CN112915217B - Prostate cancer targeted prodrug and synthesis method thereof - Google Patents

Prostate cancer targeted prodrug and synthesis method thereof Download PDF

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CN112915217B
CN112915217B CN202110126832.8A CN202110126832A CN112915217B CN 112915217 B CN112915217 B CN 112915217B CN 202110126832 A CN202110126832 A CN 202110126832A CN 112915217 B CN112915217 B CN 112915217B
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沈浪涛
周旭
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Atom High Tech Co ltd
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Abstract

The invention belongs to the technical field of cancer targeted drugs, and particularly relates to a precursor of a prostate cancer targeted metal drug and a synthesis method thereof, wherein the structural general formula of the metal drug precursor M is as follows:

Description

Prostate cancer targeted prodrug and synthesis method thereof
Technical Field
The invention belongs to the technical field of cancer targeted drugs, and particularly relates to a prostate cancer targeted prodrug and a synthesis method thereof.
Background
Prostate cancer is one of the malignant tumors that seriously threaten the health of men. The incidence of prostate cancer has been increasing in recent years and has become the fastest growing disease species in malignant tumors.
At present, the clinical diagnosis of the prostate cancer mainly depends on rectal digital examination, serum Prostate Specific Antigen (PSA) examination, transrectal ultrasonic examination, computed Tomography (CT), magnetic Resonance Imaging (MRI) and the like, and all the examination methods have certain values but have defects and cannot effectively carry out early diagnosis of the prostate cancer.
PET/CT (positron emission tomography) is one way of nuclear medicine imaging. It can reveal the condition of early onset and development of disease at molecular or cellular level, and is a powerful means for early imaging diagnosis of prostate cancer and other tumors.
Positron-emitting radiopharmaceuticals have to be used in PET/CT imaging. The radioactive medicines for the PET/CT imaging diagnosis of the prostatic cancer mainly comprise C-11 labeled choline, F-18 labeled methyl choline and F-18 labeled fluciclovine. C-11 labeled choline is used for detection of primary prostate cancer, but it is difficult to distinguish prostate cancer from prostatitis or benign prostatic hypertrophy since the drug has a high uptake also in prostatitis or benign prostatic hypertrophy. F-18 labeled methyl or ethyl choline makes it difficult to diagnose locally recurrent prostate cancer. The sensitivity and specificity of diagnosing prostate cancer by F-18 labeled fluciclovine imaging are not high. In addition, these drugs require the use of the F-18 species, which can only be produced by expensive cyclotrons. After the F-18 nuclide is obtained, the F-18 labeled PET medicine needs to be synthesized, separated and purified by an automatic synthesizer which is not expensive and has complex operation. The entire process of F-18 labeling PET drugs is complex and time consuming. Therefore, there is a need for developing a non-F-18 labeled PET drug with better prostate cancer imaging diagnosis effect and easy production.
Ga-68 is generally made of a less expensive material 68 Ge/ 68 Ga generator. The half-life of Ge-68 was about 271 days, so one was 68 Ge/ 68 The Ga generator can stably supply Ga-68 nuclide for about 1 year, which provides great convenience for preparing various Ga-68 medicines at any time. The Ga-68-labeled PET medicine is prepared by the coordination reaction of trivalent Ga-68 ions and coordination groups in the medicine. The coordination reaction (i.e., radiolabelling) of Ga-68 ions with ligands is usually fast (complete in a matter of minutes-ten and several minutes) and high in labeling rate (generally greater than 90%, even almost quantitative), without additional isolation and purification of the drug. The synthesis process of the Ga-68 labeled PET medicine is simple and takes short time. Thus, is composed of 68 Ge/ 68 The Ga-68 marked PET medicine generated by the Ga generator is beneficial to popularization and use and has wide application prospect.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a class of prostate cancer-targeting prodrugs that form coordination compounds with gallium.
The structural general formula of the prodrug M is as follows:
Figure BDA0002924290930000021
Figure BDA0002924290930000031
the m is an integer of 2-5, the n is an integer of 1-9, and m at different positions can be the same or different.
The prostate specific membrane antigen PSMA (prostate specific membrane antigen) is overexpressed on the surface of all prostate cancer cells. It has been shown to have high sensitivity and specificity in the diagnosis of prostate cancer. The compound M can be specifically combined with a PSMA binding site on the cell surface, so that the targeted early diagnosis of the prostate cancer is realized; can also be chelated with a specific nuclide Ga, thereby achieving the purpose of tumor diagnosis or treatment.
Preferably, m is an integer of 2 to 5, and n is an integer of 1 to 5;
preferably, m is 3,n is 2;
preferably, the synthetic route of the prodrug is as follows:
Figure BDA0002924290930000032
Figure BDA0002924290930000041
the synthesis of the compounds B and D comprises the following steps:
Figure BDA0002924290930000042
Figure BDA0002924290930000051
preferably, in the process of synthesizing the compound B from the compound A, the feeding mole number of the diamine compound is 1.4 to 1.8 times of that of the compound A;
in the reaction process, firstly adding a diamine compound, then adding NaOH, and finally adding a compound A;
preferably, in the process of synthesizing the compound C, nitromethane is added, the temperature is preheated to 65-70 ℃, triton B is added, and tert-butyl acrylate is slowly added, and the reaction temperature is controlled not to exceed 80 ℃.
Preferably, in the process of synthesizing the compound H from the compound G, the feeding mole number of the compound B is more than 4 times of that of the compound G, and the reaction time is more than 3 days;
in the post-treatment process of the reaction, silica gel used for column chromatography is 200-300 meshes, and an eluent comprises the following components: dichloromethane: methanol: triethylamine =5:1:0.05;
preferably, in the process of synthesizing the compound I from the compound H, reactants and hydrazine hydrate are added into ethanol, and the mixture is refluxed for 6 to 10 hours;
preferably, after the synthesis of compound K from compound I and compound J, the silica gel used for column chromatography in the post-treatment is 200-300 mesh, and the eluent consists of: dichloromethane: methanol: triethylamine =5:1:0.05;
preferably, in the synthesis of compound L from compound K, a Pd/C catalyst is used, and the reaction is carried out in the presence of hydrogen for 2 to 4 days;
during the process of synthesizing the compound M from the compound L, trifluoroacetic acid is used for reacting for 1.5-2.5 h at room temperature.
Preferably, in the process of preparing the compound F from the compound E, preparing the compound H from the compound G, preparing the compound J from the compound I and preparing the compound K from the compound I, the adopted active ester is any one of dicyclohexylcarbodiimide, 1-propylphosphoric anhydride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, N-hydroxysuccinimide, 1-hydroxybenzotriazole, O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroboric acid or a combination thereof.
The invention also protects the application of the prodrug in the preparation of early diagnosis drugs for prostate cancer.
Preferably, the prodrug is reacted with 68 Ga forms a coordination compound and is used for preparing a medicine for early diagnosis of the prostatic cancer.
The invention also protects the application of the prodrug in the preparation of a prostate cancer treatment drug.
The invention also protects the application of the prodrug of the invention in preparing a excretion-promoting medicament.
Preferably, in the preparation of promoted Al 3+ 、Fe 3+ 、Ac 3+ 、Th 4+ And other radioactive lanthanide metal ions.
Preferably, the prodrug is introduced into the human body in combination with Al in the body 3+ 、Fe 3+ 、Ac 3+ 、Th 4+ And other radioactive lanthanide series metal ions form coordination compounds, promote the discharge of the metal ions in the human body and play a role in detoxification.
The invention has the following beneficial effects:
1) The compounds of the invention contain 3 functional groups of 2-methyl-3-hydroxy-4-pyridone, facilitating coordination to the metal ions of stable metallospecies such as trivalent gallium (Ga) and its radioactive isotopes gallium-68/67/66, and all isotopes of trivalent iron (Fe), indium (In), bismuth (Bi), lutetium (Lu), yttrium (Y), scandium (Sc), samarium (Sm), terbium (Tb), gadolinium (Gd), actinium (Ac), aluminium (Al) and tetravalent thorium (Th), including stable isotopes and radioactive isotopes.
2) The compounds of the present invention contain 1 DUPA (Glu-urea-Glu: glutamic acid-urea-glutamic acid). Can be specifically and firmly combined with PSMA (prostate specific membrane antigen), thereby targeting prostate cancer.
3) The spacing of the compound DUPA fragments of the invention from the central backbone of the compound is separated by different chain lengths (n =1,2,.., 9). This chain length can modulate the spacing between DUPA and the metal chelating group, affecting the degree of binding firmness of DUPA to PSMA and modulating the lipid solubility of the overall compound.
4) The spacing of the 2-methyl-3-hydroxy-4-pyridone functional groups in the compounds of the invention from the central backbone of the compound is separated by different chain lengths (m =2,3,4,5). The chain length can adjust the coordination environment when 3 2-methyl-3-hydroxy-4-pyridone functional groups coordinate with various metal ions with different ionic radii and adjust the fat solubility of the whole compound.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound PSMA-GK;
FIG. 2 shows PSMA-GK and gallium nitrate (Ga (NO) 3 ) 3 ) Mass spectrum of mixed solution (pH = 6.5).
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1
The compounds referred to in the examples are numbered as follows:
a compound A:
Figure BDA0002924290930000071
compound B:
Figure BDA0002924290930000072
compound C:
Figure BDA0002924290930000073
compound D:
Figure BDA0002924290930000081
compound E:
Figure BDA0002924290930000082
compound F:
Figure BDA0002924290930000083
compound G:
Figure BDA0002924290930000084
compound H:
Figure BDA0002924290930000091
a compound I:
Figure BDA0002924290930000092
compound J:
Figure BDA0002924290930000093
compound K:
Figure BDA0002924290930000101
a compound L:
Figure BDA0002924290930000102
compound M:
Figure BDA0002924290930000111
the compound is prepared by the following method:
a compound A: methyl maltol (20 g) was used as a starting material, and methanol (100 mL) was used as a solvent, and the starting material was dissolved by stirring. To the above solution was added dropwise a 7M NaOH solution (12.5 mL). After completion of the dropwise addition, benzyl chloride (13.2 g) was added dropwise to the above solution, followed by refluxing overnight. The white solid formed in the reaction was removed by filtration, the solvent was removed by rotary evaporation, the crude product was dissolved in dichloromethane, washed three times with 5% NaOH solution and water, respectively, and the organic phase was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, the dichloromethane removed by rotary evaporation and the remaining oil dried in vacuo. Yield: 80 to 95 percent.
Compound B: (m =2,3,4,5) m =3 as an example: propylene diamine (1.7 g) was used as a starting material, and was dissolved in a mixed solution of 10mL of ethanol and 20mL of deionized water, and 2M NaOH solution (2 mL) was added to the solution. Compound A (5 g) was dissolved in ethanol (10 mL) and slowly dropped into the above solution using a constant pressure dropping funnel. The reaction was carried out at 60 ℃ overnight. Ethanol was removed by rotary evaporation and 50mL of water was added to the system. The pH =1,dcm50ml was adjusted with 2M HCl and washed three times, leaving the aqueous phase. The aqueous phase was adjusted to pH =12 with 10M NaOH and extracted four times with dcm 100ml. The organic phases were combined and dried over sodium sulfate. The sodium sulfate was removed by filtration and the organic phase was spin-dried to give a brown yellow viscous oil. Yield: 50 to 70 percent.
Compound C: DME 20mL, nitromethane 6.1g, stirred in a round bottom flask. The temperature was monitored with a thermometer. The temperature was preheated to 65-70 degrees Celsius and 1mL of Triton B (40% in MeOH) was added with no significant change in temperature. 39.7 g of tert-butyl acrylate were added in portions by syringe. And continuously dropwise adding tert-butyl acrylate until all the tert-butyl acrylate is completely dripped. When 13 g and 26 g of t-butyl acrylate were added dropwise, 1ml of Triton B was added. After all the solution is added, the reaction is carried out for 2 to 3 hours at a temperature of between 70 and 75 ℃. Return to room temperature and spin dry the solvent. The resulting large amount of solid was dissolved in 150mL of dichloromethane, and washed with 10% HCl 50mL and saturated brine 3 × 50mL, respectively. Drying over sodium sulfate and spin-drying to remove dichloromethane afforded a large amount of a milky white solid. 90mL 95% ethanol. Yield: 40 to 80 percent.
Compound D: note that: the used aluminum-nickel alloy catalyst can be discarded after being diluted by a large amount of water and treated by dilute acid, and cannot be discarded at will.
100mL of absolute ethanol and 4.46g of compound C were added to the activated AlNiAl alloy catalyst (protected by absolute ethanol). Replacing nitrogen for three times; the hydrogen was replaced three more times. The reaction was carried out for 3 days at 60 ℃ using a hydrogen balloon. The aluminum nickel alloy is removed by the diatomite, and the diatomite is washed by ethanol until the filtrate is spotted on the plate and no product is spotted. The filtrates are combined and spin-dried. And (3) passing ethyl acetate through a column, performing spin drying after passing the ethyl acetate through the column to obtain colorless viscous oil, and standing at a low temperature to gradually solidify the oil to obtain a white solid. Yield: 85 to 100 percent.
Compound E: (n =2,3,4, …, 9) for example n = 2: 10g of phthalic anhydride, 6g of beta-aminopropionic acid and 66mL of acetic acid were added to a round-bottomed flask, and the mixture was refluxed for 4 hours. Spin dry directly, wash with water to pH =7, dry in vacuo. Yield: 86 to 95 percent.
Compound F: compound E (0.53 g) and compound D (0.83 g) were added to 15mL of dichloromethane in an ice bath. Anhydrous HOBT (0.31 g), EDC (0.48 g) was added. The reaction was warmed up overnight. Three times of deionized water washing. Drying with sodium sulfate, removing solvent by rotary drying, and passing through a column. Eluent proportioning: ethyl acetate/petroleum ether (boiling range: 60-90 degrees celsius) =1:1. yield: 70 to 90 percent.
Compound G: compound F was dissolved in as little formic acid as possible and stirred overnight at room temperature. Spin-dry to give a white solid. Residual formic acid was removed in a vacuum drying oven. Yield: 90 to 100 percent.
Compound H: compound B (3.9G) and compound G (1.6G) were added to 15mL of N, N-dimethylformamide and cooled in an ice bath. Anhydrous HOBT (2.1 g), EDC (3.0 g) was added. The reaction was warmed up overnight. The solvent was removed by rotary evaporation, the remaining oil was dissolved with dichloromethane and washed three times with deionized water. Dried over sodium sulfate, rotary dried to remove dichloromethane, and passed through a column. Eluent proportioning: dichloromethane/methanol/triethylamine =5:1:0.05. yield: 20 to 30 percent.
A compound I: compound H (900 mg) was dissolved in 20mL of ethanol. To the above solution was added 900mg of hydrazine hydrate (purity 5% -50%) and refluxed for 3-8 hours. The system was cooled to 0 ℃, the pH was adjusted to 1 with concentrated hydrochloric acid, and the white solid was removed by filtration. The filtrate was spin-dried and the residue was dissolved in 30 ml of deionized water, adjusted to pH 12 with 10M sodium hydroxide solution and extracted three times with chloroform. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the sodium sulfate and the organic phase was spin dried. Yield: 90 to 100 percent.
Compound J: l-glutamic acid di-tert-butyl ester hydrochloride (5 g) was charged into a round-bottomed flask, and dissolved by adding 100mL of dichloromethane. Triethylamine (7.8 mL) was added to the above solution and the system was cooled to-78 ℃. At this temperature, a solution of triphosgene (1.71 g) in dichloromethane (10 mL) was added to the system and the temperature was maintained at-78 ℃ for one hour. The system was returned to room temperature and held for one hour. The system was again cooled to-78 deg.C, and a solution of L-glutamic acid-5-benzyl ester-1-tert-butyl ester hydrochloride (6 g) in dichloromethane (25 mL) and triethylamine (5.7 mL) were added thereto, and the mixture was allowed to react overnight at room temperature.
After the reaction, the system was quenched with 1M hydrochloric acid, the organic phase was separated with dichloromethane, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and dichloromethane was spin-dried. And (5) passing through the column. Eluent polarity: ethyl acetate: petroleum ether =1:1.
the product is dissolved in dichloromethane, and 1-10% Pd/C catalyst is added. The system was purged with nitrogen three times and with hydrogen three times. The reaction was carried out under hydrogen conditions at room temperature for 24 hours.
After the reaction, the mixture was diluted with dichloromethane and passed through celite. Spin-drying to remove organic solvent, and passing through the column. Eluent polarity: petroleum ether: ethyl acetate =4:6. and recrystallizing by using petroleum ether/dichloromethane. Total yield: 60 to 90 percent.
Compound K: compound J (0.6 g), compound I (1.1 g), was added to 15mL of N, N-dimethylformamide and cooled in ice. Anhydrous HOBT (160 mg), EDC (240 mg) was added. The reaction was warmed up overnight. The solvent was removed by rotary evaporation, the remaining oil was dissolved in dichloromethane and washed three times with deionized water. Dried over sodium sulfate, rotary dried to remove dichloromethane, and passed through a column. Eluent proportioning: dichloromethane/methanol/triethylamine =5:1:0.05. yield: 20 to 80 percent.
A compound L: dissolving the compound K (100 mg) in ethanol, and adding 1-10% of Pd/C catalyst. The system was purged with nitrogen three times and with hydrogen three times. The reaction was carried out under hydrogen conditions at room temperature for 24 hours. After the reaction, the mixture was diluted with ethanol and passed through celite. The organic solvent was removed by spin-drying.
Compound M: compound L (100 mg) was dissolved in trifluoroacetic acid, reacted at room temperature for 3 hours, and the solvent was spin-dried.
Nuclear magnetic resonance hydrogen spectrum data and high resolution mass spectrum data for the compound PSMA-GK (i.e., when n =2 and M =3 for the compound of general formula M) are shown below. The hydrogen spectrum is shown in figure 1:
1 H NMR(400MHz,DMSO-d6)δ1.72(m,CHCH 2 CH 2 COOH,2H),1.79-1.97(m,CONHCH 2 CH 2 CH 2 ,CCH 2 CH 2 ,CHCH 2 CH 2 CONH,14H),2.04(m,CCH 2 CH 2 ,6H),2.12(m,CHCH 2 CH 2 COOH,2H),2.24(m,CONHCH 2 CH 2 ,CHCH 2 CH 2 CONH,4H),2.50(s,CH 3 ,9H),3.10(m,CONHCH 2 CH 2 CH 2 ,6H),3.25(t,CONHCH 2 CH 2 ,2H),4.06(m,CONHCHCOO,1H),4.11(m,CONHCHCOO,1H),4.31(t,CONHCH 2 CH 2 CH 2 ,6H),6.40(t,Urea-H,2H),7.16(d,COCHCHN,3H),7.29(s,CONHC,1H),7.91(m,CONHCH 2 ,1H),8.00(m,CONHCH 2 ,3H),8.22(d,COCHCHN,3H).
HRMS M/z calculated 1113.5099 (M + H) + Found 1113.5094 (M + H) + .
Example 2
The difference compared to example 1 is that the active ester used in the synthesis of compound F is DCC.
Example 3
The difference compared to example 1 is that the active ester used in the synthesis of compound H is EDC.
Example 4
The difference from example 1 is that the active ester used in the synthesis of compound K is HBTU.
Experimental example 1
The experiment takes the case that a prodrug compound PSMA-GK forms a metal complex with a naturally-occurring gallium (namely, gallium stable isotope without radioactivity) trivalent ion as an example, and shows that the invented prodrug has the function of chelating metal ions such as gallium and the like.
The experimental method comprises the following steps:
adding gallium nitrate (Ga (NO) 3 ) 3 ) The solution was mixed with an aqueous solution of PSMA-GK (prepared in example 1) and then treated with a hydrochloric acid solution (0.1 mol/l HCl) and sodium bicarbonate solution (1 mol/l NaHCO) 3 ) The pH of the mixture was adjusted to pH =6.5. The final concentration of the mixture was 0.022. Mu. Mol/l, and the mixture was left at room temperature.
The mass spectrum of the mixture was measured by time-of-flight mass spectrometry (MAIDI-TOF), and the results are shown in fig. 2.
The experimental results are as follows:
in the mass spectrum, a mass/charge ratio (m/z) of 1179.858 is observed as the most intense mass peak. The peak corresponds to the molecular formula C 51 H 70 N 10 O 18 M +1 peak of Ga compound. Compound C 51 H 70 N 10 O 18 The molecular weight of Ga is 1178.404 and its M +1 peak calculated 1179.412, consistent with the observation (1179.858). In addition, a mass at 1201.639 was observedA peak corresponding to the molecular formula C 51 H 69 N 10 O 18 M + Na peak for compound of GaNa. Compound C 51 H 69 N 10 O 18 GaNa has a molecular weight of 1201.395, also consistent with observations (1201.639).
This indicates that 3 2-methyl-3-hydroxy-4-pyridone functional groups in the PSMA-GK compound are each dissociated into 1 hydrogen ion and Ga 3+ A metal complex of trivalent gallium is effectively formed. In the mixed solution, the formula is C 51 H 70 N 10 O 18 The complexes of Ga are the most predominant components.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims (6)

1. The application of a class of prodrugs in the preparation of early diagnosis drugs for prostate cancer is characterized in that the prodrugs and 68 ga forms a coordination compound to be used for preparing an early diagnosis medicament for the prostatic cancer, and the structural general formula of the medicament precursor M is as follows:
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M
m at different positions is 3,n is 2.
2. The use according to claim 1, wherein the prodrug is synthesized by the following route:
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Figure DEST_PATH_IMAGE007
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。
3. the use according to claim 2, characterized in that the synthesis of compounds B and D comprises the following steps:
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。
4. the use according to claim 3, wherein the molar amount of diamine compound(s) added during the synthesis of compound (B) from compound (A) is 1.4 to 1.8 times the molar amount of compound (A);
in the reaction process, firstly adding a diamine compound, then adding NaOH, and finally adding a compound A;
and/or, in the process of synthesizing the compound C, adding nitromethane, preheating to 65-70 ℃, adding Triton B, then slowly adding tert-butyl acrylate, and controlling the reaction temperature to be not more than 80 ℃.
5. Use according to any one of claims 2 to 4, characterized in that it comprises the following steps:
in the process of synthesizing the compound H from the compound G, the feeding mole number of the compound B is more than 4 times of that of the compound G, and the reaction time is more than 3 days;
in the work-up of the reaction product from compound G to compound H, the silica gel used for column chromatography is 200-300 mesh, and the eluent composition is: dichloromethane: methanol: triethylamine =5:1:0.05;
and/or adding a reactant and hydrazine hydrate into ethanol in the process of synthesizing the compound I from the compound H, and refluxing for 6 to 10 hours;
and/or after compound K is synthesized by the compound I and the compound J, silica gel used for column chromatography in post-treatment is 200-300 meshes, and the eluent comprises the following components: dichloromethane: methanol: triethylamine =5:1:0.05;
and/or, in the synthesis of compound L from compound K, using a Pd/C catalyst, the reaction is in the presence of hydrogen for 2~4 days;
during the synthesis of the compound M from the compound L, trifluoroacetic acid was used for reaction at room temperature for 1.5 to 2.5 hours.
6. The use according to claim 2, wherein in the process of producing the compound F from the compound E, the compound H from the compound G, the compound K from the compound J and the compound K from the compound I, the active ester used is any one of dicyclohexylcarbodiimide, 1-propylphosphoric anhydride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, N-hydroxysuccinimide, 1-hydroxybenzotriazole, O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroboric acid or a combination thereof.
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