CN113198117B

CN113198117B - Combination of chlorin derivatives and ultrasound medical systems

Info

Publication number: CN113198117B
Application number: CN202110478625.9A
Authority: CN
Inventors: 苏江安; 赵伟杰; Q·李; 王夏青; 于波
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-08-18
Filing date: 2021-04-29
Publication date: 2023-12-22
Anticipated expiration: 2041-04-29
Also published as: CN113198117A

Abstract

The present invention relates to a combination of a chlorin derivative or a pharmaceutically acceptable salt thereof having a structure of formula (I) and an ultrasound medical system comprising a transducer sound bed and a contact agent, wherein the transducer sound bed comprises a bottom portion and a wall portion extending upwardly from the bottom portion; the base has at least one ultrasonic transducer at positions corresponding to the head, torso and limbs of the subject, respectively, for emitting ultrasonic waves toward the subject located thereabove; the wall portion has at least one ultrasonic transducer at its positions corresponding to the head and limbs of the subject, respectively, for emitting ultrasonic waves toward the subject; the contact agent is for transmitting ultrasound between the target and the ultrasound transducer. The invention also relates to a method for preparing chlorin derivatives or pharmaceutically acceptable salts thereof.

Description

Combination of chlorin derivatives and ultrasound medical systems

Technical Field

The invention belongs to the field of biomedical treatment; more particularly, the present invention relates to a combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and an ultrasound medical system for the omnidirectional treatment of a patient.

Background

Photodynamic therapy (Photodynamic therapy, PDT) and photodynamic therapy (Sonodynamic therapy, SDT) are modern medical techniques in which a photosensitizer (photosensitizer) or sonosensitizer (sonosizer), respectively, is stimulated by light or ultrasound power to initiate a biochemical reaction to kill tumor cells.

Photodynamic therapy (PDT) is a new method for treating tumors or diseases by photosensitizing drugs and laser activation, which is to generate singlet oxygen by irradiation of photosensitizers at specific wavelengths in the presence of oxygen ¹ O ₂ ) And free radicals, etc. react to kill tumor cells. Compared with the traditional treatment methods such as surgery, chemotherapy, radiotherapy and the like, PDT has the advantages of small side effect on organisms, no damage to internal organs and the like, but has no great effect on treatment of deep tumors in the body. At present, certain photosensitive compounds have an ultrasonic sensitivity effect in experimental research.

Photodynamic therapy (SDT) is a new therapy developed on the basis of photodynamic therapy (PDT) for clinical treatment of malignant and deep tumours. The ultrasonic wave has the characteristics of penetration of organism, no wound, no invasion and the like. The used sound sensitive molecules have tumor tissue targeting, are like molecular machines, respond after being given with ultrasonic power, and operate efficiently to play an anti-tumor effect. Ultrasonic wave is used as power to form ultrasonic cavitation at the tumor part enriched by the sound sensitive medicament, generate singlet oxygen with tumor cell killing power, biochemical reaction and the like, trigger apoptosis or death of tumor cells, and have superposition effects on chemotherapy, photodynamic therapy and the like. Compared to photodynamic therapy, sonodynamic therapy has the following advantages: 1. the external ultrasonic treatment device not only can treat superficial tumors on the body surface of a human body, but also can treat deep tumors on any part of the human body, does not need to pass through an endoscope for treating the deep tumors, adopts external ultrasonic irradiation during treatment, and causes no pain to patients; 2. after the treatment of the patient, the patient does not need to be protected from light, and the treatment can be repeated at any time; 3. can effectively prevent malignant tumor metastasis, and is an effective way for killing malignant tumor.

The acoustic sensing agent reported so far has the defects of large difference of selectivity to tumor cells, narrow treatment window, poor solubility under physiological conditions, slower in vivo clearance rate, difficulty in embodying clinical value and the like. In addition, when the acoustic power treatment is carried out at present, the adopted treatment system has single structure and small volume, can only act on the local part of a patient, can not carry out the omnibearing treatment on the patient, and can not effectively kill the very small malignant tumor which has lesions in the human body and is not detected by the prior medical equipment and instruments. Thus, for patients whose malignant tumor has developed systemic metastasis, or for patients whose malignant tumor is developing systemic metastasis after cancer surgery, the existing therapeutic system cannot perform timely and effective treatment. Because the existing ultrasonic treatment systems are all single-head transducers and focus on different parts of the same patient, doctors cannot simultaneously treat and select the ultrasonic transducers according to the treatment requirement. Moreover, the single-head ultrasonic transducer is adopted to carry out whole-body treatment on the patient, and the continuous operation can be completed for more than tens of hours, so that the workload of doctors is greatly increased, the treatment time which the patient cannot bear is caused, and the optimal treatment time is also missed. Therefore, medical professionals want a device which can fully radiate the human body to expel the dry body, and the energy exceeds the energy of light, so that the deep part of the human body can be reached, and the medicine can be activated to kill cancer cells in the deep part of the human body.

Therefore, there is a need to develop a sonosensitizer with good water solubility, and use the combination of the sonosensitizer and the ultrasound medical system to perform an omnidirectional photodynamic therapy on a patient, so as to promote the development of the photodynamic therapy.

Disclosure of Invention

In view of the above, the present invention contemplates a combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and an ultrasound medical system for the omnidirectional photodynamic treatment of a patient. Specifically, according to the combination, the patient can take the chlorin derivative or the pharmaceutically acceptable salt thereof, and then in the process of carrying out omnibearing acoustic power treatment on the patient, the treatment parameters of the ultrasonic transducer at each part are modified at any time according to the treatment needs of each part of the body of the patient and the feeling of the patient, so that the ultrasonic medical system with the optimal curative effect is achieved.

According to a first aspect of the present invention there is provided a combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and an ultrasound medical system, said chlorin derivative or pharmaceutically acceptable salt thereof having the structure shown in formula (I):

wherein,

R ₁ the method comprises the following steps:

wherein R is ₁₄ is-H, C ₁ -C ₆ Alkoxy or C ₁ -C ₄ A haloalkyl group; or (b)

Wherein n is any integer from 2 to 7;

R ₂ is thatC ₁ -C ₆ Alkoxy or-OH, wherein R ₈ Is any one of the following groups:

wherein R is ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And R is ₁₃ May be the same or different and are each independently selected from C ₁ -C ₆ Alkyl group, and

at R ₂ Is thatWhen R is ₃ And R is ₄ Each independently is C ₁ -C ₆ Alkoxy or-OH;

at R ₂ Is C ₁ -C ₆ In the case of alkoxy or-OH, R ₃ And R is ₄ One of which is any one of the following groups:

wherein R is ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And R is ₁₃ As defined above,

and R is ₃ And R is ₄ Another one of them is C ₁ -C ₆ Alkoxy or-OH;

m is 2H or a metal ion, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ² ⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴⁺ ；

The ultrasound medical system includes a transducer acoustic bed and a contact agent, wherein the transducer acoustic bed includes a bottom portion and a wall portion extending upwardly from the bottom portion; the base has at least one ultrasonic transducer at positions corresponding to the head, torso and limbs of the subject, respectively, for emitting ultrasonic waves toward the subject located thereabove; the wall portion has at least one ultrasonic transducer at its positions corresponding to the head and limbs of the subject, respectively, for emitting ultrasonic waves toward the subject; the contact agent is for transmitting ultrasound between the target and the ultrasound transducer.

The invention has the beneficial effects that:

the omnibearing ultrasonic medical system provided by the invention effectively solves the problem of death of tumor patients, especially malignant tumor patients, caused by tumor diffusion and metastasis, can omnibearing irradiate ultrasonic waves of a human body, not only can reach deep tissues of the human body, but also can penetrate the human body, and can successfully activate the sonosensitizer medicament chlorin derivative or pharmaceutically acceptable salt thereof to kill tumors of various parts of the human body.

In addition, the invention can flexibly select the working parameters of the ultrasonic transducer in the acoustic power treatment process, thereby increasing the convenience of doctors in treatment and greatly shortening the treatment time of patients. The invention uses in vitro ultrasound to kill malignant tumor without damaging normal tissue, with good selectivity and little side effect.

In addition, the chlorin derivative and the corresponding medicinal salt are obtained by modifying the chlorin e6, the water solubility of the chlorin e6 is greatly improved while the chlorin e6 is reserved as a sound sensitizer, and the chlorin derivative or the medicinal salt can act as an injection.

Drawings

In order to more clearly illustrate the examples of the invention or the technical solutions of the prior art, the drawings used in the examples will be briefly described below, it being obvious that the drawings in the following description are only examples of the invention and that other embodiments can be obtained according to these drawings without inventive effort for a person skilled in the art.

Fig. 1 is a bar graph showing the weight effect of compound 9-BA (Pd) treatment and ultrasound kinetic treatment according to the invention, alone or in combination, on tumor tissue in primary breast cancer mice (P < 0.01-0.001).

Fig. 2 is a photograph showing the inhibition of lung metastasis of primary breast cancer by the compound 9-BA (Pd) treatment and ultrasound dynamic treatment according to the present invention, alone or in combination.

Fig. 3 is a photograph showing the inhibitory effect of the compound 17-MPA treatment and ultrasonic dynamic treatment according to the present invention on hepatic metastasis of colorectal cancer tumor alone or in combination.

Fig. 4 is a bar graph (P < 0.01-0.001) showing the effect of compound 17-MPA treatment and ultrasound power treatment according to the invention, alone or in combination, on mouse liver weight.

Fig. 5 shows a top view of a transducer acoustic bed 1 according to an embodiment of the invention.

Fig. 6 shows a top view of a transducer acoustic bed 2 according to another embodiment of the invention.

Fig. 7 shows a side view of a transducer module 3 according to an embodiment of the invention.

Fig. 8 shows a side view of a transducer module 4 with a two-dimensional numerically controlled movement means according to another embodiment of the invention.

Fig. 9 shows a top view of an ultrasound medical system 100 according to one embodiment of the invention.

Fig. 10 shows a top view of an ultrasound medical system 300 according to another embodiment of the invention.

Fig. 11 shows a block diagram of an ultrasound medical system 500 with a PLC automatic control system according to yet another embodiment of the present invention.

Fig. 12 shows a transducing head of an ultrasound transducer 8 according to an embodiment of the invention.

Fig. 13 shows a flowchart of the operation of the ultrasound medical system 100 according to one embodiment of the present invention.

Fig. 14 shows a flowchart of the operation of an ultrasound medical system 300 according to another embodiment of the present invention.

Fig. 15 shows a flowchart of the operation of an ultrasound medical system 500 with a PLC automatic control system according to yet another embodiment of the present invention.

Fig. 16 shows a man-machine interface of a main screen of the PLC automatic control system according to the present invention.

Fig. 17 illustrates a human-machine interface for patient treatment area selection of a PLC automatic control system in accordance with the present invention.

Fig. 18 shows a man-machine interface of the operation mode and sound intensity setting of the PLC automatic control system according to the present invention.

Fig. 19 shows lesion information generated by an ultrasound medical system according to the present invention.

Detailed Description

The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments that can be obtained by a person skilled in the art based on the embodiments of the present invention are within the scope of the present invention.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. In the present invention, illustrative examples of the "alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

The term "haloalkyl" as used herein refers to a group formed by substitution of one or more hydrogen atoms in an alkyl group with a halogen such as F, cl, br, I. "haloalkyl" according to the present invention includes fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl groups, depending on the kind of halogen atom. "haloalkyl" according to the present invention includes monohaloalkyl, dihaloalkyl, polyhaloalkyl, depending on the number of halogen atoms. In the present invention, illustrative examples of "haloalkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-n-butyl and the like.

The term "alkoxy" as used herein refers to a group having a specified number of carbon atoms in which a straight or branched chain alkyl group is attached to oxygen and through oxygen to the rest of the molecule. Examples of "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.

The term "substituted terminal alkene" as used herein refers to an alkene having a carbon-carbon double bond (-c=c-) at the terminal end. In the present invention, examples of the "substituted terminal ene" include propylene, 1-hexene, p-methoxystyrene, p-trifluoromethylstyrene and the like.

In sonodynamic therapy, sonosensitizers play an important role as a bridge to the response. In the field of sonodynamic therapy of tumors, chlorin e6 is an important sonosensitizer, which is one of chlorophyll degrading derivatives, with ideal sonodynamic effect on tumors. The chlorin e6 serving as a sound sensitizer has the advantages of high tumor specific aggregation, high tumor part absorption speed, high in vivo clearance speed, small toxic and side effects and the like. Meanwhile, chlorin e6 has the disadvantages of poor water solubility, relatively low activity and the like when being used as a sound sensitizer. The invention improves the sound power activity, water solubility and the like of the chlorin e6 structure by modifying some functional groups.

Accordingly, the present invention provides a combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and an ultrasound medical system, said chlorin derivative or pharmaceutically acceptable salt thereof having the structure shown in formula (I):

wherein,

R ₁ the method comprises the following steps:

Wherein n is any integer from 2 to 7;

at R ₂ Is C ₁ -C ₆ R in the case of alkoxy or-OH ₃ And R is ₄ One of which is any one of the following groups:

and R is ₃ And R is ₄ Another one of them is C ₁ -C ₆ Alkoxy or-OH;

In the present invention,r represents ₁₄ May be a substituent at any position on the phenyl group, such as ortho, meta or para. Preferably, R ₁₄ Is a para substituent.

In the present invention, C ₁ -C ₆ Alkoxy refers to a group obtained by linking a straight or branched alkyl group having 1 to 6 carbon atoms to an oxygen atom. Thus, in the structure shown in formula (I), R is ₁₄ 、R ₂ 、R ₃ 、R ₄ Is C ₁ -C ₆ In the case of the alkoxy group, it may be specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, or the like. Preferably, R ₁₄ 、R ₂ 、R ₃ 、R ₄ Is methoxy (-OCH) ₃ )。

In the present invention, C ₁ -C ₄ Haloalkyl refers to a straight or branched alkyl group having 1 to 4 carbon atoms, and wherein one or more hydrogen atoms are replaced with a halogen such as F, cl, br, I. Thus, in the structure shown in formula (I), R is ₁₄ Is C ₁ -C ₄ In the case of haloalkyl, for example, it may be monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoro-n-propyl, trifluoro-n-butyl, etc. Preferably, R ₁₄ Is trifluoromethyl (-CF) ₃ )。

In the present invention,refers to a straight chain alkyl group having n carbon atoms, where n is any integer from 2 to 7, e.g., 2, 3, 4, 5, 6, 7. Thus, in the structure shown in formula (I), R is ₁₄ Is->In the case of ethyl, n-propylA group, n-butyl, n-pentyl, n-hexyl, n-heptyl. Preferably, R ₁₄ Is butyl.

In the present invention, the pharmaceutically acceptable salt of the chlorin derivative is a sodium or potassium salt corresponding to the carboxylate in the chlorin derivative, or any other suitable pharmaceutically acceptable salt form.

In one embodiment, the chlorin derivative or a pharmaceutically acceptable salt thereof is:

wherein,

R ₁ is thatOr->Wherein n is any integer from 2 to 7,

R ₃ 、R ₄ and R is ₈ Is any one of the following groups:

wherein R is ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And R is ₁₃ As defined above;

m is as defined above.

wherein M is as defined above.

By "sonosensitizer" is meant a substance that is activated under ultrasonic radiation and after activation reacts in series with surrounding oxygen molecules to produce an active substance with high oxidative activity, such as singlet oxygen. Singlet oxygen is an oxygen free radical with strong activity, has cytotoxicity, is most sensitive to cell membrane, mitochondria and other parts, can act with various biological macromolecules in cells, and can cause damage to a cell membrane system through combination with molecules.

In practice, sonosensitizers are often used in sonodynamic therapy. Acoustic power therapy is a new method for treating tumor diseases by using acoustic sensitizers and ultrasonic waves. The treatment utilizes the characteristics of strong penetrating power of ultrasonic waves in biological tissues, no wound and accurate focusing of ultrasonic waves to transfer energy, transfers the energy to tumor parts, activates the sound sensitive agent which is specifically combined with the tumor tissues in advance, and initiates chemical reaction to generate chemical energy, thereby damaging the tumor and achieving the aim of further improving the survival rate of the tumor.

As described above, the chlorin derivative or a pharmaceutically acceptable salt thereof of the present invention is obtained by modifying the structure of chlorin e6 in order to obtain a chlorin derivative having further improved properties (e.g., stronger tumor selectivity, good water solubility) relative to chlorin e6, and the improved properties are further confirmed in the examples below, while the original sound sensitive properties of chlorin e6 are still maintained. Thus, the chlorin derivative of the present invention or a pharmaceutically acceptable salt thereof can be used in sonodynamic therapy.

In one embodiment, the ultrasound medical system further comprises a transducer module, wherein the transducer module is mounted above the transducer acoustic bed, comprising at least one ultrasound transducer for emitting ultrasound waves towards a target located therebelow, the contact agent also being for transmitting ultrasound waves between the target and the at least one ultrasound transducer.

In one embodiment, the transducer module further comprises a digitally controlled movement device for controlling the transducer module to move in a horizontal and/or vertical direction.

In one embodiment, the ultrasonic wave is a pulsed wave or a continuous wave.

In one embodiment, the ultrasonic frequency is 0.3-3MHz; preferably, the sound intensity of the ultrasonic wave is 0.1-3W/cm ² 。

In one embodiment, the contact agent is at least one of water and vacuum degassing cold/hot water.

In one embodiment, the ultrasound medical system further comprises a programmable logic controller automatic control system and a contact agent supply system, wherein the contact agent supply system is connected to the transducer acoustic bed for supplying contact agent to the transducer acoustic bed; the programmable logic controller automatic control system is respectively connected with the transducer sound bed, the transducer module and the contact agent supply system, and is used for controlling the contact agent supply system to supply the contact agent to the transducer sound bed and controlling the operation of at least one part of ultrasonic transducers in the transducer sound bed and the transducer module.

In one embodiment, the programmable logic controller automatic control system further comprises a monitoring system for displaying at least one of: a. working parameters of at least a part of ultrasonic transducers in the transducer sound bed and the transducer module; b. lesion information within the target.

In one embodiment, the chlorin derivative or a pharmaceutically acceptable salt thereof is prepared by a process comprising:

a ₁ : esterifying compound 1, namely chlorin e6, with an alcohol to give compound 2:

/>

b ₁ : under the action of condensing agent, the compound 2 and beta-alanine tert-butyl ester hydrochloride (H-beta-Ala-OtBu. HCl) are subjected to condensation reaction to obtain a compound 3:

c ₁ : by reacting compound 3 with a substituted terminal alkene under the action of a catalystMetathesis of olefins occurs, yielding compound 4:

wherein R is ₁ Is thatWherein n is any integer from 2 to 7;

d ₁ : the compound 4 undergoes hydrolysis reaction to obtain a compound 5:

e ₁ : under the action of condensing agent, compound 5 and amino acid ester hydrochloride undergo condensation reaction to obtain compound of formula II (a):

wherein M is 2H, or is a metal ion upon reaction with a metal chloride or acetate complex, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ²⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴ ⁺ Wherein R is ₈ As defined above;

optionally, subjecting the compound of formula II (a) to hydrolysis under basic conditions to form the corresponding salt, i.e. the compound of formula II (b);

or (b)

a ₂ : reacting compound 1, chlorin e6, with an alkyl halide under basic conditions to provide compound 10:

b ₂ : compound 10 and substituted terminal alkene under the action of catalystMetathesis of olefins occurs, yielding compound 11:

/>

wherein R is ₁ Is thatWherein n is any integer from 2 to 7;

wherein M is 2H, or is a metal ion upon reaction with a metal chloride or acetate complex, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ²⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴ ⁺ ；

c ₂ : subjecting compound 11 to hydrolysis reaction under basic conditions to give compound 13:

d ₂ : condensing compound 13 with an amino acid ester hydrochloride to give a compound of formula III (a):

wherein M is 2H, or is a metal ion upon reaction with a metal chloride or acetate complex, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ²⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴ ⁺ Wherein R is ₃ As defined above;

optionally, under alkaline conditions, the compound of formula III (a) undergoes a hydrolysis reaction to form the corresponding salt, i.e., the compound of formula III (b);

or (b)

a ₃ Under the action of condensing agent, compound 19 and amino acid ester hydrochloride undergo condensation reaction to obtain compound 20:

b ₃ : by reacting compound 20 with a substituted terminal alkene under the action of a catalystMetathesis of the olefin occurs to give a compound of formula IV (a):

Wherein R is ₁ Is thatWherein n is any integer from 2 to 7,

wherein M is 2H, or is a metal ion upon reaction with a metal chloride or acetate complex, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ²⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴ ⁺ Wherein R is ₄ As defined above;

optionally, the compound of formula IV (a) undergoes hydrolysis under basic conditions to form the corresponding salt, i.e. IV (b) compound.

According to a preferred embodiment of the present invention, in the process for preparing a chlorin derivative or a pharmaceutically acceptable salt thereof, step a ₁ In the process, chlorin e6 and methanol are subjected to esterification reaction in 5% solution of methanol sulfate (MeOH) to obtain a compound 2.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step b ₁ The reaction solvent is Dimethylformamide (DMF), and the condensing agent is benzotriazole-N, N, N ', N' -tetramethylurea Hexafluorophosphate (HBTU) or N, N-Diisopropylethylamine (DIEA). In a further preferred embodiment, the molar ratio of compound 2 to HBTU, DIEA, β -alanine tert-butyl ester hydrochloride is 1:1-2:2-5:2-3.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step c ₁ The Catalyst was Grabbs Catalyst (Grubbs' Catalyst), and the reaction solvent was Dichloromethane (DCM). In a further preferred embodiment, the molar ratio of compound 3 to substituted terminal alkene is from 1:10 to 30.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step d ₁ In trifluoroacetic acid (TFA) in Dichloromethane (DCM). In a further preferred embodiment, the volume fraction of the solution is 20% -30%. In a still further preferred embodiment, the volume fraction of the solution is 25%.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step e ₁ Wherein the amino acid ester hydrochloride is amino acid methyl ester hydrochloride, and the reaction solvent isDMF, condensing agent is HBTU and DIEA. In a further preferred embodiment, the amino acid methyl ester hydrochloride may be aspartic acid methyl ester hydrochloride, serine methyl ester hydrochloride, lysine methyl ester hydrochloride or histidine methyl ester hydrochloride. In a further preferred embodiment, compound 5 is dissolved in DMF, HBTU and DIEA are added, followed by stirring and then the amino acid methyl ester hydrochloride and DIEA are added and the reaction is continued to give compound 6. In a still further preferred embodiment, the molar ratio of compound 5 to HBTU, DIEA, amino acid ester hydrochloride is 1:1-2:2-5:2-3.

According to a preferred embodiment of the present invention, in the process for preparing a chlorin derivative or a pharmaceutically acceptable salt thereof, step a ₂ In (2) dissolving chlorin in DMF, adding methyl iodide and anhydrous potassium carbonate, and reacting to obtain a compound 10. In a further preferred embodiment, chlorins: an alkyl halide: the molar ratio of the anhydrous potassium carbonate is 1:2-10:2-10.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step b ₂ The catalyst is a Grabbs catalyst, and the reaction solvent is DCM. In a further preferred embodiment, the molar ratio of compound 10 to substituted terminal alkene is from 1:10 to 30.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step c ₂ The reaction solution is tetrahydrofuran and KOH aqueous solution. In a further preferred embodiment, the concentration of the aqueous KOH solution is 1M. In a further preferred embodiment, the volume ratio of tetrahydrofuran to 1M aqueous KOH solution is 1:1.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step d ₂ Wherein the amino acid ester hydrochloride is amino acid methyl ester hydrochloride, the reaction solvent is DMF, and the condensing agent is 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) and DIEA. In a further preferred embodiment, compound 13: EDCI: amino groupAcid ester hydrochloride: the molar ratio of DIEA is 1:1-2:1-2:0.1-0.5.

According to a preferred embodiment of the present invention, in the process for preparing a chlorin derivative or a pharmaceutically acceptable salt thereof, step a ₃ Wherein the amino acid ester hydrochloride is amino acid methyl ester hydrochloride, the reaction solvent is DMF, and the condensing agent is HBTU or DIEA. In a further preferred embodiment, compound 19 is dissolved in DMF, HBTU and DIEA are added, followed by stirring and then the amino acid methyl ester hydrochloride and DIEA are added and the reaction is continued to give compound 20. In a further preferred embodiment, the molar ratio of compound 19 to HBTU, DIEA, amino acid ester hydrochloride is 1:1-2:2-5:2-3.

According to a preferred embodiment of the present invention, in said process for the preparation of a chlorin derivative or a pharmaceutically acceptable salt thereof, in step b ₃ The catalyst is a Grabbs catalyst, and the reaction solvent is DCM. In a further preferred embodiment, the molar ratio of compound 20 to substituted terminal alkene is from 1:10 to 30.

In an optional embodiment, compounds of formula II (a), formula II (b), formula III (a), formula III (b), formula IV (a) or formula IV (b) wherein M is in the form of 2H may be prepared by reaction with a metal chloride or acetate complex to give the corresponding compound wherein M is in the form of a metal ion.

In another optional embodiment, the compound of formula II (a), formula III (a), or formula IV (a) may undergo hydrolysis under basic conditions to yield the corresponding salt form, i.e., the compound of formula II (b), formula III (b), or formula IV (b).

As mentioned above, the salt form may be a sodium or potassium salt, or any other suitable pharmaceutically acceptable salt form.

Of course, in each step of the above preparation method, other solvents, solutions, condensing agents, catalysts, etc. known in the art to be capable of achieving the above reaction may be used, and the present invention is not limited thereto.

In a specific embodiment, the method of preparing a chlorin derivative or a pharmaceutically acceptable salt thereof comprises the steps of:

a ₁ : the preparation method comprises the steps of taking self-made compound 1-Chlorin e6 (Chenghai Chlorin, CHC, equivalent commercial Chlorin e 6) as a raw material, dissolving the raw material in 5% sulfuric acid methanol solution with the concentration of 0.1M, carrying out reduced pressure concentration after reacting for 10 hours, diluting the obtained acid liquor with an equal volume of DCM, washing the diluted acid liquor with water for multiple times to remove sulfuric acid, collecting an organic phase, drying and concentrating to obtain a compound 2;

b ₁ : dissolving the compound 2 in DMF with the concentration of 0.1M, adding HBTU and DIEA, stirring for 0.5-1 hour, sequentially adding beta-alanine tert-butyl ester hydrochloride and DIEA, wherein the molar ratio of the compound 2 to the HBTU, the DIEA and the beta-alanine tert-butyl ester hydrochloride is 1:1-2:2-5:2-3, continuing to react for 1-2 hours, adding DCM to dilute the reaction solution after the reaction is finished, washing for multiple times, collecting an organic phase, concentrating, and performing silica gel column chromatography to obtain the compound 3;

c ₁ : dissolving the compound 3 and 10-30 times of substituted terminal alkene in DCM with the concentration of 0.02-0.1M, adding a Grabbs catalyst, carrying out reflux reaction for 16-24 hours, filtering the reaction solution, transferring the filtrate into a separating funnel, washing with water solution for multiple times, collecting an organic phase, concentrating, and carrying out silica gel column chromatography to obtain a series of compounds 4;

d ₁ : dissolving the compound 4 in a DCM solution of 25% TFA with the concentration of 0.1M, stirring and reacting for 2-5 hours, concentrating the reaction solution, dissolving the residue in DCM, washing with water, collecting an organic phase, and concentrating to obtain a series of compounds 5;

e ₁ : dissolving a compound 5 in DMF (dimethyl formamide) with the concentration of 0.1M, adding HBTU and DIEA, stirring and reacting for 0.5-1 hour, adding selected amino acid methyl ester hydrochloride and DIEA, wherein the molar ratio of the compound 5 to the HBTU, the DIEA and the amino acid methyl ester hydrochloride is 1:1-2:2-5:2-3, continuing to react for 1-2 hours, adding DCM (DCM) to dilute a reaction solution after the reaction is finished, washing for multiple times, collecting an organic phase, concentrating, and performing silica gel column chromatography to obtain a compound 6 which is a chlorin derivative shown as a formula (I), wherein M is 2H;

e ₁₁ : dissolving compound 6 in DCM at a concentration of 0.1M, adding chloride or acetate complex of the selected metal, wherein compound 6 is mixed with the metal chloride or acetate complexThe molar ratio of the acetate complex is 1:1-6, the reaction is heated and refluxed for 2-8 hours, the reaction liquid is washed with water, the organic layer is collected, and the corresponding compound 7 is obtained by concentration, wherein M is a metal ion as defined above;

f ₁ : dissolving the compound 6 in acetone with the concentration of 0.03M, adding an equal volume of 0.5N NaOH or KOH aqueous solution, stirring and reacting for 2-10 hours, adding absolute ethyl alcohol into the reaction solution, separating out solid, and filtering to obtain a compound 8, namely a sodium salt or potassium salt form of carboxylic acid corresponding to the compound 6, wherein M is 2H;

f ₁₁ : compound 7 prepared above is used as a raw material, and compound 9 is synthesized according to the synthesis method of compound 8, namely, a sodium salt or potassium salt form of carboxylic acid corresponding to compound 7, wherein M is a metal ion as defined above.

Here, compounds 6 and 7 are compounds of formula II (a), and compounds 8 and 9 are compounds of formula II (b).

In the preparation method, the specific reaction process is as follows:

wherein,

R ₁ is thatWherein n is any integer from 2 to 7;

R ₈ Is any one of the following groups:

wherein R is ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ And R is ₁₃ May be the same or different and are each independently selected from C ₁ -C ₆ An alkyl group;

m is 2H or a metal ion, e.g. a divalent metal ion such as Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ 、Pd ² ⁺ Or tetravalent metal ions such as Sn ⁴⁺ Or Ti (Ti) ⁴⁺ 。

In another specific embodiment, the method of preparing a chlorin derivative or a pharmaceutically acceptable salt thereof comprises the steps of:

a ₂ : compound 1-chlorin e6 was dissolved in DMF at a concentration of 0.1M, methyl iodide and anhydrous potassium carbonate were added, wherein compound 1: methyl iodide: the molar ratio of the anhydrous potassium carbonate is 1:2-10:2-10, stirring and reacting for 1-4 hours, diluting the reaction solution with DCM, washing with water, collecting an organic phase, concentrating, and performing silica gel column chromatography to obtain a compound 10;

b ₂ : dissolving the compound 10 and 10-30 times of substituted terminal alkene in DCM (molar ratio) at a concentration of 0.02-0.1M, adding a Grabbs catalyst, carrying out reflux reaction for 16-24 hours, filtering the reaction solution, transferring the filtrate into a separating funnel, washing with water, collecting an organic phase, concentrating, and carrying out silica gel column chromatography to obtain a series of compounds 11, wherein M is 2H;

b ₂₁ : dissolving the compound 11 in DCM with the concentration of 0.1M, adding chloride or acetate complex of selected metal, wherein the molar ratio of the compound 11 to the metal chloride or acetate complex is 1:1-6, heating and refluxing for 2-8 hours, washing the reaction solution with water, collecting an organic layer, and concentrating to obtain a corresponding compound 12, wherein M is metal ions as defined above;

c ₂ : dissolving the compound 11 in a volume ratio of THF to 1M aqueous solution of KOH with the concentration of 0.05M, reacting for 2-5 hours, concentrating under reduced pressure to remove the THF, adding water to dilute the rest alkali liquor, adjusting the pH to 5-6, separating out solids, and filtering to obtain a series of compounds 13, wherein M is 2H;

d ₂ : compound 13 was dissolved in DMF at a concentration of 0.1M, and EDCI, amino acid methyl ester hydrochloride, triethylamine (Et) ₃ N) and DIEA, compound 13: EDCI: amino acid methyl ester hydrochloride: the molar ratio of DIEA is 1:1-2:1-2:0.1-0.5, stirring and reacting for 0.5-2 hours, adding aqueous solution of formic acid, separating out the product, and passing throughFiltering and silica gel column chromatography to obtain a series of compounds 15, wherein M is 2H;

e ₂ : dissolving compound 15 in acetone with the concentration of 0.03M, adding an equal volume of 0.5N NaOH or KOH aqueous solution, stirring and reacting for 2-10 hours, adding absolute ethyl alcohol into the reaction solution, separating out solid, and filtering to obtain a series of compounds 17, namely, sodium salt or potassium salt forms of carboxylic acid corresponding to the compound 15, wherein M is 2H;

e ₂₁ : compounds 16 and 18 were synthesized according to the synthesis method of compounds 15 and 17 starting from compound 12 prepared as described above, wherein compound 18 was in the form of the sodium or potassium salt of the carboxylic acid corresponding to compound 16, and wherein M was a metal ion as defined above.

Here, compounds 15 and 16 are compounds of formula III (a), and compounds 17 and 18 are compounds of formula III (b).

In the preparation method, the specific reaction process is as follows:

wherein,

R ₁ is thatWherein n is any integer from 2 to 7;

R ₃ is any one of the following groups:

In yet another specific embodiment, the method of preparing a chlorin derivative or a pharmaceutically acceptable salt thereof comprises the steps of:

a ₃ dissolving a compound 19 in DMF (dimethyl formamide) to obtain a solution with the concentration of 0.1M, adding HBTU and DIEA, stirring and reacting for 0.5-1 hour, adding selected amino acid methyl ester hydrochloride and DIEA, continuing to react for 1-2 hours, wherein the molar ratio of the compound 19 to the HBTU, the DIEA and the amino acid methyl ester hydrochloride is 1:1-2:2-5:2-3, diluting the reaction solution with DCM, washing with water, concentrating, dissolving the obtained residue in a 1% methanol solution of sodium methoxide, stirring and reacting for 5-10 hours, adjusting the pH value to be 6-7, concentrating under reduced pressure to remove methanol, washing with water after the residue is dissolved in the DCM, collecting an organic phase, concentrating, and performing silica gel column chromatography to obtain a series of compounds 20;

b ₃ : dissolving the compound 20 and 10-30 times of substituted terminal alkene in DCM (molar ratio) at a concentration of 0.02-0.1M, adding a Grabbs catalyst, carrying out reflux reaction for 16-24 hours, filtering the reaction solution, transferring the filtrate into a separating funnel, washing with aqueous solution for multiple times, collecting an organic phase, concentrating, and carrying out silica gel column chromatography to obtain a series of compounds 21, wherein M is 2H;

b ₃₁ : dissolving compound 21 in DCM at a concentration of 0.1M, adding chloride or acetate complex of selected metal, wherein the molar ratio of compound 21 to metal chloride or acetate complex is 1:1-6, heating and refluxing for 2-8 hours, washing the reaction solution with water, collecting the organic layer, and concentrating to obtain corresponding metal complex 22, wherein M is metal ion as defined above;

c ₃ dissolving compound 21 in acetone with the concentration of 0.03M, adding an equal volume of 0.5N NaOH or KOH aqueous solution, stirring and reacting for 2-10 hours, adding absolute ethyl alcohol into the reaction solution, separating out solid, and filtering to obtain compound 23, namely a sodium salt or potassium salt form of carboxylic acid corresponding to compound 21, wherein M is 2H;

c ₃₁ : using the above-mentioned 22 as raw material according to the following stepsThe synthesis of compound 23 provides compound 24, i.e., in the form of the sodium or potassium salt corresponding to compound 22, wherein M is a metal ion as defined above.

Here, the compounds 21 and 22 are compounds of formula IV (a), and the compounds 23 and 24 are compounds of formula IV (b).

In the preparation method, the specific reaction process is as follows:

wherein,

R ₁ is thatWherein n is any integer from 2 to 7;

R ₄ is any one of the following groups:

The chlorin derivatives of the present invention or pharmaceutically acceptable salts thereof and their anti-tumor effect when used as sonosensitizers in combination with ultrasound medical systems are described in further detail below in connection with specific examples.

Examples

EXAMPLE 1 preparation of Compounds 8-BA and 9-BA (Pd)

The synthetic routes for compounds 8-BA and 9-BA (Pd) are as follows:

the steps in the above synthetic route are specifically as follows:

541mg of compound 1 was dissolved in 5% sulfuric acid methanol solution at a concentration of 0.1M, reacted for 10 hours and concentrated under reduced pressure, and the obtained acid was diluted with an equal volume of Dichloromethane (DCM), washed with water, and the organic phase was collected and concentrated to give compound 2, which was used in the next reaction without isolation.

The product compound 2 of the above step was dissolved in Dimethylformamide (DMF) at a concentration of 0.1M, 435mg of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) and 189. Mu. L N, N-Diisopropylethylamine (DIEA) were added, followed by stirring for 0.5 to 1 hour, followed by sequentially adding 417mg of β -alanine tert-butyl hydrochloride and 379. Mu.L of DIEA, continuing the reaction for 1 to 2 hours, diluting the reaction solution with Dichloromethane (DCM) after the completion of the reaction, washing with water, collecting the organic phase, concentrating, 200 to 300 mesh silica gel column chromatography, eluting with petroleum ether/acetone=3:1 to obtain 545mg of compound 3, and the yield in two steps was 80%.

Compound 3 (C) ₄₃ H ₅₅ N ₆ 0 ₇ ，MW＝766.4127)： ¹ H NMR(400MHz,CD3COCD3)δ9.59(1H,s),9.57(1H,s),9.07(1H,s),8.14(1H,m),8.05(1H,dd,J＝11.6,17.8Hz),6.35(1H,m),6.25(1H,dd,J＝1.3,17.8Hz),6.98(1H,dd,J＝1.3,17.8Hz),5.65(1H,d,J＝19.1Hz),5.38(1H,d,J＝19.1Hz),4.65(1H,q,J＝7.2Hz),4.50(1H,m),3.91(1H,m),3.79(1H,m),3.75(3H,s),3.60(3H,s),3.56(2H,m),3.54(2H,q,J＝7.6Hz),3.47(3H,s),3.42(3H,s),3.14(3H,s),2.69(1H,m),2.34(1H,m),2.26(1H,m),1.79(1H,m),1.70(3H,d,J＝7.2Hz),1.59(3H,t,J＝7.6Hz),1.44(9H,s),-1.66(1H,s),-1.95(1H,s)。ESI-MS m/z：C ₄₃ H ₅₅ N ₆ O ₇ [M+H]Calculated 767.4127, measured 767.4143;

500mg of Compound 3 and 1.660mL of 1-hexene were dissolved in Dichloromethane (DCM) at a concentration of 0.03M, and after adding 169mg of the second generation glabrous catalyst, the reaction was refluxed for 20 hours, the filtrate was transferred to a separating funnel after the reaction solution was filtered, and saturatedWashing with aqueous ammonium chloride, collecting the organic phase, concentrating, 200-300 mesh silica gel column chromatography, eluting with petroleum ether/acetone=9:2 to give 376mg of compound 4-B (C) ₄₇ H ₆₁ N ₅ O ₇ ,MW＝807.4571)： ¹ H NMR(400MHz,CD ₃ COCD ₃ )δ9.59(1H,s),9.55(1H,s),9.03(1H,s),8.13(1H,m),8.01(1H,dd,J＝11.6,17.8Hz),6.31(1H,m),6.22(1H,dd,J＝1.3,17.8Hz),6.97(1H,dd,J＝1.3,17.8Hz),6.44(1H,d,J＝19.1Hz),6.06(1H,d,J＝19.1Hz),4.59(1H,q,J＝7.2Hz),4.49(1H,m),3.90(1H,m),3.77(1H,m),3.74(3H,s),3.59(3H,s),3.54(2H,m),3.51(2H,q,J＝7.6Hz),3.45(3H,s),3.42(3H,s),3.13(3H,s),2.67(1H,m),2.34(1H,m),2.25(1H,m),2.16(2H,m)，1.77(1H,m),1.68(3H,d,J＝7.2Hz),1.57(3H,t,J＝7.6Hz),1.42(9H,s),1.38(2H,m)，1.29(2H,m)，0.98(3H,m)，-1.65(1H,s),-1.93(1H,s)。ESI-MS m/z：C ₄₇ H ₆₂ N ₅ O ₇ [M+H] ⁺ Calculated 808.4571, measured 808.4577.

300mg of compound 4 was dissolved in a Dichloromethane (DCM) solution of trifluoroacetic acid (TFA) with a volume fraction of 25% at a concentration of 0.1M, the reaction was concentrated after stirring for 2-5 hours, the residue was dissolved in DCM, washed with water, and the organic phase was collected and concentrated to yield 279mg of compound 5-B.

Directly weighing 250mg of compound 5-B, dissolving in Dimethylformamide (DMF) with the concentration of 0.1M, adding 189mg of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) and 87 mu L N, N-Diisopropylethylamine (DIEA), stirring and reacting for 0.5-1 hour, adding 197mg of L-aspartic acid methyl ester hydrochloride and 174 mu L N, N-Diisopropylethylamine (DIEA), continuing to react for 1 hour, adding Dichloromethane (DCM) to dilute the reaction solution after the reaction is finished, washing for multiple times, collecting an organic phase, concentrating, performing 200-300-mesh silica gel column chromatography, eluting with petroleum ether/acetone=1:1, and obtaining 253mg of compound 6-BA (C) ₄₉ H ₆₂ N ₆ O ₁₀ Mw= 894.4527), yield 85%; compound 6-BA: ¹ H NMR(400MHz,CD ₃ COCD ₃ )δ8.41(1H,s),8.32(1H,s),8.13(1H,m),8.01(1H,dd,J＝11.6,17.8Hz),6.31(1H,m),6.22(1H,dd,J＝1.3,17.8Hz),6.97(1H,dd,J＝1.3,17.8Hz),6.44(1H,d,J＝19.1Hz),6.06(1H,d,J＝19.1Hz),5.03(1H,m)，4.59(1H,q,J＝7.2Hz),4.49(1H,m),3.90(1H,m),3.77(1H,m),3.74(3H,s),3.59(3H,s),3.66(6H,s)，3.54(2H,m),3.51(2H,q,J＝7.6Hz),3.45(3H,s),3.42(3H,s),3.13(3H,s),3.04(2H,m)，2.79(1H,m),2.34(1H,m),2.25(1H,m),2.16(2H,m)，1.77(1H,m),1.68(3H,d,J＝7.2Hz),1.57(3H,t,J＝7.6Hz),1.38(2H,m)，1.29(2H,m)，0.98(3H,m)，-1.65(1H,s),-1.93(1H,s)。ESI-MS m/z：C ₄₉ H ₆₁ N ₆ O ₁₀ [M-H] ^- calculated 893.4527, measured 893.4523.

200mg of compound 6-BA was dissolved in Dichloromethane (DCM) at a concentration of 0.1M, 79mg of palladium dichloride was added, the reaction was heated under reflux for 5 hours, the reaction was washed with water, the organic layer was collected, concentrated, 200-300 mesh silica gel was stirred, petroleum ether/acetone=3:1 was eluted, 239mg of metal complex 7-BA was obtained, which was readily soluble in water, and the yield was 90%.

200mg of each of the compounds 6-BA and 7-BA was dissolved in acetone (acetone) at a concentration of 0.03M, an equal volume of a 0.5N aqueous NaOH solution was added, and after stirring and reaction for 5 hours, absolute ethanol was added to the reaction solution to precipitate solids, and the solids were filtered to obtain 205mg of each of the compounds 8-BA and 206mg of 9-BA (Pd). Compound 9-BA (Pd): c (C) ₄₅ H ₄₈ N ₆ Na ₄ O ₁₉ Pd，MW＝1030.2058。 ¹ H NMR(400MHz,MeOD)：δ8.44(1H,s)，8.37(1H,s)，6.70(1H,s)，6.40(1H,s)，6.43(1H,d,J＝19.1Hz),6.09(1H,d,J＝19.1Hz),5.03(1H,m),4.30(1H,s)，3.90(1H,m),3.44(2H,m)，3.44(2H,m),2.90(2H,m)，2.65(1H,m)，2.44(4H,m)，2.42(3H,s)，2.33(2H,m)，2.37(3H,s)，2.20(1H,m)，2.12(3H,s)，1.79(2H,m)，1.88(1H,m)，1.38(2H,m)，1.29(2H,m)，0.93(3H,m)，0.89(3H,m)，0.86(3H,d,J＝7.2Hz)。HRMS(ESI)m/z：C ₄₅ H ₄₈ N ₆ Na ₂ O ₁₉ Pd[M-2Na] ^- Calculated 984.2262, measured 984.2269.

Example 2 Effect of the Compound 9-BA (Pd) on breast cancer metastasis

The sonodynamic therapy of breast cancer lung metastasis-bearing mice was evaluated using the ultrasound medical system provided in example 7 using the water-soluble chlorin derivative 9-BA (Pd) synthesized in example 1 as a sonosensitizer (abbreviated as sonosensitizer).

The water-soluble chlorin derivative 9-BA (Pd) was dissolved in physiological saline to prepare a drug solution for administration. 4T1 mice breast cancer cells were inoculated under a second pair of nipples on the left side of Balb/c (female, 18-22 g) mice, a model of breast cancer lung metastasis of the mice was constructed, tumor volumes and mouse weights were recorded starting on day 7 of inoculation, and measurements were taken every other day. Tumor-bearing mice were randomly divided into 4 groups: (1) a control group (saline alone), (2) b ultrasound group, (3) c administration (9-BA (Pd)) group, (4) d administration+ultrasound (9-BA (Pd) +ultrasound) group (i.e., sonodynamic treatment group). The ultrasound treatments were administered on days 12, 14, 18, 20, 24, 26 of tumor inoculation, respectively. The tail of the mouse is intravenous injected with 16mg/kg of sound sensitizer, and after 2 hours of administration, ultrasonic power treatment is carried out; re-administration after 24h interval and re-ultrasound power treatment after 2h with 1.88W/cm ² And (5) treating by ultrasonic irradiation for 30 min. Anatomical tumor tissue analysis, weight recorded. Lung tissue was stained with Bouin's fixative, ethanol decolorized, and lung nodule numbers recorded and statistically data.

The observation shows that the average volume increase speed of the tumors of the mice in the control group and the ultrasonic group is faster; the pure sound sensitizer 9-BA (Pd) has slight inhibition effect on the growth of the tumor, the sound power treatment group has the most obvious inhibition effect on the tumor and the growth of the tumor is the slowest (P is less than 0.01 compared with the rest groups).

After the experiment is finished, the peeled tumor tissues are weighed and measured. Figure 1 shows the effect of each treatment group on the weight of tumor tissue in primary breast cancer mice. As can be seen from fig. 1, after 9-BA (Pd) combined with ultrasound treatment (i.e. sonodynamic treatment group), the tumor tissue weight was reduced and significantly different relative to the other groups. Correspondingly, the tumor tissue which is stripped out can also be observed to obviously shrink in the acoustic power treatment group, and the statistical analysis P is less than 0.01-0.001.

Fig. 2 is a photograph showing the inhibition of lung metastasis of primary breast cancer by each treatment group. As can be seen from fig. 2, tumor-bearing mice in each treatment group had tumor lung metastasis to different degrees, and the control group mice had more severe lung metastasis and more lung tumor nodules. After treatment, the number of tumor nodules in the lung of the mice is reduced, wherein the degree of tumor lung metastasis is obviously reduced in a sound sensitive agent and ultrasonic power group, which shows that the compound 9-BA (Pd) can inhibit the lung metastasis of breast tumors in combination with free field ultrasonic power.

In conclusion, in the invention, the water-soluble chlorin sound sensitive agents such as the compound 9-BA (Pd) and the like are combined with ultrasound to perform ultrasonic power treatment, so that the compound has remarkable inhibition effect on tumors and tumor tissues, can inhibit lung metastasis of primary breast cancer of mice, and has clinical value.

EXAMPLE 3 preparation of Compounds 17-MPA and 18-MPA (Pd)

The synthetic routes for compounds 17-MPA and 18-MPA (Pd) are as follows:

the steps in the above synthetic route are specifically as follows:

1000mg of Compound 1-chlorin e6 was dissolved in Dimethylformamide (DMF) at a concentration of 0.1M, 1043. Mu.L of methyl iodide and 4633mg of anhydrous potassium carbonate were added, and after stirring for 2 hours, the reaction solution was diluted with Dichloromethane (DCM), washed with water, the organic phase was collected and concentrated, and 200-300 mesh silica gel column chromatography, ethyl acetate/dichloromethane=1:100 was eluted to give 962mg of Compound 10 in a yield of 90%.

800mg of compound 10 and 675 mu L of p-methoxystyrene were dissolved in Dichloromethane (DCM) at a concentration of 0.03M, 319mg of the Grabbs catalyst was added and then refluxed for 20 hours, the reaction solution was filtered, the filtrate was transferred to a separating funnel, the aqueous solution was washed a plurality of times, the organic phase was collected, concentrated, and 200-300 mesh silica gel column chromatography was performed, ethyl acetate/dichloromethane=1:100 was eluted, thereby obtaining 654mg of compound 11-MP, and the yield was 70%.

500mg of 11-MP was dissolved in Dichloromethane (DCM) at a concentration of 0.1M, 79mg of palladium acetate was added, the reaction was heated under reflux for 5 hours, the reaction solution was washed with water, the organic layer was collected and concentrated, 200-300 mesh silica gel column chromatography, and petroleum ether/acetone=5:1 was eluted to give 490mg of 12-MP (Pd) as a metal complex in 86% yield.

400mg of 11-MP and 12-MP (Pd) metal complex were dissolved in a volume ratio of 1:1 Tetrahydrofuran (THF) to 1M aqueous KOH solution at a concentration of 0.05M for 4 hours, and after reaction, THF was removed by concentration under reduced pressure, water was added to adjust pH to 5-6, and solids were separated out and filtered to give 350mg of 13-MP and 345mg of 14-MP (Pd) metal complex, which were used directly in the next reaction without isolation.

The above-mentioned compounds 13-MP and 14-MP (Pd) were dissolved in Dimethylformamide (DMF) at a concentration of 0.1M, and 170mg of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI), 318mg of aspartic acid methyl ester hydrochloride, 452. Mu.L of Et were sequentially added ₃ N and 466. Mu.LN, N-Diisopropylethylamine (DIEA), stirring and reacting for 1 hour, gradually adding aqueous formic acid, precipitating a solid, filtering, subjecting the obtained residue to 200-300 mesh silica gel column chromatography, eluting with methanol/dichloromethane=1:20, to obtain 215mg of compound 15-MPA and 210mg of compound 16-MPA (Pd).

200mg of the compound 15-MPA and 16-MPA (Pd) were dissolved in acetone at a concentration of 0.03M, an equal volume of a 0.5N aqueous NaOH solution was added, after 10 hours of reaction, absolute ethanol was added to the reaction solution, and solids were precipitated and filtered to obtain 180mg of the compound 17-MPA and 175mg of the compound 18-MPA (Pd), both of which were readily soluble in water.

Compound 17-MPA: c (C) ₄₅ H ₄₃ N ₅ Na ₄ O ₁₀ ，MW:＝905.2601。 ¹ H NMR(400MHz,DMSO-d6)δ8.58(m,1H),8.21(m,1H),8.09(m,1H),7.98(m,2H),7.71(m,1H),7.54(m,2H),7.44(m,1H),6.70(s,1H),5.32(m,2H),4.62(m,1H),4.55(m,1H),4.38(m,1H),3.66(m,2H),3.52(s,6H),3.36(m,2H),3.20(s,3H),2.71(m,1H),2.58(m,2H),2.40(m,2H),2.18(m,2H),1.73(d,J＝7.0Hz,3H),1.61(m,4H),-1.81(1H,s),-2.10(1H,s)。HRMS(ESI)m/z：C ₄₅ H ₄₆ N ₅ O ₁₀ [M-4Na-H] ^- Calculated 816.3250, measured 816.3255.

EXAMPLE 4 Effect of Compound 17-MPA on colorectal cancer and colorectal cancer metastasis

The water-soluble chlorin derivative 17-MPA synthesized in example 3 was used as a sound sensitive agent, and the ultrasonic medical system provided in example 7 was used to evaluate the sound power treatment of colon cancer liver cancer metastasis tumor-bearing mice.

The water-soluble chlorin derivative 17-MPA is dissolved in physiological saline to prepare a liquid medicine for administration. In the scheme, CT26 mouse colon cancer cells are used, inoculated into the half spleen of a Balb/c (female, 18-22 g) mouse, a mouse half spleen transfer liver cancer model is constructed, the body weight of the mouse is recorded from the 7 th day of inoculation, and the body weight is measured at intervals. Liver cancer mice were randomly divided into 4 groups: (1) control group (normal saline alone), (2) group (17-MPA), (3) ultrasound group, (4) group (17-mpa+ultrasound) administration+ultrasound group, (5) talaporfin (Talaporfin sodium, a photodynamic therapy agent) as control group. On day 12 of inoculation, mice were injected with 16mg/kg 17-MPA intravenously at 1.88W/cm 4h later ² And irradiating for 30min by ultrasonic power. Continuously administering and performing ultrasonic treatment, wherein 3 days is a treatment course. The second and third treatment sessions were performed on days 17 and 22, respectively. The effect of compound 17-MPA mediated photodynamic therapy (SDT) on deep tumours in animals was assessed.

The image of fig. 3 shows: the control group and the ultrasound group of mice had a large number of macroscopic tumor liver metastases, and the tumor tissue of the administration (17-MPA) group was slightly reduced, while the metastatic lesions of the administration+ultrasound (17-MPA+ultrasound) group were significantly reduced.

Fig. 4 shows the liver average weight for each treatment group. As can be seen from fig. 4, the average weight of the liver of the 17-MPA + ultrasound group was significantly lower than that of the control group, and also significantly lower than that of the administration group, the ultrasound group and the control group.

From the above experiments, the compound 17-MPA can be used in combination with ultrasound for ultrasound power therapy for effectively reducing and curing colon cancer metastasis.

EXAMPLE 5 pharmacokinetic experiment study of Compound 17-MPA

The pharmacokinetic property of the compound 17-MPA in SD rats and the distribution of the compound 17-MPA in ICR tumor-bearing mice are researched by using a high performance liquid chromatography method, so that basis is provided for continuous administration time and intervention time of sonodynamic treatment in pharmacodynamics research.

And (3) establishing high performance liquid chromatography to detect the daily internal precision and stability (room temperature storage, low temperature storage and repeated freezing and thawing) of the plasma sample. The precision of the daily precision experiment and the stability experiment of the obtained plasma sample are less than 15 percent, and the accuracy is within +/-20 percent. The extraction recovery rates of 17-MPA in plasma were detected as 65.89.+ -. 2.38%, 69.71.+ -. 0.22%, 74.39.+ -. 1.13% and 80.73.+ -. 0.35% for the high, medium, low and lowest detection lower limit concentrations, respectively, and 68.10.+ -. 0.99% for the internal standard. On the basis of the established quantitative analysis method, the drug concentration in the plasma of SD rats after tail vein injection administration is detected, and the pharmacokinetic atrioventricular model of 17-MPA in the SD rats is determined to be in accordance with a two-chamber model, wherein the distribution half-life (t 1/2 alpha) is 0.627+/-0.256 h, and the elimination half-life (t 1/2 beta) is 7.421 +/-0.802 h. In addition, the binding rate of DYSP-C07 and SD rat plasma protein is measured by adopting a balance dialysis method, and finally the binding rates of DYSP-C07 with high, medium and low concentrations and SD rat plasma protein are respectively 90.94+/-1.90%, 92.25+/-1.40% and 95.78+/-1.20%. 17-MPA was detected in heart, liver, spleen, lung, kidney and tumor tissues of ICR tumor-bearing mice, wherein 17-MPA showed high concentration in liver and kidney tissues, gradually accumulated in tumor tissues and maintained at a higher concentration for 6-12 h.

Through the research of a pharmacokinetics experiment, the pharmacokinetics of the compound 17-MPA in SD rats accords with a two-chamber model, the combination of the compound and SD rat plasma protein is high, the aggregation degree in the liver and kidney of ICR tumor-bearing mice is high, and the compound and SD rat plasma protein show a gradual aggregation trend in tumor tissues. Finally, the research on the dynamics and the tissue distribution of the high performance liquid chromatography ultraviolet detection method applied to the 17-MPA intravenous injection in the mice is established. Based on the resulting pharmacokinetic data, it is suggested to perform systematic pharmacodynamic evaluation of compound 17-MPA with the elimination half-life of compound 17-MPA as a reference starting point of study for phototherapy time.

Mice were given 16mg/kg of compound 17-MPA in the tail vein and the distribution of compound 17-MPA in the tissues of ICR mice and the concentration of compound 17-MPA in the tissues at each time point were examined over each period of 1h to 12 h. The results were as follows:

1h: kidney > lung > spleen, heart > tumor, liver;

2h: liver > kidney > lung, heart, spleen > tumor;

4h: liver > kidney > lung, heart, spleen, tumor;

6h: liver > kidney > tumor, lung, spleen, heart;

8h: liver > kidney > spleen, tumor, heart, lung;

12h: liver > kidney > tumor, lung, spleen, heart;

EXAMPLE 6 preparation of Compounds 25-tFPL and 26-tFPL (Pd)

The synthetic routes for compounds 25-tFPL and 26-tFPL (Pd) are as follows:

the steps in the above synthetic route are specifically as follows:

starting from compound 19, 500mg of compound 19 was dissolved in Dimethylformamide (DMF) at a concentration of 0.1M, 479mg of benzotriazole-N, N' -tetramethyluronium Hexafluorophosphate (HBTU) and 220 μ L N, N-Diisopropylethylamine (DIEA) were added, followed by stirring for 0.5 hours, 393mg of lysine methyl ester hydrochloride and 293 μ L N, N-Diisopropylethylamine (DIEA) were added, the reaction was continued for 1 hour, the reaction solution was diluted with Dichloromethane (DCM), washed with water, concentrated, the resulting residue was dissolved in 1% sodium methoxide in methanol, stirred for 8 hours, ph=6-7 was adjusted, concentrated under reduced pressure, and after dissolution of the residue in Dichloromethane (DCM), the organic phase was collected, concentrated, 200-300 mesh silica gel column chromatography, methanol/dichloromethane=1:15 was eluted, yielding 550mg of compound 20-L, yield 85%.

400mg of compound 20-L and 1540. Mu.L of p-trifluoromethyl styrene are dissolved in Dichloromethane (DCM) with the concentration of 0.03M, after 133mg of the Grabbs catalyst is added, reflux reaction is carried out for 24 hours, the filtrate after the reaction solution is filtered is transferred to a separating funnel, the aqueous solution is washed for a plurality of times, the organic phase is collected, concentrated, 200-300 mesh silica gel column chromatography and methanol/dichloromethane=1:15 are eluted, 309mg of compound 21-tFPL is obtained, and the yield is 65%.

200mg of compound 21-tFPL was dissolved in DCM at a concentration of 0.1M, 79mg of palladium acetate was added, the reaction was heated under reflux for 5 hours, the reaction solution was washed with water, the organic layer was collected and concentrated, 200-300 mesh silica gel column chromatography, and petroleum ether/acetone=3:1 was eluted, to give 205mg of metal complex 22-tFPL (Pd) in 93% yield.

200mg of compound 21-tFPL and 22-tFPL (Pd) were dissolved in 3mL of Dichloromethane (DCM), 1mL of trifluoroacetic acid (TFA) was added thereto and the reaction was stirred for 1h, and the reaction solution was concentrated to dryness under reduced pressure to obtain 190mg of compound 23-tFPL and 185mg of compound 24-tFPL (Pd) crude product (TFA salt).

150mg of the compounds 23-tFPL and 24-tFPL (Pd) were dissolved in acetone at a concentration of 0.03M, an equal volume of a 0.5N aqueous NaOH solution was added thereto, and after stirring and reacting for 5 hours, absolute ethanol was added to the reaction solution to precipitate solids, and filtration was carried out to obtain 140mg of the compounds 25-tFPL and 143mg of the water-soluble compounds 26-tFPL (Pd).

Compound 26-tFPL (Pd) C ₄₇ H ₄₆ F ₃ N ₆ Na ₃ O ₇ Pd,MW＝1038.2108： ¹ HNMR(400MHz,DMSO-d ₆ )δ8.72(d,J＝16.6Hz,1H),8.06(d,J＝7.5Hz,2H),8.03(s,1H),7.29(s,1H),7.82(d,J＝16.6Hz,1H),7.58(t,J＝7.5Hz,2H),7.45(m,1H),5.28(m,2H),4.60(m,1H),3.77(q,J＝7.5Hz,2H),3.57(s,3H),3.53(s,3H),3.51(m,2H),3.28(s,3H),3.15(m,4H),3.07(m,1H),2.59(m,1H),2.46(m,1H),2.12(m,2H),1.71(d,J＝7.1Hz,3H),1.65(t,J＝7.5Hz,3H),1.57(m,2H),1.33(m,4H)。HRMS(ESI)m/z：C ₄₇ H ₄₆ F ₃ N ₆ Na ₂ O ₇ Pd[M-Na] ^- Calculated 1015.2216, measured 1015.2221.

Example 7 ultrasound medical System

Fig. 5 shows a top view of a transducer acoustic bed 1 according to an embodiment of the invention. As shown in fig. 5, the transducer acoustic bed 1 includes a bottom portion 10 and a wall portion 11 extending upward from the bottom portion 10. The base 10 is divided into three areas of the head 12, the torso 13 and the limbs 14 in the shape of a human body, in which three areas a number of ultrasonic transducers 8 are respectively arranged. Although fig. 5 specifically shows the number of ultrasonic transducers 8, this is for illustration purposes only and not for limitation. Depending on the desired therapeutic effect and the mechanical strength of the transducer acoustic bed 1, the number of arranged ultrasound transducers 8 in the respective region may be increased or decreased. Preferably, 127 ultrasonic transducers 8 are uniformly arranged on the bottom 10. In addition, the base 10 of the transducer acoustic bed 1 shown in fig. 5 is a flat area with the torso 13 and limbs 14 being slightly lower than other areas, but other shapes of base are well known to those skilled in the art, such as concave, curved, even wavy, etc., where the patient can be placed upon it to receive ultrasonic radiation. Although not shown in the drawings, the bottom of the transducer acoustic bed 1 may also have a recess adapted to the shape of the human body to facilitate the placement of the human body therein. In this case, however, the plurality of ultrasonic transducers 8 are preferably disposed in the recess.

Fig. 6 shows a top view of a transducer acoustic bed 2 according to another embodiment of the invention. As shown in fig. 6, the transducer bed 2 includes a bottom 20 and a wall portion 21 extending upwardly from the bottom 20. The bottom 20 and the wall 21 are both provided with the ultrasonic transducer 8, and since the arrangement and shape of the bottom 20 are the same as the bottom 10 of fig. 5, a detailed description is omitted for the sake of brevity. On the wall portion 21, three regions of the head top 212, the shoulder 2141, and the sole 2142 are divided according to the shape of the human body, in which a number of ultrasonic transducers 8 are respectively arranged, and although fig. 6 specifically shows the number of ultrasonic transducers 8, this is for the purpose of example only and not for the purpose of limitation, the number of ultrasonic transducers 8 arranged in each region may be increased or decreased according to the desired therapeutic effect and mechanical strength of the transducer sound bed 2. Preferably, the number of ultrasonic transducers 8 disposed on the crown 212, the shoulder 2141, and the sole 2142 are 2, and 4, respectively.

It should be noted that while the transducer bed is shown in figures 5 and 6 as being in the form of a substantially rectangular bathtub, the transducer bed may take other shapes, such as elliptical, etc. The inclination angle of the wall portion of the transducer sound bed with respect to the vertical direction may be changed, and may be various shapes such as a curved surface. Such variations are to be regarded as within the scope of the invention.

Fig. 7 shows a side view of a transducer module 3 according to an embodiment of the invention. As shown in fig. 7, the transducer module 3 includes an upper surface 31 and a lower surface 32, the upper surface 31 is provided with a heat dissipating electric fan, and the side 33 is used for connection with a fixing means, which may be any means known in the art that may be suitable for fixing the transducer module 3. On the lower surface 32, several ultrasonic transducers 8 are arranged. The number of ultrasound transducers 8 arranged may be increased or decreased depending on the desired therapeutic effect and the mechanical strength of the transducer module 3. Preferably, 28 ultrasound transducers 8 are uniformly arranged on the lower surface 32.

While the transducer module 3 is shown in fig. 7 as having a rectangular configuration with a flat lower surface 32, it should be understood that the transducer module is not limited to this configuration and shape, but may be a portal configuration with an arcuate surface or other shape on the lower surface.

Fig. 8 shows a side view of a transducer module 4 with a two-dimensional numerically controlled movement means 40 according to another embodiment of the invention. As shown in fig. 8, the two-dimensional numerically-controlled movement device 40 is connected to the transducer module 42 by a cantilever 41 mounted thereon. In operation, the transducer module 42 is capable of moving along the X-axis and the Y-axis under the control of the two-dimensional numerically controlled motion device 40. The X-axis here refers to an axis extending in a horizontal direction parallel to the longitudinal direction of the transducer bed, and the Y-axis refers to an axis extending in a vertical direction perpendicular to the horizontal plane of the transducer bed. In this exemplary embodiment, the shape of the transducer module 42 and the arrangement of the ultrasound transducers 8 are the same as the transducer module 3 shown in fig. 7, and therefore, for the sake of brevity, a description is omitted.

It should be noted that while the transducer module 42 is shown in fig. 8 as moving only longitudinally along the transducer bed in a horizontal direction, the transducer module 42 may be configured to move laterally along the transducer bed as desired, such as when the transducer bed is relatively large in lateral dimension, for example, when multiple targets are being treated simultaneously. The two-dimensional numerical control movement device 40 will now be replaced by a three-dimensional numerical control movement device.

Fig. 9 shows a top view of an ultrasound medical system 100 according to one embodiment of the invention. As shown in fig. 9, the ultrasonic medical system 100 includes a transducer acoustic bed 1 and a contact agent 9, with an ultrasonic transducer 8 immersed in the contact agent 9. The contact agent 9 may be a coupling substance (contact agent) whose acoustic resistance forms an acoustic interface between the ultrasonic transducer 8 and human tissue, and may be water, vacuum deaerated (cold, hot) water, or the like. Preferably, vacuum deaerated (cold, hot) water is used. Since the transducer acoustic bed 1 has been described in detail above, a detailed description is omitted for the sake of brevity. Alternatively, the transducer acoustic bed 1 may be replaced with the transducer acoustic bed 2.

Fig. 10 shows a top view of an ultrasound medical system 300 according to another embodiment of the invention. As shown in fig. 10, the ultrasound medical system 300 includes a transducer acoustic bed 1, a transducer module 4, and a contact agent 9, the transducer module 42 is located above the transducer acoustic bed 1, and the ultrasound transducer 8 is immersed in the contact agent 9. Since the transducer acoustic bed 1, the transducer module 4 and the contact agent 9 have been described in detail above, a detailed description is omitted here for the sake of brevity. Alternatively, the transducer acoustic bed 1 may be replaced with the transducer acoustic bed 2, or the transducer module 4 may be replaced with the transducer module 3, or both.

Fig. 11 shows a block diagram of an ultrasound medical system 500 with a PLC automatic control system according to yet another embodiment of the present invention. As shown in fig. 11, the ultrasound medical system 500 includes a transducer acoustic bed 5001, a contact agent supply system 5003, a transducer module 5005, and a PLC automatic control system 5007. The PLC automatic control system 5007 is respectively connected with the transducer sound bed 5001, the contact agent supply system 5003 and the transducer module 5005 to control the cooperative work among the three according to the treatment requirement. The contact agent supply system 5003 is connected to the transducer acoustic bed 5001 so as to supply the contact agent 9 to the transducer acoustic bed 5001 under the control of the PLC automatic control system 5007. The connection may be a wired connection or a wireless connection. The transducer acoustic bed 5001 may be a transducer acoustic bed 1 or 2, or may be any other suitable variation of a transducer acoustic bed 1 or 2. The transducer module 5005 may be a transducer module 3 or 4, or any other suitable variation of a transducer module 3 or 4.

Preferably, the PLC automatic control system 5007 also includes a monitoring system 5008 (not shown). The monitoring system 5008 includes a monitor 5009, such as a 10.4 touch screen, for displaying operating parameters of the transducer acoustic bed and at least a portion of the ultrasound transducers in the transducer module that may be selected for a patient treatment area as shown in fig. 17, operating mode and acoustic intensity settings as shown in fig. 18, and the like. More preferably, the monitor 5009 is also capable of displaying lesion information in the human body, which may be a patient treatment regimen, etc. as shown in fig. 19, so that treatment is achieved, treatment parameters are modified at any time depending on the feeling of the patient, so that optimal treatment effect is achieved.

Fig. 12 shows a transducing head of an ultrasound transducer 8 according to an embodiment of the invention. As shown in fig. 12, a wafer 807 is placed in the inner cavity of the wafer holder, the outer spherical surface of the wafer is tightly contacted with the inner cavity surface of the wafer holder, a conductor and a limit are formed between the two, an O-shaped rubber ring 806 is placed on the inner surface side of the wafer, a compression spring 808 with a wire 810 welded on the upper part is placed in the inner hole of the fastening copper bolt, and then the copper bolt 811 is screwed with the wafer holder 805. The assembled wafer seat 805 is placed into a reserved round hole of the transducer head on the wall part 11 or 21 of the transducer sound bed 1 or 2, a rubber flat washer 804 is placed between the wafer seat 805 and the round hole, meanwhile, a copper bolt also has the function of connecting and fixing the transducer sound bed 1 or 2, after the sealing rubber ring 803 and the flat washer 802 are placed on the wafer seat, a round nut 809 is screwed into the copper bolt 811, and the transducer head is locked with the wall part 11 or 21 of the transducer sound bed 1 or 2.

The various components of the ultrasound medical system are described above in detail, and the specific workflow of the ultrasound medical system will be described next by way of example.

Fig. 13 shows a flowchart of the operation of the ultrasound medical system 100. As shown in fig. 13, in step 901, a contact agent is injected into the transducer sound bed such that the contact agent floods all of the ultrasound transducers on the transducer sound bed. In step 903, the human body is placed on the bottom of the transducer acoustic bed. Step 905, turning on an ultrasonic transducer to emit ultrasonic waves to a human body, and performing ultrasonic treatment The sound intensity of the sound wave should be in a range that the human body can withstand and effectively activate the sound-sensitive agent, for example, the sound intensity is set in a range of 0.1-3W/cm ² At intervals of 0.1W/cm ² For example 0.1, 0.2, 0.3, & gt, 1.0, 1.1, 1.2, & gt, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0W/cm ² The waveform is a continuous wave or a pulse wave. Preferably, sufficient contact agent is injected into the transducer acoustic bed to enable the human body to float therein and thereby create a slight lateral drift that can cause the human body to be exposed to more intense ultrasonic radiation in the transducer acoustic bed. Preferably, the contact agent is vacuum deaerated (cold, hot) water. Preferably, the ultrasonic wave is emitted at a pulse wave frequency of 0.3MHz to 3 MHz. Preferably, ultrasound waves are emitted simultaneously from the wall and bottom of the transducer acoustic bed to the human body.

Fig. 14 shows a workflow diagram of an ultrasound medical system 300. As shown in fig. 14, in step 1001, a contact agent is injected into the transducer sound bed such that the contact agent floods all of the ultrasound transducers on the transducer sound bed. In step 1003, the human body is placed on the bottom of the transducer acoustic bed. In step 1005, the transducer module is moved downward to be immersed in the contact agent. In step 1007, the ultrasonic transducer is turned on to emit ultrasonic waves to the human body, and the ultrasonic waves emitted from the ultrasonic transducer and the transducer module have a frequency of 0.3-3MHz and a waveform of continuous waves or pulse waves. Preferably, sufficient contact agent is injected into the transducer acoustic bed to enable the human body to float therein and thereby create a slight lateral drift that can cause the human body to be exposed to more intense ultrasonic radiation in the transducer acoustic bed. Preferably, the contact agent is vacuum deaerated (cold, hot) water. Preferably, the ultrasonic waves emitted from the transducer acoustic bed are pulsed waves of 1 MHz. Preferably, the ultrasonic waves emitted from the transducer module are continuous waves of 1 MHz. Preferably, ultrasound waves are emitted simultaneously from the wall and bottom of the transducer acoustic bed to the human body. Preferably, the transducer module emits ultrasonic waves to the human body in a horizontal movement.

Fig. 15 shows a workflow diagram of an ultrasound medical system 500. As shown in fig. 15, step 1101, the PLC automatic control system is started upThe medical system is remotely controlled through a human-machine interface of the PLC automatic control system, such as a color touch screen as shown in fig. 16. At step 1103, the contact agent supply system is started. In step 1105, the contact agent supply system begins to inject contact agent into the transducer acoustic bed. In step 1107, judging whether the liquid level of the contact agent in the transducer sound bed reaches a preset height, if so, turning to step 1105, and continuously injecting the contact agent into the transducer sound bed; otherwise, step 1109 is entered, the human body is placed on the bottom of the transducer acoustic bed. In step 1111, a treatment region of the patient is selected, and as shown in fig. 17, for example, a local region may be selected for treatment according to the condition of the patient, or a whole body treatment may be selected. In step 1113, the intensity of the ultrasound of the selected treatment area is set, for example, to 0.1-3W/cm ² Ranges, intervals of 0.1W/cm, e.g., 0.1, 0.2, 0.3, and/or 1.0, 1.1, 1.2, and/or 2.5, 2.6, 2.7, 2.8, 2.9, 3.0W/cm) ² . In step 1115, the waveform of the ultrasound waves of the selected treatment region is set, for example, as a pulse wave or a continuous wave. In step 1117, as shown in FIG. 18, the treatment time required for the selected treatment area is set, for example, 30 minutes. In step 1119, it is determined whether or not the setting needs to be continued, and if the setting needs to be continued, the process may jump to step 1111 again, and the rest of the parts may be set; otherwise, step 1121 is entered. In step 1121, the transducer module is moved downward to be immersed in a contact agent. In step 1123, the ultrasound transducers on the selected treatment area and transducer module are turned on, emitting ultrasound waves to the human body.

In the treatment process, the treatment can be suspended at any time by utilizing the PLC automatic control system, so that the operations from the step 1111 to the step 1117 are carried out again, the corresponding settings are modified, and the treatment needs of patients are immediately adapted. In step 1111, selection of a treatment region may be performed by selecting only the ultrasound transducer on the transducer couch to operate, selecting the ultrasound transducer of the transducer module to operate, or selecting both to operate, as required by the patient's condition. More preferably, a part of the ultrasound transducers on the bottom surface of the transducer bed may be selected to operate, or a part of the ultrasound transducers on the wall of the transducer bed may be operated, or a part of the ultrasound transducers of the bottom may be operated together with a part of the ultrasound transducers of the wall, or only a part of the ultrasound transducers of the transducer module may be selected to operate, or a part of the ultrasound transducers of the transducer module may be operated together with a part of the ultrasound transducers on the bottom surface of the transducer bed and/or on the wall. The particular choice will depend on the therapeutic needs. In step 1113, the intensity of the ultrasonic wave is set, and the same or different sound intensities can be selected according to the different conditions of each selected treatment area, wherein the sound intensity range is 0.1-3W/cm. In step 1115, the waveform of the ultrasonic wave may be set, and a pulse or a succession may be selected according to each selected treatment area, wherein the pulse mode may be 1% -99%, preferably 30%, 50% or 75% of the treatment time. In step 1117, a treatment time is set, and the treatment time may be selected to be 5-30 minutes according to each selected treatment area. In step 1123, the ultrasonic transducer on the transducer module may be fixed at a position above the human body to emit ultrasonic waves to the human body, or may be moved uniformly in the horizontal direction above the human body to emit ultrasonic waves to the human body, where the moving speed is the ratio of the height of the human body to the treatment time.

More preferably, the PLC automatic control system may be further configured such that the ultrasonic transducers located in different areas irradiate the human body with different intensities.

It should be understood that the transducer module may also be configured in the shape of the upper cover, or as part of the upper cover of the transducer acoustic bed. In this case, a plurality of ultrasonic transducers of the transducer module may be distributed on the upper cover in various forms. The upper cover can cover the transducer sound bed after the therapeutic target is placed on the transducer sound bed. The ultrasonic transducer emission frequency is 0.3MHz-3MHz, preferably 0.5, 1, 1.5MHz.

The system can effectively solve the death problem of malignant tumor patients caused by malignant tumor diffusion and metastasis, can comprehensively irradiate ultrasonic waves of human bodies, can reach deep tissues of the human bodies and penetrate the human bodies, and can successfully activate the sound-sensitive agent medicine by energy so as to kill malignant tumors of all parts of the human bodies. In addition, the system can flexibly select the ultrasonic transducer in the acoustic power treatment process, thereby increasing the convenience of doctors in treatment and greatly shortening the treatment time of patients. The invention uses in vitro ultrasound to kill malignant tumor without damaging normal tissue, with good selectivity and little side effect.

Although the present invention has been described in connection with the preferred embodiments and specific examples, it is not intended that the scope of the invention be limited by the specific embodiments set forth herein, as the embodiments herein are described in all respects and not for purposes of limitation. For example, in the above embodiments, the transducer module is described as a rectangular component that is smaller than the transducer acoustic bed, but the transducer module may be manufactured in a complementary configuration to the transducer acoustic bed, or any other suitable configuration that meets the therapeutic needs. In addition, unless specifically stated, any workflow presented herein should not be construed as requiring that its steps be performed in the particular order listed in the embodiments. It will be apparent that the invention is applicable to animals or other subjects in need of treatment in addition to treatment of the human body.

Although only the combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and the present ultrasound medical system is shown in the present specification for the treatment of malignant tumors, the ultrasound medical system provided by the present invention is also applicable to the aspects of drug activation, cardiovascular and cerebrovascular treatment, body beautification, physiotherapy, and the like.

The foregoing is only illustrative of the present invention and is not to be construed as limiting thereof, but rather, it is contemplated that various modifications, equivalent arrangements, improvements or the like may be made within the spirit and principles of the present invention.

Claims

1. A combination of a chlorin derivative or a pharmaceutically acceptable salt thereof and an ultrasound medical system, wherein the chlorin derivative or pharmaceutically acceptable salt thereof has a structure represented by formula (I):

wherein,

R ₁ the method comprises the following steps:

Wherein n is any integer from 2 to 7;

wherein R is ₉ 、R ₁₀ And R is ₁₂ Identical or different and are each independently selected from C ₁ -C ₆ Alkyl group, and

wherein R is ₉ 、R ₁₀ And R is ₁₂ As defined above,

and R is ₃ And R is ₄ Another one of them is C ₁ -C ₆ Alkoxy or-OH;

m is 2H, a divalent metal ion or a tetravalent metal ion;

2. The combination of claim 1, wherein the divalent metal ion is Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ Or Pd ²⁺ 。

3. The combination of claim 1, wherein the tetravalent metal ion is Sn ⁴⁺ Or Ti (Ti) ⁴⁺ 。

4. The combination according to claim 1, wherein the chlorin derivative or pharmaceutically acceptable salt thereof is:

wherein,

R ₁ is thatWherein n is any integer from 2 to 7,

R ₃ 、R ₄ and R is ₈ Is any one of the following groups:

wherein R is ₉ 、R ₁₀ And R is ₁₂ As defined in claim 1;

m is as defined in any one of claims 1 to 3.

5. The combination according to claim 1, wherein the chlorin derivative or pharmaceutically acceptable salt thereof is:

wherein M is as defined in any one of claims 1 to 3.

6. The combination of any one of claims 1-5, wherein the ultrasound medical system further comprises a transducer module, wherein the transducer module is mounted above the transducer acoustic bed and comprises at least one ultrasound transducer for emitting ultrasound waves towards a target located therebelow, the contact agent also being for transmitting ultrasound waves between the target and the at least one ultrasound transducer.

7. The combination of claim 6, wherein the transducer module further comprises a digitally controlled movement device for controlling the transducer module to move in a horizontal and/or vertical direction.

8. The combination of any one of claims 1-5, wherein the ultrasonic wave is a pulsed wave or a continuous wave.

9. The combination of any one of claims 1-5, wherein the ultrasonic waves have a frequency of 0.3-3MHz.

10. The combination according to any one of claims 1-5, wherein the sound intensity of the ultrasonic waves is 0.1-3W/cm ² 。

11. The combination of any one of claims 1-5, wherein the contact agent is at least one of water and vacuum degassing cold/hot water.

12. The combination of claim 6, wherein the ultrasound medical system further comprises a programmable logic controller automatic control system and a contact agent supply system, wherein:

the contact agent supply system is connected with the transducer sound bed and is used for supplying contact agent to the transducer sound bed;

the programmable logic controller automatic control system is respectively connected with the transducer sound bed, the transducer module and the contact agent supply system, and is used for controlling the contact agent supply system to supply the contact agent to the transducer sound bed and controlling the operation of at least one part of ultrasonic transducers in the transducer sound bed and the transducer module.

13. The combination of claim 12, wherein the programmable logic controller automatic control system further comprises a monitoring system for displaying at least one of:

a. working parameters of at least a part of ultrasonic transducers in the transducer sound bed and the transducer module;

b. lesion information within the target.

14. The combination according to any one of claims 1 to 5, wherein the chlorin derivative or pharmaceutically acceptable salt thereof is prepared by:

b ₁ : under the action of condensing agent, the compound 2 and beta-alanine tert-butyl ester hydrochloride are subjected to condensation reaction to obtain a compound 3:

wherein R is ₁ Is thatWherein n is any integer from 2 to 7;

d ₁ : the compound 4 undergoes hydrolysis reaction to obtain a compound 5:

wherein M is 2H, or is a divalent metal ion or a tetravalent metal ion upon reaction with a metal chloride or acetate complex, wherein R ₈ As defined in claim 1;

or (b)

wherein R is ₁ Is thatWherein n is any integer from 2 to 7;

wherein M is 2H, or is divalent metal ion or tetravalent metal ion after reaction with metal chloride or acetate complex;

c ₂ : in alkaline conditionsUnder the condition that the compound 11 undergoes hydrolysis reaction, the compound 13 is obtained:

wherein M is 2H, or is a divalent metal ion or a tetravalent metal ion after reaction with a metal chloride or acetate complex,

wherein R is ₃ As defined in claim 1;

or (b)

wherein R is ₁ Is thatWherein n is any integer from 2 to 7,

Wherein M is 2H, or is a divalent metal ion or a tetravalent metal ion upon reaction with a metal chloride or acetate complex, wherein R ₄ As defined in claim 1.

15. The combination of claim 14, wherein the divalent metal ion is Cu ²⁺ 、Fe ²⁺ 、Zn ²⁺ 、Mg ² ⁺ 、Ni ²⁺ 、Co ²⁺ 、Pt ²⁺ Or Pd ²⁺ 。

16. The combination of claim 14, wherein the tetravalent metal ion is Sn ⁴⁺ Or Ti (Ti) ⁴⁺ 。

17. The combination of claim 14, wherein the method further comprises: in step e ₁ In the presence of alkaline conditions, the compound of formula II (a) undergoes hydrolysis to form the corresponding salt, namely the compound of formula II (b);

or (b)

In step d ₂ In the presence of alkaline conditions, the compound of formula III (a) undergoes hydrolysis to form the corresponding salt, namely the compound of formula III (b);

or (b)

In step b ₃ In (b), the compound of formula IV (a) is subjected to hydrolysis under basic conditions to form the corresponding salt, i.e. IV (b) compound.