TWI656126B - A precursor of a histone deacetylase inhibitor pet imaging compound for tracking cerebral neurodegenerative and tumor diseases - Google Patents

Abstract

The invention provides a nuclear medicine tracer imaging technique marking method, comprising the label precursor of the HDAC inhibitor BNL-26 (C ₂₂ H ₂₃ N ₃ O) and its derivatives, wherein the first category includes BNL-26 (C ₂₂ H ₂₃ N ₃ O) analogues BNL-26a (C ₂₁ H ₂₁ N ₃ O), BNL-26b (C ₂₂ H ₂₂ N ₂ O) and the signature precursors of four compounds, the marking method can be divided into two In part, the first part includes BNL-26-CH ₂ CH ₂ OTs (C ₃₁ H ₃₃ N ₃ O ₄ S), BNL-26a-CH ₂ CH ₂ OTs (C ₃₀ H ₃₁ N ₃ O ₄ S), BNL-26b -CH ₂ CH ₂ OTs (C ₃₁ H ₃₂ N ₂ O ₄ S), the precursor of the label is transmitted through the -CH ₂ CH ₂ OTs structure, and the second part includes pre-BNL-26 (C ₂₈ H ₃₄ N ₃ O ₃ B), pre-BNL-26a (C ₂₇ H ₃₂ N ₃ O ₃ B), pre-BNL-26b (C ₂₈ H ₃₃ N ₂ O ₃ B), through 4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl structure is the precursor of the marker effect. The second class includes BNL-26 (C ₂₂ H ₂₃ N ₃ O) and ruthenium/porphyrin, a precursor of a series of derivatives formed by a combination of secondary guanamine bonds.

Description

A novel brain neurodegenerative and tumor disease tissue protein to B Marker precursor of chymase inhibitor PET contrast compound

The invention relates to a nuclear medicine tracer imaging technique marking method, in particular to a method for manufacturing a HDAC inhibitor BNL-26 (C ₂₂ H ₂₃ N ₃ O) and a derivative precursor thereof.

Neurodegenerative diseases are a state of disease in which cellular neurons of the brain and spinal cord are lost. Because neuronal cells do not have the ability to regenerate, excessive damage will lead to dysfunction. Common disease Alzheimer's disease (Alzheimer disease), Parkinson's disease (Parkinson 's disease), Huntington's chorea (Huntington' s disease) and so on.

The global population is rapidly aging, with approximately 44 million patients worldwide suffering from neurodegenerative diseases in 2013 and an increase to 135 million in 2050. 2015 for the United States to take care of The cost of treating patients with neurodegenerative diseases is about 1.1 trillion. The huge market has become the target of major pharmaceutical companies, and "HDAC inhibitors" are one of the hot options.

Tissue protein deacetylase inhibitor (HDAC inhibitor, abbreviated as HDACi or HDAC inhibitor), is a drug class that inhibits the function of the tissue protein in the body to deacetylase. Currently, the medical community has studied through tissue protein deacetylase. Inhibitors are used to treat neurodegenerative diseases. In recent years, studies have also pointed out that chromatin modification in brain cells is related to the formation of memory. The research team pointed out that HDAC enzyme plays a key role. This enzyme secretes abnormal mice with memory loss, and also suffers from neurodegeneration. A similar situation was found in the brains of patients with disease.

In recent years, the medical profession has also studied the treatment of cancer through the "tissue protein deacetylase inhibitor". The specific mechanism of these inhibitors, the literature suggests possible characterization of genetic pathways, such as Richon et al. found that HDAC inhibitors can regulate p53 tumor suppressor function by directing p21 (WAF1). At present, cancer treatment and drug treatment, surgical resection and radiation therapy are the three major options for treating cancer. In terms of drug treatment, although the general chemotherapy drugs have a powerful effect on killing cancer cells, they will also kill normal cells. Therefore, all major international pharmaceutical companies are fully committed to developing targeted drugs that can accurately attack cancer cells.

Targeted drugs Since 2004, due to significant medical results, sales volume has grown rapidly. Target treatment in 2005 is only $5 billion market, estimated by 2025 It will reach 60 billion US dollars. Therefore, the application of tissue protein deacetylase inhibitor drugs (HDAC inhibitors) will be a new hope for the future treatment of malignant tumor diseases and neurodegenerative diseases.

The invention relates to a nuclear medicine tracer imaging technique, which comprises an HDAC inhibitor BNL-26 (C ₂₂ H ₂₃ N ₃ O) and its analogues BNL-26a (C ₂₁ H ₂₁ N ₃ O), BNL-26b (C Another four compounds, such as ₂₂ H ₂₂ N ₂ O), mark the radionuclide F-18, producing a series of novel nuclear medical tracers such as BNL-26-CH ₂ CH ₂ ¹⁸ F, BNL-26a-CH ₂ CH ₂ ¹⁸ F, BNL-26b-CH ₂ CH ₂ ¹⁸ F, etc., for binding to the overexpressed tissue protein deacetylase in the body, resulting in a novel group of compounds of the focused HDAC nuclear image.

The present invention aims to provide a novel compound for diagnosing malignant tumor diseases and cranial nerve degenerative diseases, and utilizing the positron decay characteristic of the fluorine-18 isotope, when the positrons released by the decays encounter the electrons of the cells, a "mutual destruction reaction" occurs. (annihilation reaction), forming a pair of 511 keV gamma rays in opposite directions, and obtaining images by positron emission tomography (PET).

In the past, for many organs such as colon, rectum, cervix, stomach, prostate cancer and developmental disorders and other related diseases, the efficacy has not yet broken through. In addition to the above studies, which have not yet had satisfactory results, recent studies have also pointed out that in the process of natural aging, The brain is atrophied and it is an early feature of neurodegenerative diseases associated with impaired cognitive function and memory loss. Dementia-related diseases such as Alzheimer's disease cause significant loss of cognitive function, often causing the patient to deteriorate to a state where they cannot recover. There are no known methods for treating Alzheimer's disease and related cranial nerve degenerative diseases, and the causes of these diseases are not well understood.

As a new generation of targeted anti-tumor drugs, Histone Deacetylase (HDAC) inhibitors have become a hot spot in drug research. Existing HDAC inhibitors can be mainly classified into: Hydroxamic acids: including Vorinostat; Cyclic tetrapeptides: including Romidepsin (FK228) and depsipeptide; Benzamidines: including MS-275 and SC-027, are also undergoing relevant clinical trials in degenerative brain diseases; Short-chain fatty acids: including valproic acid, butyric acid, and the like. Therapeutic effects of HDAC inhibitors on hematological tumors and solid tumors have been demonstrated in both in vivo and in vitro assays. In vitro experiments have confirmed that HDAC inhibitors have a good anti-tumor effect on a variety of tumor cells, including the bladder, bone, breast, uterus, central nervous system, esophagus, lung, ovary, pancreas, prostate, etc., which can make these tumor cells appear obvious Apoptosis, proliferation inhibition, and cell cycle arrest. A variety of HDAC inhibitors have entered Phase I or Phase II or Phase III clinical studies of anti-tumor therapy due to their multi-channel efficient anti-cancer therapy.

There are already Vorinostat (suberoylanilide hydroxamic acid, SAHA) and Romidepsin (ring) Peptides) have been approved by the US FDA for the application of cutaneous T-cell lymphoma (CTCL) as an indication, and their application in the treatment of solid tumors is also in clinical trials.

According to 2015 molecules, the current clinical trials of HDACi small molecule drugs including MS275, CI994, etc. are slow due to side effects or lack of clinical expectations. Related literatures such as Mocules 2015, 20 Table 3 "Benzamide short chain fatty acid and cyclic peptide based HDAC inhibitors in clinical trials".

The benzotriamide HDAC inhibitor citabin has been approved by the microbial organisms in the mainland for SFDA approval. For the non-Hodgkin's lymphoma in clinical phase II/III studies, the FDA approved clinical research in the United States in 2010. The novel HDAC inhibitor can induce tumor cell differentiation and selective apoptosis at low dose and low concentration, and is non-toxic to normal cells, and its anti-tumor proliferation.

According to the IMS market survey, the global market for anticancer drugs is more than $100 billion annually, and it is growing at a compound annual growth rate of 8.4%, with unlimited business opportunities. This patent combines HDAC target and chemotherapeutic drug (Indoline) to reduce the dose and improve the therapeutic effect. This is the technical feature of this patent.

Diagnosis of tumor, whether it is a tumor, the nature of the tumor, benign or malignant, the stage of the malignant tumor and the presence or absence of metastasis Often important. Tumors are often found late. At this point it has damaged one or more functions of vital vital organs and has even transferred to the body. Therefore, the key issue in the treatment of tumors is how to detect such tumors early, but early detection of malignant tumors is still very difficult.

Clinical imaging diagnosis includes X-ray examination, ultrasound examination, magnetic resonance imaging, X-ray tomography (CT) and radioisotope examination. The diagnosis of tumor and neurodegenerative diseases of the brain is of great significance, because only early diagnosis can obtain the treatment, in order to obtain better therapeutic effect. However, due to various subjective and objective reasons, most patients have advanced tumors at the time of treatment or diagnosis, and the treatment effect is not satisfactory. Although the diagnosis of tumors is rapidly developing, many tumor examination methods are not practical enough. When the diameter is 1~1.5cm, the image map can be clearly displayed.

General blood tests are not accurate enough. For example, prostate specific antigen (APA) is a glycoprotein. This antigen can only be produced by prostate cells. When there is a problem with the prostate (such as prostate cancer), the prostate cells will hyperplasia, producing excessive PSA, which increases the concentration of PSA in the blood. The doctor can analyze the patient's likelihood of developing prostate cancer based on the blood PSA concentration. However, there are several factors that lead to an increase in PSA, such as prostate infection, benign hyperplasia of the prostate. In addition, not all patients with prostate cancer have elevated PSA, resulting in a PSA test that cannot be diagnosed.

For the diagnosis of degenerative diseases of the brain, basic examinations include neuropsychological tests, blood routine, biochemical tests (liver and kidney function), vitamin B12 concentration, thyroid function, syphilis serum test, and brain computerized tomography or magnetic resonance imaging. High-order PET positron imaging diagnostic methods include: F-18-AV45 and F-18-PIB based on the theory of Amyloid hypothesis; based on the theory of microtubule-associated protein hypothesis (Tau hypothesis) The drug is not yet available.

The diagnosis of Alzheimer's disease, taking the latest F-18-AV45 and F-18-PIB PET drugs as an example, the image can only confirm the diagnosis of Alzheimer's disease, but can not confirm whether there is A Zhaimer's disease can also produce the same image response due to aging.

Many malignant tumors and developmental disorders have been found to have excessive HDAC-2 performance. In recent years, studies have also pointed out that chromatin modification in brain cells is related to the formation of memory. The research team pointed out that HDAC enzyme plays a key role. The mice secreted by this enzyme have memory loss, and also suffer from degeneration of brain nerves. A similar situation was found in the brains of patients with disease. Therefore, the use of tissue protein deacetylase inhibitor drugs (HDAC inhibitors) to mark radionuclides will be a new hope for the early diagnosis of tumor diseases and neurodegenerative diseases in the future.

Tissue protein deacetylase inhibitor (HDAC inhibitor, abbreviated as HDACi or HDAC inhibitor) is a function of inhibiting the activity of tissue in the body by deacetylase In the drug category, the medical community treats cancer and neurodegenerative diseases through "tissue protein deacetylase inhibitors".

The invention relates to a traditional nuclear medicine tracer imaging technique marking method, and describes a HDAC inhibitor BNL-26 (C ₂₂ H ₂₃ N ₃ O) and a derivative precursor thereof, which are classified into two categories: the first category includes BNL- 26 (C ₂₂ H ₂₃ N ₃ O) analogues BNL-26a (C ₂₁ H ₂₁ N ₃ O), BNL-26b (C ₂₂ H ₂₂ N ₂ O) and the signature precursors of four compounds, the labeling methods are different It can be divided into two parts, which are subdivided into two parts due to different marking methods: the first part includes BNL-26-CH ₂ CH ₂ OTs (C ₃₁ H ₃₃ N ₃ O ₄ S), BNL-26a-CH ₂ CH ₂ OTs (C ₃₀ H ₃₁ N ₃ O ₄ S), BNL-26b-CH ₂ CH ₂ OTs (C ₃₁ H ₃₂ N ₂ O ₄ S), a precursor of the mark through the -CH ₂ CH ₂ OTs structure; the second part Including pre-BNL-26 (C ₂₈ H ₃₄ N ₃ O ₃ B), pre-BNL-26a (C ₂₇ H ₃₂ N ₃ O ₃ B), pre-BNL-26b (C ₂₈ H ₃₃ N ₂ O ₃ B ), a precursor to the marker effect achieved by the 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl structure. The second class includes BNL-26 (C ₂₂ H ₂₃ N ₃ O) and ruthenium/porphyrin, a precursor of a series of derivatives formed by a combination of secondary guanamine bonds. These two classes of precursors are used in the back-end marker on the radioactive nuclear F-18, which in turn produces a new class of nuclear medical tracers.

The structural backbone of Group 1 containing the HDAC inhibitor BNL-26 and its analog precursors is shown in Table 1 below:

The procedure for synthesizing the above precursors is illustrated by the flow of the steps described below.

The (4-hydroxyphenyl) boronic acid and 5-chloro-2-nitroaniline are reacted in a solution of Pd(OAc) ₂ and K ₃ PO ₄ in DMF:H ₂ O=1:1 by heating at 100 ° C for 3 hours to form 3'. -amino-4'-nitro-[1,1'-biphenyl]-4-ol.

The -OH group in the structure of 3 ' -amino-4 ' -nitro-[1 , 1 ' -biphenyl]-4-ol was protected by -MOM, and the reaction was carried out in DCMEA in a low temperature reaction at a temperature of 0- 4 ' -(methoxymethoxy)-4-nitro-[1 , 1 ' -biphenyl]-3-amine was formed at 20 °C.

4 ' -(methoxymethoxy)-4-nitro-[1,1 ' -biphenyl]-3-amine and p-benzenecarboxylic acid with R group, coupling reagents such as HOBt, DMAP, EDCI in DCM and DMF solution The nucleophilic substitution reaction of the Bank of China forms N- (4 ' -(methoxymethoxy)-4-nitro-[1,1 ' -biphenyl]-3-yl)benzamide with an R group. The R group herein is -CH ₂ N(CH ₃ ) ₂ , -N(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₃ And other substituents.

N-(4 ' -(methoxymethoxy)-4-nitro-[1 , 1 ' -biphenyl]-3-yl)benzamide with R group is heated with iron powder, acetic acid in ethanol and water to form nitro group Reduction to an amine group forms N-(4-amino-4 ' -(methoxymethoxy)-[1 , 1 ' -biphenyl]-3-yl)benzamide with an R group.

N-(4-amino-4 ' -(methoxymethoxy)-[1 , 1 ' -biphenyl]-3-yl)benzamide with R group was removed by MOM protection with Me3SiBr in DCM solution at a temperature of 20 ° C. N-(4-amino-4 ' -hydroxy-[1 , 1 ' -biphenyl]-3-yl)benzamide with an R group.

N-(4-amino-4 ' -hydroxy-[1 , 1 ' -biphenyl]-3-yl)benzamide with R group is replaced by Tf ₂ O in a pyridine solution at low temperature to replace the -OH group -OTf group to form 4 '-amino-3' -benzamido- [ 1, 1 '-biphenyl] with a group R -4-yl trifluoromethanesulfonate.

There will be 4 '-amino-3' -benzamido- [ 1, 1 '-biphenyl] -4-yl trifluoromethanesulfonate to B2Pin, Pd2 (dba) 3, Xphos, KOAc replaced 4 R's in the solution was -OTf dioxane, 4 , 5 , 5-tetramethyl-1,3,2-dioxaborolane, at a temperature of 90 ° C, finally forming a precursor with an R group: (N-(4-amino-4 ' -(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-[1 , 1 ' -biphenyl]-4-yl)benzamide

Group 2 involves the replacement of Benzene with F-18-BNL-26 and its analog precursors into Pyridine:

1. Replace the A ring from Benzene to Pyridine, as follows:

2. Replace the B benzene ring with Benzene to pyridine, as follows:

3. Replace the C phenyl ring with Benzene to pyridine, as follows:

Group III contains the HDAC inhibitors BNL-26 and 吲哚/carboline derivatives. The structure of the precursors is shown in Table 3 below: (* indicates the bonding position)

The synthetic steps of the above precursors are illustrated by the following table:

The present invention aims to provide a novel diagnostic compound for malignant tumor diseases and Alzheimer's disease, which utilizes the positron decay characteristics of isotopes such as fluorine-18 or zirconium-89, and when the decay of the positrons is met, the cell electrons are generated. "annihilation", forming a pair of 511keV gamma rays in opposite directions, and obtaining images by positron emission tomography (PET).

Whether tumors and neurodegenerative diseases can be detected, diagnosed, and treated in a timely manner depends on the diagnostic method used. Recent advances in molecular biology have opened up several new avenues for the discovery, diagnosis, and treatment of malignant tumors. Although these new approaches are still in the process of research, the prospects are very promising. These new assays can be used to detect subtle changes in cells and to detect malignant tumors earlier. Such new technologies also contribute to the development of treatment regimens that are tailored to individual differences in patients and move toward the scientific goals of personalized therapy.

Claims (3)

A compound selected from the group consisting of any one of Groups 1 to 3, wherein Group 1 comprises a precursor of F-18-BNL-26 and its analogs, such as the following: Group 2 consists of replacing Benzene with F-18-BNL-26 and its analog precursors with Pyridine: 1. Replace the first (A) benzene ring with Benzene to Pyridine, as follows: 2. Replace the second (B) benzene ring with Benzene to pyridine, as follows: 3. Replace the third (C) benzene ring with Benzene to pyridine, as follows: Group III contains the signature precursors of a series of derivatives of F-18-BNL-26 and 吲哚/porphyrin: The above are the compounds of groups one, two and three respectively. A developer comprising the compound of item 1 and a tissue protein deacetylase inhibitor. A method for synthesizing a compound, wherein the compound is selected from Group 1 of Group 1, Group 2 and Group 3; wherein the method of synthesizing Group 1 comprises the step of: (4-hydroxyphenyl) boronic acid and 5-chloro -2-nitroaniline was heated to 100 ° C for 3 hours in a solution of Pd(OAc) ₂ and K ₃ PO ₄ in DMF:H ₂ O=1:1 to form 3'-amino-4'-nitro-[1, 1'-biphenyl]-4-ol; The -OH group in the 3'-amino-4'-nitro-[1,1'-biphenyl]-4-ol structure is protected with -MOM and reacted in DCMEA in DCM solution at a temperature of 0 to 20. °C, forming 4'-(methoxymethoxy)-4-nitro-[1,1'-biphenyl]-3-amine; 4'-(methoxymethoxy)-4-nitro-[1,1'-biphenyl]-3-amine and p-phenylcarboxylic acid with R group, in HOBt, DMAP, EDCI coupling reagent in DCM and DMF solution Nucleophilic substitution reaction to form N- (4'-(methoxymethoxy)-4-nitro-[1,1'-biphenyl]-3-yl)benzamide with an R group where the R group is -CH ₂ N(CH ₃ ) ₂ , -N(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₃ substituent; N-(4'-(methoxymethoxy)-4-nitro-[1,1'-biphenyl]-3-yl)benzamide with an R group is heated with iron powder, acetic acid in ethanol and water to form a nitro group. Reduction to an amine group to form N-(4-amino-4'-(methoxymethoxy)-[1,1'-biphenyl]-3-yl)benzamide with an R group; N-(4-amino-4'-(methoxymethoxy)-[1,1'-biphenyl]-3-yl)benzamide with R group was removed by -MOM protection with Me3SiBr in DCM solution at a temperature of 20 ° C. Forming N-(4-amino-4'-hydroxy-[1,1'-biphenyl]-3-yl)benzamide with an R group; N-(4-amino-4'-hydroxy-[1,1'-biphenyl]-3-yl)benzamide with R group is reacted with Tf ₂ O in pyridine solution to replace -OH group with -OTf a group forming a 4'-amino-3'-benzamido-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate having an R group; 4'-amino-3'-benzamido-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate will be substituted with 4 for B2Pin, Pd2(dba)3, Xphos, KOAc in dioxane solution, 4,5,5-tetramethyl-1,3,2-dioxaborolane, at a temperature of 90 ° C, finally forming a precursor with an R group: (N-(4-amino-4'-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)benzamide Among them, the synthetic group II compound is a tissue protein deacetylase (HDAC) inhibitor BNL-26 precursor (N-(4-amino-4 ' -(4 , 4 , 5 , 5-tetramethyl-1, 3, The first (A), the second (B), and the third (C) benzene ring of 2-dioxaborolan-2-yl)-[1 , 1 ' -biphenyl]-4-yl)benzamide are respectively substituted with Pyridine; Replace the A ring from Benzene to Pyridine, as follows: 2. Replace the B benzene ring with Benzene to pyridine, as follows: 3. Replace the C phenyl ring with Benzene to pyridine, as follows: Among them, the synthetic group III compound is a tissue protein deacetylase (HDAC) inhibitor BNL-26 precursor (N-(4-amino-4'-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)benzamide is a structure formed by combining a precursor of a ruthenium/porphyrin derivative, and comprises the following procedure: The above are the synthesis steps of groups one, two and three respectively.