Biheterocycle-substituted porphyrin derivatives, process for preparation thereof and their use 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 description; the invention also relates to a preparation method of the compound and application of the compound as a photosensitizer in photodynamic therapy. The biheterocycle substituted porphyrin derivative has high ROS yield, high activity and good biological safety, the preparation method is simple in process and low in cost, a target product can be obtained with good yield, and the biheterocycle substituted porphyrin derivative is especially suitable for industrial production and has wide application prospects. The compound can be used as a high-efficiency photosensitizer to treat hyperproliferative diseases such as cancer or precancerous lesions, especially cervical cancer or precancerous lesions of cervical cancer, or treat oral diseases # imgabs0 # (I) such as periodontitis, gingivitis, dental plaque and decayed teeth caused by bacteria Gram-negative anaerobic bacillus such as porphyromonas gingivalis through photodynamic therapy.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a bicyclic 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 bacterial 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 cell contents, thereby causing irreversible damage to tumor cells and tissues, achieving the purpose of treating cancer, microbial infections and other diseases.

[0003] 5-aminolevulinic acid (5-ALA) is a second-generation photosensitizer developed in recent years. It itself has no photosensitivity. After exogenous 5-ALA enters the body, it can be selectively absorbed and accumulated by actively proliferating cells and converted into protoporphyrin IX (PPIX) in the cells. PPIX in the cells is a photosensitive substance. After being irradiated with red light of a specific wavelength, a photodynamic reaction occurs, generating reactive oxygen species such as singlet oxygen, which kills actively proliferating cells.

[0004] Periodontitis is a chronic inflammatory disease that is mainly caused by the destruction of periodontal tissues by bacteria in dental plaque. Porphyromonas gingivalis is a Gram-negative coccobacillus and the main pathogen of periodontitis and gingivitis. Currently, drugs such as metronidazole tablets and amoxicillin capsules can be used for treatment, but frequent use of antibiotics will produce drug resistance, and some patients may even develop adverse reactions such as allergies, so safer, less toxic, and non-invasive alternative therapies 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 in the world, and they are in the clinical trial stage. There are no photosensitizer drugs for the treatment of cervical cancer or precancerous lesions on the market, so it is urgent to develop such new photosensitizers to promote the development of the industry.

[0006] In summary, it is of great significance to develop porphyrin photosensitizers with high efficiency in killing cancer cells and / or antibacterial ability. 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, (I) in 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, carboxy-(C1-C8)-alkylcarbonyl, di-(C1-C8)-alkylamino or (C6-C 14 )-aryl-(C1-C8)-alkyl, wherein the heterocyclic group or heteroaryl 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.

[0009] On the other hand, the present invention provides a method for preparing the compound of formula (I) as described above, the method 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 above.

[0010] On the other hand, the present invention also provides the use of the compound of formula (I) or a salt thereof as described above in the preparation of a medicament for treating hyperproliferative diseases (especially cervical cancer or cervical precancerous lesions).

[0011] 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, the subject is a mammal, more preferably a human.

[0012] In another aspect, the present invention also provides the 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.

[0013] In addition, the present invention also relates to a method for inhibiting Gram-negative or positive cocci, bacilli or coccobacilli for non-therapeutic purposes, the method comprising contacting the compound of formula (I) or a salt thereof with Gram-negative or positive cocci, bacilli or coccobacilli and irradiating the compound with an effective inhibitory amount of light of a specific wavelength. The contact can be carried out in vivo or in vitro, for example, in vitro.

[0014] 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.

[0015] 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.

[0016] In addition, the present invention also relates to a drug kit, which comprises a therapeutically effective amount of the compound of formula (I) or a salt thereof, or the pharmaceutical composition, and instructions for using it as a photosensitizer in photodynamic therapy.

[0017] Surprisingly, the present invention has the following beneficial effects: The present invention develops a novel class of biheterocyclic substituted porphyrin derivatives, which can be used as photosensitizers in photodynamic therapy. The compounds of the present invention have high ROS production, high activity and good biosafety, and the preparation method thereof is simple, low-cost, can obtain the target product in good yield and is particularly suitable for industrial production. It can be used as a highly efficient photosensitizer to treat hyperproliferative diseases such as cancer or precancerous lesions, especially cervical cancer or cervical precancerous lesions, through PDT, and its efficacy is significantly better than that of drugs 5-ALA and HAL, especially when the dosage is significantly smaller. In addition, the compounds of the present invention also have a good inhibitory effect on bacteria such as Porphyromonas gingivalis, and have a therapeutic effect in oral diseases such as periodontitis, gingivitis, dental plaque and caries. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The ultraviolet absorption spectrum of the compound of the present invention is shown.

[0019] Figure 2The singlet oxygen ( 1 O2) Production curve diagram.

[0020] Figure 3 The graph shows the inhibition rates of PPIX, 5-ALA and the compound of the present invention on Porphyromonas gingivalis, wherein compared with PPIX, the compound of the present invention had ***P<0.001, ****P<0.0001.

[0021] Figure 4 The figure shows the PDT killing effect of different concentrations of PPIX, HAL, 5-ALA and the compound of the present invention on Hela cells under 2 J of 630 nm laser irradiation.

[0022] 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 (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

[0023] 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.

[0024] 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 pharmaceutically acceptable salts thereof are sometimes also collectively referred to as "compounds of the present invention".

[0025] 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.

[0026] Unless expressly stated otherwise, the names of chemical groups are generally to be understood as being linked to the rest of the backbone or molecule 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", meaning that the link of the designated heterocyclyl or heteroaryl group containing a nitrogen atom to the rest of the backbone or molecule is via a nitrogen atom.

[0027] The term "optionally" as used herein means that the subsequently described event, circumstance or material may or may not occur or exist, and that such description includes instances in which the event, circumstance or material occurs or exists and instances in which the event, circumstance or material does not occur or exist.

[0028] Unless otherwise stated, the following definitions apply to radicals or substituents used throughout the present description and claims. Within the scope of the present invention, the meanings of all radicals occurring repeatedly are independent of one another.

[0029] As used herein, the term "halogen" when applied to a radical means a fluorine, chlorine, bromine, or iodine atom.

[0030] 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.

[0031] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more identical or different halogen atoms, 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-trifluoropropan-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 1,1,1-trifluoropropan-2-yl.

[0032] As used herein, the term "cycloalkyl" refers to a carbocyclic saturated ring system having the specified number of carbon atoms in each case, examples including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. In particular, the cycloalkyl has 3 to 6 carbon atoms.

[0033] According to the present invention, "alkoxy" means 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.

[0034] As used herein, the term "dialkylamino" means that the two hydrogen atoms on the amino group N are replaced by alkyl groups as described above, such as di-(C1-C8)-alkylamino, di-(C1-C6)-alkylamino and di-(C1-C4)-alkylamino, examples include but are not limited to dimethylamino, diethylamino, dipropylamino and the like.

[0035] 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 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.

[0036] 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 carboxy-(C1-C8)-alkylcarbonyl, carboxy-(C1-C6)-alkylcarbonyl or carboxy-(C1-C4)-alkylcarbonyl, examples include but are not limited to carboxymethylcarbonyl, carboxyethylcarbonyl, and the like.

[0037] 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, in particular 6 to 10 ring carbon atoms, and the ring system may be a monocyclic ring or a fused polycyclic ring (such as a bicyclic ring or a tricyclic ring). Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. In particular, the aryl refers to phenyl.

[0038] Unless otherwise defined, the term "arylalkyl" means a combination of the groups "aryl" and "alkyl" as defined according to the present invention, wherein the group is usually connected to the backbone or the rest of the molecule via the alkyl group. Examples include, but are not limited to, benzyl, phenethyl or α-methylbenzyl, preferably benzyl.

[0039] Unless otherwise defined, the term "heterocyclyl" means 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 the 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, especially 1, 2 or 3 heteroatoms in the heterocycle, the heteroatoms being 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 with 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.

[0040] 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.

[0041] 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 in the ring, which are selected from N, O and S, but two oxygen atoms should not 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl , 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, 4-(4-nitrophenyl)-1,4-diazole, 1,2,4-triazine, 1,3,5 ... 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.

[0042] 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.

[0043] Any description 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.

[0044] Depending on the nature of the substituents, the compounds of formula (I) described anywhere herein may also be in the form of stereoisomers, ie optical isomers. The invention provides both the pure stereoisomers and any desired mixtures of these isomers, although generally only compounds of formula (I) are discussed herein.

[0045] Compounds obtained from combinations which are contrary to the laws of nature and which the skilled person 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.

[0046] In the context of the present invention, reference to the salt of the compound of formula (I) means its pharmaceutically acceptable salt, generally those salts that are considered safe and suitable for use in pharmaceutical preparations. 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.

[0047] As used herein, the term “IC 50 " is called the half 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 an in vitro test. The stronger the effect of the drug, the higher the IC 50 The smaller.

[0048] 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.

[0049] Unless otherwise clearly defined, "precancerous lesions" in this article refer to abnormal cell proliferation with a high possibility of becoming cancerous. Examples include but are not limited to cervical precancerous lesions, oral leukoplakia, myelodysplastic diseases, familial intestinal polyps, skin nevi, psoriasis, solar keratosis, etc.

[0050] 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.

[0051] As used herein, the terms "therapeutically effective amount" or "inhibitory effective amount" or "effective dose" refer to the 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.

[0052] As used herein, the term "kit" means any commercial package, which comprises a container for holding a compound of the present invention or a pharmaceutical preparation comprising the same, and optionally further comprises a separate container such as a separate vial or foil package, for example, to hold a reconstituted dissolution matrix. The container may be any conventional shape or form known in the art, which is made of pharmaceutically acceptable materials.

[0053] Administration and Dosage The compound or medicine 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, lung, nose, sublingual, tongue, cheek, rectum, vagina, dermal, transdermal, conjunctival or ear canal route 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 means of a kind of explanted reservoir medication.

[0054] Preferred are oral mucosal administration, oral administration, intramuscular injection, topical administration, vaginal administration, rectal administration, intraperitoneal administration or intravenous administration. Oral mucosal administration includes local injection, local coating, local washing, oral gargle, local controlled / slow release, microneedle and other device administration.

[0055] 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 new delivery system, such as an emulsified drug delivery system, a bionic drug delivery system, a living cell delivery system, an exosome drug delivery system, a microneedle drug delivery system, a nano drug delivery system, or a protein or polypeptide delivery system.

[0056] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[0057] 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 microparticle 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 dripping pill, a pill, a powder, a granule, a suppository, a freeze-dried powder injection, an inclusion compound, an implant, a patch, etc.

[0058] The compounds according to the invention can be incorporated into the administration forms mentioned. This can be achieved in a known manner by mixing with pharmaceutically suitable carriers, excipients and / or other auxiliaries.

[0059] 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, still 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.

[0060] 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. Here, the term "active ingredient" refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof in the present invention.

[0061] plan According to one aspect of the present invention, the present invention provides a compound of formula (I) or a salt thereof, (I) in 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, carboxy-(C1-C8)-alkylcarbonyl, di-(C1-C8)-alkylamino or (C6-C 14 )-aryl-(C1-C8)-alkyl, wherein the heterocyclic group or heteroaryl 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.

[0062] In a preferred embodiment, wherein in formula (I), 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 hydroxyl, 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.

[0063] 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.

[0064] In a more preferred embodiment, wherein in formula (I), R each independently represents a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one nitrogen atom, wherein the heterocyclic group or heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: hydroxyl, 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.

[0065] In a further more preferred embodiment, wherein in formula (I), 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, wherein the heterocyclic group or heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: hydroxyl, 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.

[0066] In a particularly preferred embodiment, wherein in formula (I), R each 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 following: 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).

[0067] In a very particularly preferred embodiment, in which, in formula (I), 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.

[0068] 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.

[0069] Very particular preference is given to the compounds of the formula (I) according to the invention listed in Table 1 below.

[0070] Table 1: Compounds of formula (I) in which R has the meaning given below.

[0071]

[0072] Note:" " indicates connection with the carbonyl group of the compound of formula (I).

[0073] According to another aspect of the present invention, the present invention provides a method for preparing a compound of formula (I) as described above, the method comprising

[0074] 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 compounds of the general formula (II): RH (II) wherein R is as defined above.

[0075] 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.

[0076] 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 ...HATU). borate ester (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.

[0077] 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.

[0078] 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-butyloxycarbonylpiperazine, 3-(imidazolidin-1-yl)-3-oxopropionic acid, N,N-diethylpyrrolidin-3-amine.

[0079] 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: 2.5≤q / [np / (n+p)]≤4.5; Best 2.7≤q / [np / (n+p)]≤4.3; More preferred 2.9≤q / [np / (n+p)]≤4.1.

[0080] 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, and more preferably (0.9-2):1.

[0081] 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), and more preferably 1:(0.7-2).

[0082] 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.

[0083] According to the reaction requirements, the compound having a reactive hydrogen atom may optionally carry an amino protecting group commonly used in condensation reactions known to those skilled in the art, such as tert-butyloxycarbonyl (-Boc). The removal of the amino protecting group may be carried out by conventional methods known to those skilled in the art, such as 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.

[0084] 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 imidazoline-1-carboxylic acid tert-butyl ester or 1-tert-butyloxycarbonylpiperazine.

[0085] Preferably, the hydrogen chloride concentration of the hydrogen chloride-dioxane solution is 4 mol / L; in the reaction mixed solution, the molar ratio of the hydrogen chloride to the intermediate compound is 1:(0.001-0.5), preferably 1:(0.005-0.1), and more preferably 1:(0.006-0.06).

[0086] If present, the intermediate compound preferably has the structure shown in Table 2 below.

[0087] Table 2: Intermediate compounds

[0088] Note:" " indicates connection with the carbonyl group of the compound of formula (I).

[0089] 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, especially a combination of DIPEA and HATU in a specific ratio, and can obtain a target compound with high purity in a good yield through simple post-treatment. Too low or too high an amount of the catalyst or the condensing agent will have an adverse effect on the target product. For example, too high or too low an amount of the base will lead to difficulties in post-treatment, an increase in the proportion of by-products, and a low yield of the target product.

[0090] 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.

[0091] In the above method for preparing the compound of the present invention, 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, drying, etc. 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, infrared drying, vacuum drying, etc., preferably freeze drying.

[0092] In a preferred embodiment, 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 / methanol (elution gradient 100% / 0% to 50% / 50%, gradient elution time 20 min).

[0093] Unless explicitly stated otherwise, all operations were performed at room temperature; reagents used were either commercially available or prepared by methods known to those skilled in the art.

[0094] 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.

[0095] 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 (especially cervical cancer or cervical precancerous lesions).

[0096] 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, the subject is a mammal, more preferably a human.

[0097] 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.

[0098] 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 cancer, 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 solar keratosis, more preferably cervical precancerous lesions.

[0099] According to another aspect of the present invention, the present invention also provides the use of the 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.

[0100] In addition, the present invention also relates to a method for inhibiting Gram-negative or positive cocci, bacilli or coccobacilli, which comprises contacting a compound of formula (I) as described above or a salt thereof with Gram-negative or positive cocci, bacilli or coccobacilli and irradiating the compound with an effective amount of light of a specific wavelength. Preferably, the inhibition is for non-therapeutic purposes. The contact can be carried out in vivo or in vitro, for example, in vitro.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] More preferably, the disease or condition is selected from one or more of the following: swollen gums, bleeding gums, gum pain, bad breath, periodontal pocket formation, alveolar bone resorption and loose teeth.

[0105] 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 coccobacilli, Gram-negative aerobic bacilli or Gram-positive facultative anaerobic cocci.

[0106] In a preferred embodiment, the Gram-negative or Gram-positive cocci, bacilli or coccobacilli is Porphyromonas gingivalis ( Porphyromonas gingivalis ), Actinobacillus actinomycetemcomitans ( Actinobacillus actinomycetemcomitans ), Tannerella forsythiae ( Tannerella forsythia )、Fusobacterium nucleatum( Fusobacterium nucleatum ), Prevotella intermedia ( Prevotella intermedia ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ) or Staphylococcus aureus ( Staphylococcus aureus gingivalis); more preferably Porphyromonas gingivalis.

[0107] 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 positive cocci, bacilli or coccobacilli.

[0108] 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.

[0109] 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, 2J, 10 J, 20 J, 40 J, 60 J, 80 J, 100 J, 120 J, 150 J, 180 J, etc.

[0110] 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, 630 nm is preferred; when used to treat diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli, 405 nm is preferred.

[0111] Preferably, the optical power of the light irradiation is 30-1000 mW, preferably 60-600 mW, more preferably 80-300 mW.

[0112] 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.

[0113] 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.

[0114] 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 for treating diseases or conditions caused by Gram-negative or Gram-positive cocci, bacilli or coccobacilli.

[0115] In addition, the present invention also relates to a drug kit, which comprises a therapeutically effective amount of the compound of formula (I) or a salt thereof, or the pharmaceutical composition, and instructions for using it as a photosensitizer in photodynamic therapy.

[0116] In a preferred embodiment, the kit comprises a lyophilized preparation of a compound of formula (I) in a therapeutically effective amount; a dissolving matrix (such as water for injection or a gel matrix containing auxiliary materials such as a cosolvent, etc.) for reconstituting the lyophilized preparation for administration; and instructions for using the compound of formula (I) as a photosensitizer in photodynamic therapy.

[0117] The various components of the kit, such as the compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical preparation containing 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 may also include a device for assisting in administering the drug to the patient. The device may be a patch, an inhaler, a syringe, a pipette, a spoon with a measuring unit, or any delivery device approved for medical use.

[0118] 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.

[0119] In a preferred embodiment, the medicine also includes a pharmaceutically acceptable carrier, excipient and / or other adjuvants. When comprising a pharmaceutically acceptable carrier, excipient and / or other adjuvants, usually an effective dose of the compound of formula (I) or its salt and one or more pharmaceutically acceptable carriers, excipients and / or other adjuvants are combined to form a suitable form of administration or dosage form, and this procedure includes mixing, granulating, compressing, dissolving or lyophilizing the 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.

[0120] 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.

[0121] The NMR peaks reported in the synthetic examples are 1H NMR spectral data were obtained on a Bruker 400 MHz or 600 MHz NMR spectrometer and the signals listed have the meanings given below: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet, br s = broad singlet. The deuterated solvents used in each case are also specified in the table.

[0122] 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).

[0123] Unless otherwise expressly stated, the contents and percentages in the context of this application are based on weight; all operations are carried out at room temperature and normal pressure; the reagents or instruments used without indicating the manufacturer are all commercially available conventional products commonly used in the art.

[0124] A. Synthesis Examples Example 1: Synthesis of BLDT-1213 Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 2.5 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 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the target compound BLDT-1213 (97 mg, yield 78%) in the form of a black powder.

[0125] LC-MS (m / z): 701.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): 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).

[0126] Example 2: Synthesis of BLDT-1214 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. 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the intermediate BLDT-1214-01 (120 mg, yield 77%) in the form of a black powder.

[0127] 120 mg of the intermediate BLDT-1214-01 was added to 10 mL of 4 mol / L hydrogen chloride dioxane solution, stirred for 4 hours, concentrated under reduced pressure, and freeze-dried to obtain the target compound BLDT-1214 (90 mg, yield 98%) as a reddish-brown solid.

[0128] 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).

[0129] Example 3: Synthesis of BLDT-1216 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 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the target compound BLDT-1216 (120 mg, yield 84%) in the form of black powder.

[0130] 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).

[0131] Example 4: Synthesis of BLDT-1220 Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL DMF, and HATU (403 mg, 1.06 mmol, 3 equ) and DIPEA (276 mg, 2.14 mmol, 6 equ) were added in sequence. 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the target compound BLDT-1220 (267 mg, yield 87%) in the form of black powder.

[0132] 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).

[0133] Example 5: Synthesis of BLDT-1222 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 ( S )-2-benzylaziridine (71 mg, 0.53 mmol, 3 equ), after reacting 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%) in the form of a black powder.

[0134] 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).

[0135] Example 6: Synthesis of BLDT-2202 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. 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the intermediate BLDT-2202-01 (93 mg, yield 58%) in the form of a black powder.

[0136] 93 mg of the intermediate BLDT-2202-01 was added to 10 mL of 4 mol / L hydrogen chloride dioxane solution, stirred for 4 hours, concentrated under reduced pressure, and freeze-dried to obtain the target compound BLDT-2202 (68 mg, yield 94%) as a reddish-brown solid.

[0137] 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).

[0138] Example 7: Synthesis of BLDT-2203 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 (92 mg, 0.71 mmol, 4 equ) were added in sequence. 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 mixture 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, yield 65%) as a reddish-brown solid.

[0139] 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).

[0140] Example 8: Synthesis of BLDT-2210 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 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 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 100% / 0% to 90% / 10%, 15 min), and lyophilized to obtain the target compound BLDT-2210 (257 mg, yield 89%) as a reddish brown solid.

[0141] 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).

[0142] Comparative Example 1: Synthesis of BLDT-1220 The product was synthesized in a similar manner 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 give BLDT-1220 (130 mg, 42% yield).

[0143] B. Absorption spectroscopy and ROS production detection B-1. Absorption spectrum of the compound of the present invention In order to explore the optimal excitation wavelength of the drug, the absorption wavelengths of all compounds prepared by the method of the present invention were detected. The specific steps are as follows: Prepare the mother solution of dimethyl sulfoxide (brand: Shanghai Runjie Chemical Reagent Co., Ltd.) of the porphyrin derivative prepared in Example 1-8 with a concentration of 1 mg / mL, and then dilute it to 25 μg / mL with phosphate buffered saline (PBS, brand: gibico), take 4 mL of each and place it in a cuvette. Use an ultraviolet spectrophotometer (purchased from Shanghai Yuanxi Instrument Co., Ltd., model: X-8S) to scan the absorption spectrum of the solution in the cuvette at 300-700 nm. The reference solution is a PBS solution containing 25% DMSO.

[0144] like Figure 1 As shown, the absorption wavelengths of the compounds are similar, that is, they absorb energy at 405, 510, 540, 580 and 630 nm. In particular, the absorption energy is strongest near 405 nm. Based on the above results, it is determined that the excitation wavelengths of the series of porphyrin derivatives of the present invention are 405 nm and 630 nm.

[0145] B-2. Detection of ROS production of the compounds of the present invention In order 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: A PBS (brand: biosharp) solution of protoporphyrin, sodium chrysoporphyrin and the compound of the present invention was prepared at a concentration of 12.5 μg / mL. The drug was mixed with 4 μmol / L 9,10-anthracenediyl-bis(methylene)dicarboxylic acid (brand: Bid Pharmaceutical) in equal volumes and placed under 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 min, with an output power of 135 mW. After the irradiation, the optical density (OD) value was detected at 400 nm using a microplate reader (brand: biotek).

[0146] like Figure 2 As shown, 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 thiourea was also negligible (judged to be aggregation); in contrast, the compounds of the present invention all produced singlet oxygen, and compounds BLDT-1213, BLDT-1220, BLDT-1222, BLDT-2203, etc. had significant singlet oxygen production.

[0147] The above results indicate that the compounds of the present invention can be excited by 405 nm laser to generate singlet oxygen and have a light dose trend, and are potential high-efficiency photosensitizers.

[0148] C. Effect Example C-1. Antibacterial effect 1. Materials and Methods 1.1 Information on the drug to be tested Compounds of the present invention: BLDT-1213, BLDT-1214, BLDT-2202, BLDT-2203 and BLDT-2210; Positive drug 1: protoporphyrin (PPIX), purchased from Adams, catalog number 012080662; Positive drug 2: 5-aminolevulinic acid (5-ALA), purchased from Shanghai Bid Pharmaceutical, product number BD102341-5g.

[0149] 1.2 Experimental methods Porphyromonas gingivalis (purchased from Beijing Beina Chuanglian Biotechnology Research Institute, batch number BNCC353909) was revived and 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 bacterial solution was taken, the OD value was measured, and after centrifugation and discarding the supernatant, BHI medium was added to adjust the bacterial solution concentration to 10 10 CFU / mL (1 OD≈9.52*10 9 CFU / mL) for later use.

[0150] 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 is 10 μg / mL, and the final concentration of positive drug 2 is 80 μg / mL). Protect from light, culture under the same anaerobic conditions for 4 h, centrifuge and discard the supernatant, then resuspend with 1 mL of BHI medium, add the resuspended liquid to a 96-well plate, add 100 μL of bacterial solution to each well, and set 4 replicates each time. Illuminate under a 405 nm laser, the light power is 300 mW, the irradiation is 66.67 s, and the light dose is 20 J. After the illumination, continue to culture under the same anaerobic conditions for 24 h, then measure the OD value of each group of bacterial solution at 600 nm and calculate the inhibition rate.

[0151] 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.

[0152] 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.

[0153] Blank no-light group: The only difference from the blank light group is that there is no light treatment.

[0154] The antibacterial rate calculation formula is as follows:

[0155] 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.

[0156] 1.3 Calculation of statistical differences Data were analyzed using general one-way ANOVA 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 representing a significant decrease.

[0157] 2. Results and Discussion 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.

[0158] .

[0159] C-2. Anti-tumor effect The information of the drugs to be tested is as follows: Compounds of the present invention: BLDT-1213, BLDT-1214; Positive drug 1: protoporphyrin (PPIX), purchased from Adams, catalog number 012080662; Positive drug 2: 5-aminolevulinic acid (5-ALA), purchased from Shanghai Bid Pharmaceutical, catalog number BD102341-5g; Positive drug 3: 5-aminolevulinic acid hexyl ester (HAL) hydrochloride, purchased from Shanghai Bid Pharmaceutical, product number BD102340-250mg.

[0160] Example 1: In vitro efficacy evaluation of cervical cancer 1.1 Experimental Methods 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: HeLa human cervical cancer cells in logarithmic growth phase (purchased from Shanghai Fuheng Biotechnology, catalog number FH0314) were plated at 5×10 4 100 μL of cells (5×10 3 / well), and cultured in a 5% CO2 constant temperature incubator (purchased from Phcbi) at 37°C. After 24 hours, the 1640 culture medium (purchased from Shanghai Fuheng Biology, catalog number FH-R01) was removed. In a 96-well plate, 100 μL of culture medium containing different concentrations of drugs was added to the drug-treated group, and 100 μL of culture medium was added to the negative control group. Each experimental group has 4 replicates. Among them, the concentrations of PPIX and the compounds of the present invention are 0.0625, 0.125, 0.25, 0.5 and 1 μg / mL; the concentrations of 5-ALA are 334, 167, 83.5, 41.75 μg / mL; the concentrations of HAL are 120, 60, 30, 15, 7.5 μg / mL.

[0161] After incubation at 37°C in the dark for 4 hours, the cells were placed under a 630 nm semiconductor laser photodynamic therapy device (purchased from Guilin Xingda Optoelectronic Medical Equipment Co., Ltd., model PDT630-II) for illumination (light power of 200 mW, irradiation for 10 seconds, light dose of 2 J). Then, the cells were incubated in the dark for 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 Biology, model number FH-R1011) containing 10% CCK-8 (purchased from Lab Lead, model number 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 an enzyme reader (purchased from BioTek, model number: Synergy H1), and the cell viability was calculated using the following formula:

[0162] Wherein A is the average absorbance of each drug administration group, Ab is the absorbance of 1640 complete medium containing 10% CCK-8, and Ac is the average absorbance of the negative control group.

[0163] 1.2 Experimental Results The results are as follows Figure 4 As shown in Table 4, the results show that the compounds of the present invention (BLDT-1213 and BLDT-1214) have high cytotoxicity to Hela cells and are concentration-dependent; the cytotoxicity of protoporphyrin and the compounds of the present invention is significantly better than that of 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.

[0164] Table 4: IC values ​​of PPIX, HAL, 5-ALA and compounds of the present invention 50 value .

[0165] Example 2: Evaluation of drug efficacy on subcutaneous tumors of cervical cancer 2.1 Animal Experimental Methods (1) Animal vaccination 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%; light cycle: 12 hours of light, 12 hours of no light; animal identification: ear clipping). After the acclimation period, 0.2 mL (5.0×10 6 Hela cells (cells) in the logarithmic growth phase were subcutaneously inoculated on the right back of each mouse near the hind limb.

[0166] (2) Animal grouping and drug treatment After cell inoculation, when the tumor grew for 7 days, 42 mice with appropriate tumor size were selected and randomly divided into groups according to the tumor volume. The day of grouping was recorded as D0, and drug administration began. The drug solution was prepared according to Table 5, and each group was injected into the tumor once. After drug administration, a 630 nm semiconductor laser photodynamic therapy device was used for irradiation, with a light power of 100 mW, irradiation for 10 min, and a light dose of 60 J.

[0167] .

[0168] (3) Sample collection and testing indicators After group drug treatment, the length and width of the tumor were measured twice a week with 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: ; ; 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.

[0169] At the end of the experiment, mice in each group were euthanized, and tumor tissues were removed and weighed. 重量 (%). The specific calculation formula is as follows: ; 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.

[0170] (4) Data processing and statistical analysis Based on the data obtained at the end of the experiment, general one-way analysis of variance in GraphPad Prism 8 software was used for data analysis. P < 0.05 was considered to be statistically significant, among which *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 represented significant improvements.

[0171] 2.2 Experimental Results like Figure 5 As shown in (a), during the experiment, the overall body 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.

[0172] like Figure 5 As shown in (b), on the 14th day after administration, there was no significant difference in tumor volume between the illumination group and the negative control group, indicating that illumination alone 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.

[0173] The above experimental results show that under the same lighting conditions, compared with the negative control group, the compound (4 mg / kg) treatment group has a significant inhibitory effect on Hela subcutaneous tumors, among which the tumor growth inhibition rate (TGI) calculated based on the tumor volume of 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) in the PPIX (4 mg / kg) group, which was much higher than 31.7% (P<0.05) in the 5-ALA (60 mg / kg) group, 43.1% (P<0.001) in the 5-ALA (60 mg / kg) group, and 26.5% (P>0.05) in the HAL group. 重量 The percentages of 5-ALA group and 65.8% (P<0.0001) and 52.8% (P<0.01) in the PPIX group and the HAL group were much higher than 25.6% (P>0.05) in the PPIX group, 31.4% (P>0.05) in the 5-ALA group, and 32.1% (P>0.05) in the HAL group. Therefore, in terms of the overall tumor inhibition effect, the porphyrin derivatives of the present invention are significantly better than the drugs HAL and 5-ALA in terms of the overall tumor inhibition effect at a significantly smaller dosage.

Claims

1. A compound of formula (I) or a salt thereof, (I) in 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, carboxy-(C1-C8)-alkylcarbonyl, di-(C1-C8)-alkylamino or (C6-C 14 )-aryl-(C1-C8)-alkyl, wherein the heterocyclic group or heteroaryl 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 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 hydroxyl, 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.

3. The compound or salt thereof according to claim 1 or 2, wherein R each independently represents a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one nitrogen atom, wherein the heterocyclic group or heteroaryl group is unsubstituted or substituted by one or more substituents selected from the following: hydroxyl, 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.

4. The compound or salt thereof according to claim 1 or 2, wherein R each 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 following: hydroxy, cyano, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C3-C6)-cycloalkyl, (C1-C4)-haloalkyl, carboxy-(C1-C4)-alkylcarbonyl, di-(C1-C4)-alkylamino or phenyl-(C1-C4)-alkyl.

5. A method for preparing a compound of formula (I) according to any one of claims 1 to 4, the method 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 compounds of general formula (II) RH (II) wherein R is as defined in any one of claims 1 to 4.

6. The method according to claim 5, 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 condensation agent is (0.7-3):

1.

7. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a hyperproliferative disease: cancer or precancerous lesions.

8. The method of claim 7, wherein the cancer is 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 cancer, thyroid cancer, breast cancer, anal cancer, Kaposi's sarcoma, lung cancer, gastric cancer, bile duct cancer, prostate cancer, melanoma or brain cancer; The precancerous lesions are selected from cervical precancerous lesions, oral leukoplakia, myelodysplastic diseases, familial intestinal polyps, skin nevus, psoriasis or solar keratosis.

9. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a disease or condition caused by a Gram-negative or Gram-positive coccus, bacillus or coccobacillus.

10. The method according to claim 9, wherein the Gram-negative or Gram-positive cocci, bacilli or coccobacilli are Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Tannerella forsythiae, Fusobacterium nucleatum, Prevotella intermedia, Pseudomonas aeruginosa or Staphylococcus aureus.

11. The use according to claim 9, 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.

12. The use according to claim 7 or 9, wherein the compound of formula (I) or a salt thereof is used as a photosensitizer in photodynamic therapy.

13. The use according to claim 12, wherein in photodynamic therapy, the irradiation time of light irradiation is 10-2000 s; the light dose of light irradiation is 1-300 J; the wavelength range of light irradiation is 300-800 nm; and the light power of light irradiation is 30-1000 mW.

14. A method for inhibiting Gram-negative or Gram-positive cocci, bacilli or coccobacilli for non-therapeutic purposes, the method comprising contacting the compound of formula (I) or a salt thereof according to any one of claims 1 to 4 with Gram-negative or Gram-positive cocci, bacilli or coccobacilli and irradiating the contact with light of a specific wavelength in an inhibitory effective amount.

15. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 4, optionally further comprising one or more other active compounds.

16. A kit comprising a therapeutically effective amount of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 15, and instructions for using it as a photosensitizer in photodynamic therapy.

Images