and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (74 mg, 0.53 mmol, 3 equ) was added. After reacting at room temperature for 15 h, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the target compound BLDT-1216 (120 mg, 84% yield) as a black powder.

[0164] LC-MS (m / z): 805.7 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H),10.13-9.95 (m, 3H), 8.32-8.24 (m, 2H), 6.96-6.93 (m, 1H), 6.71-6.69 (m, 1H),6.41-6.35 (m, 2H), 6.21-6.17 (m, 2H), 5.97-5.89 (m, 1H), 5.46-5.35 (m, 1H),4.66 (d, J= 9.0 Hz, 2H), 4.48-4.43 (m, 4H), 4.07-4.04 (m, 2H), 3.82-3.77 (m,2H), 3.71-3.70 (m, 6H), 3.60-3.58 (m, 6H), 3.39-3.32 (m, 6H), 2.60-2.53 (m,2H), 2.34-2.31 (m, 2H), -3.76-(-3.81) (m, 2H).

[0165] Example 4: Synthesis of BLDT-1220

[0166] Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL of DMF. HATU (403 mg, 1.06 mmol, 3 equ) and DIPEA (276 mg, 2.14 mmol, 6 equ) were added sequentially. The mixture was stirred for 5 minutes, and 1-(2,2,2-trifluoroethyl)piperazine hydrochloride (217 mg, 1.06 mmol, 3 equ) was added. After reacting at room temperature for 1 hour, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the target compound BLDT-1220 (267 mg, 87% yield) as a black powder.

[0167] LC-MS / MS (m / z): 863.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): δ 10.43-10.26 (m,4H), 8.56 (s, 2H), 6.50-6.46 (m, 2H), 6.24 (d, J = 12.0 Hz, 2H), 4.33 (s, 4H), 3.77 (d, J = 7.6 Hz, 6H), 3.64 (d, J = 6.8 Hz, 6H), 3.42 (s, 4H), 2.81-2.79 (m,4H), 2.69 (s, 2H), 2.33 (s, 4H), 2.15 (s, 4H), -3.80 (s, 2H).

[0168] Example 5: Synthesis of BLDT-1222

[0169] 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. The mixture was stirred for 0.5 h and then ( S )-2-benzylaziridine (71 mg, 0.53 mmol, 3 equ) was reacted at room temperature for 15 hours. The reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixed solution of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the target compound BLDT-1222 (114 mg, yield 81%) as a black powder.

[0170] LC-MS (m / z): 794.1 [M+H] + . 1 H NMR (600 MHz, DMSO- d 6 ): δ 10.19-10.02 (m,4H), 8.48-8.43 (m, 2H), 6.89-6.75 (m, 10H), 6.43 (d, J = 18.0 Hz, 2H), 6.22-6.20 (m, 2H), 4.26-4.23 (m, 4H), 3.68 (s, 3H), 3.67 (s, 3H), 3.51 (s, 3H),3.50 (s, 3H), 3.20-3.17 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.28 (m, 4H), 2.13-2.11 (m, 2H), 1.86-1.85(m, 2H), -4.20 (br s, 2H).

[0171] Example 6: Synthesis of BLDT-2202

[0172] Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 4 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. The mixture was stirred for 0.5 h, and 1-tert-butyloxycarbonylpiperazine (99 mg, 0.53 mmol, 3 equ) was added. After reacting at room temperature for 15 h, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the intermediate BLDT-2202-01 (93 mg, 58% yield) as a black powder.

[0173] 93 mg of the intermediate BLDT-2202-01 was added to 10 mL of a 4 mol / L hydrogen chloride-dioxane solution, stirred for 4 hours, concentrated under reduced pressure, and lyophilized to obtain the target compound BLDT-2202 (68 mg, 94% yield) as a reddish-brown solid.

[0174] LC-MS (m / z): 699.8 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 10.22-10.02 (m, 4H),8.29 (dd, J = 18.0, 11.6 Hz, 2H), 6.41-6.35 (m, 2H), 6.22-6.18 (m, 2H), 4.43(t, J = 7.2 Hz, 4H), 3.72 (s, 3H), 3.71 (s, 3H), 3.63 (s, 3H), 3.62 (s, 3H), 3.51 (s, 4H), 3.34-3.27 (m, 16H), -3.76 (s, 2H).

[0175] Example 7: Synthesis of BLDT-2203

[0176] Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 4 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (92 mg, 0.71 mmol, 4 equ) were added sequentially. The mixture was stirred for 0.5 hour, and 3-(imidazolidin-1-yl)-3-oxopropanoic acid (79 mg, 0.50 mmol, 2.8 equ) was added. After reacting at room temperature for 12 hours, the product was purified using a C18 column (water / methanol 100% / 0% to 50% / 50%, 20 min) and lyophilized to obtain the target compound BLDT-2203 (97 mg, 65% yield) as a reddish-brown solid.

[0177] LC-MS (m / z): 843.7 [M+H] + . 1 H NMR (600 MHz, CD3OD): δ 10.47-10.06 (m, 4H), 8.28-8.25 (m, 2H), 6.43-6.41 (m, 4H), 4.88-4.63 (m, 4H), 4.38 (s, 4H), 3.71-3.43 (m, 22H), 3.29-3.27 (m, 6H).

[0178] Example 8: Synthesis of BLDT-2210

[0179] Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL of DMF. HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added sequentially. The mixture was stirred for 5 minutes, and N,N-diethylpyrrolidin-3-amine (151 mg, 1.06 mmol, 3 equ) was added. After reacting at room temperature for 4 hours, the reaction solution was poured into 30 mL of water and extracted with 3 × 30 mL of a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a normal phase silica gel column (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) and lyophilized to obtain the target compound BLDT-2210 (257 mg, 89% yield) as a reddish-brown solid.

[0180] LC-MS (m / z): 811.9 [M+H] + . 1 H NMR (600 MHz, DMSO- d6+ CF3COOD): δ 10.08-9.96 (m, 4H), 8.50-8.29 (m, 2H), 6.43 (d, J = 17.8 Hz, 2H), 6.29-6.26 (m, 2H), 4.35 (s, 4H), 3.62-3.56 (m, 18H), 3.35 (m, 2H), 3.26-3.16 (m, 8H), 2.95 (s,3H), 2.84 (s, 3H), 1.92 (s, 2H), 1.05-1.00 (m, 4H), 0.87-0.83 (m, 4H), 0.58-0.47 (m, 4H).

[0181] Comparative Example 1: Synthesis of BLDT-1220

[0182] Synthesized in a manner similar to Example 4, except that benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 552 mg, 1.06 mmol, 3 equ) was used instead of HATU (403 mg, 1.06 mmol, 3 equ), to afford BLDT-1220 (130 mg, 42% yield).

[0183] B. Absorption spectroscopy and ROS production detection

[0184] B-1. Absorption spectrum of the compound of the present invention

[0185] To explore the optimal excitation wavelength for drugs, the absorption wavelengths of all compounds prepared by the method of the present invention were tested. The specific steps are as follows:

[0186] Prepare a stock solution of the porphyrin derivatives prepared in Examples 1-8 in dimethyl sulfoxide (brand: Shanghai Runjie Chemical Reagent Co., Ltd.) to a concentration of 1 mg / mL. Dilute to 25 μg / mL with phosphate buffered saline (PBS, brand: Gibico). Take 4 mL of each stock solution and place it in a cuvette. Scan the absorption spectrum of the solution in the cuvette at 300-700 nm using a UV spectrophotometer (purchased from Shanghai Yuanxi Instrument Co., Ltd., model: X-8S). A reference solution was a PBS solution containing 25% DMSO.

[0187] like Figure 1 As shown, the absorption wavelengths of each compound are similar, namely, absorbing energy at 405, 510, 540, 580, and 630 nm. The absorption is particularly strong around 405 nm. Based on these results, the excitation wavelengths of the series of porphyrin derivatives of the present invention are determined to be 405 nm and 630 nm.

[0188] B-2. Detection of ROS production by the compounds of the present invention

[0189] To screen the potential efficacy of the compounds of formula (I) prepared by the method of the present invention at 405 nm, the ROS production of each compound was detected. The specific steps are as follows:

[0190] A PBS solution of protoporphyrin, sodium cinnamate, and the compound of the present invention was prepared at a concentration of 12.5 μg / mL. The drug was mixed with equal volumes of 4 μmol / L 9,10-anthracenediyl-bis(methylene)dicarboxylic acid (Biodex Pharmaceuticals) and irradiated with a 405 nm laser (purchased from Beijing Honglan Optoelectronics Technology Co., Ltd., model: VCL-405 nm M1-1W) for 0, 2, 4, 6, and 8 minutes at an output power of 135 mW. After irradiation, the optical density (OD) was measured at 400 nm using a microplate reader (biotek).

[0191] like Figure 2 As shown in the data, when the drug concentration was 12.5 μg / mL, protoporphyrin did not produce singlet oxygen in the aqueous solution, and the singlet oxygen production of sodium thiocyanate was also negligible (judged to be aggregation). In contrast, all the compounds of the present invention produced singlet oxygen, and compounds BLDT-1213, BLDT-1220, BLDT-1222, BLDT-2203, etc. produced significant singlet oxygen.

[0192] The above results indicate that the compound of the present invention can be excited by 405 nm laser to generate singlet oxygen and has a light dose trend, and is a potential high-efficiency photosensitizer.

[0193] C. Effect Example

[0194] C-1. Antibacterial effect

[0195] 1. Materials and Methods

[0196] 1.1 Information on the drug to be tested

[0197] Compounds of the present invention: BLDT-1213, BLDT-1214, BLDT-2202, BLDT-2203, and BLDT-2210;

[0198] Positive drug 1: protoporphyrin (PPIX), purchased from Adams, product number 012080662;

[0199] Positive drug 2: 5-aminolevulinic acid (5-ALA), purchased from Shanghai Bid Pharmaceutical, product number BD102341-5g.

[0200] 1.2 Experimental Methods

[0201] After resuscitation, Porphyromonas gingivalis (purchased from Beijing Beinachuanglian Biotechnology Research Institute, batch number BNCC353909) was inoculated into BHI medium (brain heart infusion medium, purchased from Haibo Biotechnology, batch number HB8297-1) and cultured to the logarithmic phase under anaerobic conditions of 10% H2, 10% CO2, 80% N2, and 37°C; 1 mL of the bacterial solution was taken, the OD value was measured, the supernatant was discarded after centrifugation, and the bacterial solution concentration was adjusted to 10 10 CFU / mL(1 OD≈9.52*10 9 CFU / mL) for later use.

[0202] Test drug group: 100 μL bacterial solution, 898 μL BHI medium and 2 μL DMSO solution of the drug to be tested were added to the centrifuge tubes (the final concentration of the bacterial solution was 10 9 CFU / mL, the final concentration of positive drug 1 and the compound of the present invention was 10 μg / mL, and the final concentration of positive drug 2 was 80 μg / mL. Protected from light, the cells were cultured under the same anaerobic conditions as above for 4 h, the supernatant was centrifuged and discarded, and the cells were resuspended in 1 mL of BHI medium. The resuspension was added to a 96-well plate, with 100 μL of bacterial solution added to each well, and four replicates were set up for each well. Illumination was performed using a 405 nm laser with a light power of 300 mW for 66.67 s and a light dose of 20 J. After illumination, the cells were cultured under the same anaerobic conditions as above for another 24 h. The OD value of each bacterial solution at 600 nm was measured, and the inhibition rate was calculated.

[0203] Vehicle group: The above method was followed, except that 100 μL of bacterial solution, 898 μL of BHI medium and 2 μL of DMSO were added to the centrifuge tube.

[0204] Blank illumination group: The above method was followed, except that 100 μL of bacterial solution and 900 μL of BHI medium were added to the centrifuge tube.

[0205] Blank no-light group: The only difference from the blank light group is that there is no light treatment.

[0206] The formula for calculating the inhibition rate is as follows:

[0207]

[0208] 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 the bacterial solution measured in the test drug group.

[0209] 1.3 Calculation of statistical differences

[0210] Data were analyzed using one-way analysis of variance in GraphPad Prism 8 software (compared with PPIX). P < 0.05 was considered statistically significant, with *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 indicating a significant decrease.

[0211] 2. Results and Discussion

[0212] The results are as follows Figure 3 As shown in Table 3, the compound of the present invention and PPIX have good antibacterial effects, and the antibacterial effect of the compound of the present invention is significantly better than that of PPIX.

[0213] .

[0214] C-2. Anti-tumor effect

[0215] The information of the drugs to be tested is as follows:

[0216] Compounds of the present invention: BLDT-1213, BLDT-1214;

[0217] Positive drug 1: protoporphyrin (PPIX), purchased from Adams, product number 012080662;

[0218] Positive drug 2: 5-aminolevulinic acid (5-ALA), purchased from Shanghai Bidex Pharmaceuticals, product number BD102341-5g;

[0219] Positive drug 3: 5-aminolevulinic acid hexyl ester (HAL) hydrochloride, purchased from Shanghai Bid Pharmaceutical, product number BD102340-250 mg.

[0220] Example 1: In vitro efficacy evaluation of cervical cancer

[0221] 1.1 Experimental Methods

[0222] The killing effect of the compound of the present invention on Hela cells was determined by the Cell Counting Kit-8 (CCK-8) method. The specific steps are as follows:

[0223] HeLa human cervical cancer cells in logarithmic growth phase (purchased from Shanghai Fuheng Biotechnology, product number FH0314) were cultured at a concentration of 5×10 4 Cells were seeded in 96-well plates, with 100 μL of cells (5 × 10 3Each well was plated with 100 μL of culture medium containing various drug concentrations (μg / well) and cultured in a 37°C, 5% CO2 incubator (Purchased from Phcbi). After 24 hours, 1640 culture medium (Purchased from Shanghai Fuheng Biotechnology, Cat. No. FH-R01) was removed. In a 96-well plate, 100 μL of culture medium containing various drug concentrations was added to the drug-treated group, while 100 μL of culture medium was added to the negative control group. Four replicate wells were set up for each experimental group. The concentrations of PPIX and the compound of the present invention were 0.0625, 0.125, 0.25, 0.5, and 1 μg / mL; the concentrations of 5-ALA were 334, 167, 83.5, and 41.75 μg / mL; and the concentrations of HAL were 120, 60, 30, 15, and 7.5 μg / mL.

[0224] After incubation at 37°C in the dark for 4 hours, the cells were exposed to light (200 mW light power, 10 seconds, 2 J light dose) using a 630 nm semiconductor laser photodynamic therapy device (purchased from Guilin Xingda Optoelectronics Medical Devices Co., Ltd., Model PDT630-II). The cells were then incubated in the dark for another 24 hours under the same conditions as above. The old culture medium was removed, and 100 μL of 1640 complete culture medium (purchased from Shanghai Fuheng Biotechnology, Model FH-R1011) containing 10% CCK-8 (purchased from Lab Lead, Model CK001) was added to each well. After incubation in the dark for 2 hours under the same conditions as above, the absorbance at 450 nm was measured using a microplate reader (purchased from BioTek, Model: Synergy H1). Cell viability was calculated using the following formula:

[0225]

[0226] Wherein A is the average absorbance of each drug-treated group, Ab is the absorbance of 1640 complete medium containing 10% CCK-8, and Ac is the average absorbance of the negative control group.

[0227] 1.2 Experimental Results

[0228] The results are as follows Figure 4 As shown in Table 4, the results indicate that the compounds of the present invention (BLDT-1213 and BLDT-1214) have high cytotoxicity to Hela cells in a concentration-dependent manner; the cytotoxicity of protoporphyrin and the compounds of the present invention is significantly better than that of the drugs 5-ALA and HAL, and at the same concentration, the cytotoxicity of the compounds of the present invention is significantly better than that of PPIX.

[0229] Table 4: IC values ​​of PPIX, HAL, 5-ALA and compounds of the present invention 50 value

[0230] .

[0231] Example 2: Evaluation of drug efficacy on subcutaneous tumors of cervical cancer

[0232] 2.1 Animal Experimental Methods

[0233] (1) Animal vaccination

[0234] Sixty female Balb / c-nude mice (purchased from Shanghai Southern Model Organisms, 6-8 weeks old, weighing 18-22 g) were acclimated for 7 days (environmental conditions: temperature 20-26°C, humidity 30-70%; photoperiod: 12 hours light, 12 hours dark; animal identification: ear clipping). After the acclimation period, 0.2 mL (5.0 × 10 6 HeLa cells in the logarithmic growth phase (cells) were subcutaneously inoculated on the right back of each mouse near the hind limb.

[0235] (2) Animal grouping and drug treatment

[0236] After cell inoculation, 42 mice with tumors of appropriate size were randomly divided into groups at 7 days of tumor growth. The day of grouping was designated D0, and drug administration began. Drug solutions were prepared according to Table 5, and each group received a single intratumoral injection. Following drug administration, the mice were irradiated with a 630 nm semiconductor laser photodynamic therapy device at a power of 100 mW for 10 minutes, resulting in a dose of 60 J.

[0237] .

[0238] (3) Sample collection and testing indicators

[0239] After group administration and treatment, the length and width of the tumor were measured twice a week using a vernier caliper (purchased from Sanfeng Precision Measuring Instrument Co., Ltd.), and the mice were weighed at the same time. Tumor volume (TV) and tumor growth inhibition rate (TGI) were calculated. 体积 (%). The specific calculation formula is as follows:

[0240] ;

[0241] ;

[0242] Where V0 is the average tumor volume of a treatment group at the beginning of drug administration, V t It is the average tumor volume of the treatment group at the end of drug administration.

[0243] At the end of the experiment, mice in each group were euthanized, and tumor tissues were removed and weighed. Tumor growth inhibition rate (TGI) was calculated. 重量 (%). The specific calculation formula is as follows:

[0244] ;

[0245] Among them, TW给药组 represents the average tumor weight of the drug-treated group, TW 阴性对照组 The mean tumor weight of the negative control group is shown.

[0246] (4) Data processing and statistical analysis

[0247] Based on the data obtained at the end of the experiment, the data were analyzed using general one-way analysis of variance in GraphPad Prism 8 software. P < 0.05 was considered to be statistically significant, among which *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 indicated a significant improvement.

[0248] 2.2 Experimental Results

[0249] like Figure 5 As shown in (a), during the experiment, the overall weight of the mice was relatively stable and the animals were in good condition, indicating that the porphyrin derivatives of the present invention have good biosafety.

[0250] like Figure 5 As shown in (b), on the 14th day after administration, there was no significant difference in the tumor volume between the light-only group and the negative control group, indicating that light-only had no significant inhibitory effect on the growth of Hela subcutaneous tumors. Figure 5 As shown in (c), the tumor weights of each group measured at the end of the experiment were basically consistent with the tumor volume results.

[0251] The above experimental results show that under the same lighting conditions, the compound of the present invention (4 mg / kg) treatment group has a significant inhibitory effect on Hela subcutaneous tumors compared with the negative control group, among which the tumor growth inhibition rate (TGI) calculated based on the tumor volume of the compounds BLDT-1213 and BLDT-1214 is 体积 The tumor growth inhibition rate (TGI) calculated based on tumor weight was 72.7% (P<0.0001) and 68.4% (P<0.0001), which were much higher than those in the PPIX (4 mg / kg) group (31.7% (P<0.05), the 5-ALA (60 mg / kg) group (43.1% (P<0.001), and the HAL group (26.5% (P>0.05)). 重量 The porphyrin derivatives of the present invention achieved significantly better efficacy than HAL and 5-ALA in terms of overall tumor inhibition, even at significantly lower dosages.

Claims

1. A compound of formula (I) or a salt thereof, (I) in R each independently represents a 3-6 membered heterocyclic group containing at least one nitrogen atom, said heterocyclic group being unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl, carboxyl-(C1-C4)-alkylcarbonyl, di-(C1-C4)-alkylamino or phenyl-(C1-C4)-alkyl, wherein the heterocyclic group is connected to the carbonyl group in formula (I) via a nitrogen atom, With the proviso that compounds wherein each R is independently piperidinyl are excluded.

2. The compound or salt thereof according to claim 1, wherein R each independently represents an aziridine, imidazolidinyl, pyrrolidinyl, morpholinyl or piperazinyl group, which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl, carboxyl-(C1-C4)-alkylcarbonyl, di-(C1-C4)-alkylamino or phenyl-(C1-C4)-alkyl.

3. A method for preparing the compound of formula (I) according to claim 1 or 2, comprising subjecting protoporphyrin (PPIX) to a condensation reaction with a compound having a reactive hydrogen atom in a polar organic solvent in the presence of a catalyst and a condensing agent, wherein the compound having a reactive hydrogen atom is selected from the compounds of general formula (II) RH (II) wherein R is as defined in claim 1 or 2.

4. The method according to claim 3, wherein: The catalyst is an organic base catalyst selected from N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N-dimethylaminopyridine, 2,6-lutidine or a mixture thereof; The condensing agent is a urea cation type condensing agent, which is selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N' -tetramethyluronium tetrafluoroborate (TBTU), O-(1,2-dihydro-2-oxy-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU); a carbodiimide type condensing agent selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or a carbonyl imidazole type condensing agent selected from N,N-carbonyldiimidazole (CDI); and The molar ratio of the catalyst to the condensing agent is (0.7-3):

1.

5. Use of the compound of formula (I) or a salt thereof according to claim 1 or 2 in the preparation of a medicament for treating cervical cancer or cervical precancerous lesions.

6. Use of a compound of formula (I) according to claim 1 or 2 or a salt thereof in the preparation of a medicament for treating a disease or condition caused by Porphyromonas gingivalis.

7. The use according to claim 6, wherein the disease or condition is selected from one or more of the following: periodontitis, gingivitis, dental plaque and caries; or The disease or condition is selected from one or more of the following: swollen gums, bleeding gums, painful gums, bad breath, periodontal pocket formation, alveolar bone resorption, and loose teeth.

8. The use according to claim 5 or 6, wherein the compound of formula (I) or a salt thereof is used as a photosensitizer in photodynamic therapy.

9. The use according to claim 8, wherein the irradiation time of the light irradiation in photodynamic therapy is 10-2000 s; the light dose of the light irradiation is 1-300 J; the wavelength range of the light irradiation is 300-800 nm; and the light power of the light irradiation is 30-1000 mW.

10. A method for inhibiting Porphyromonas gingivalis for non-therapeutic purposes, comprising contacting the compound of formula (I) or a salt thereof according to claim 1 or 2 with Porphyromonas gingivalis and irradiating the bacteria with light of a specific wavelength in an effective inhibitory amount.

11. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof according to claim 1 or 2, and further comprising one or more other active compounds.

12. A kit comprising a therapeutically effective amount of the compound of formula (I) or a salt thereof according to claim 1 or 2, or the pharmaceutical composition according to claim 11, and instructions for using the same as a photosensitizer in photodynamic therapy.

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