KR101890993B1 - A diphenylnaphthylpyrazolinylcarbothioamide derivative with anti-cancer activity - Google Patents

Abstract

N- phenyl-naphthalenyl-pyrazolinyl-1-carbothioamide derivatives inhibit c-Abl enzyme activity and inhibit the growth of cancer cell lines at low concentrations and can be used as anticancer candidates.

Description

{A diphenylnaphthylpyrazolinylcarbothioamide derivative with anti-cancer activity}

The present invention relates to diphenylnaphthylpyrazolinylcarbothioamide derivatives having anticancer efficacy.

The simplest method for screening for substances showing anticancer effects is to measure whether or not cancer cells are killed by causing cytotoxicity against cancer cells. Since the anticancer effect is generally related to the structure of the substance, it is predicted that the difference in the anticancer effect will be large if the difference in structure is large. On the contrary, if the structural difference is similar, the difference in anticancer effect will be small. However, there is a method of measuring the colony forming ability of cancer cells (Clonogenic Assay) by a screening method that clearly distinguishes the anticancer effect caused by a minute structural difference. This method is widely used for screening substances having anticancer effect by analyzing the effect of specific substances on cell proliferation and survival. In addition, since it is widely used in recent years as a method of identifying differences in anticancer effects by microscopic structural differences, the present invention uses a measurement method for inhibiting the colony forming ability of cancer cells in order to find a substance showing anticancer effect.

On the other hand, c-Abl phosphorylase, which is known to cause cancer, plays an important role in the DNA synthesis process essential for cell growth (Van Etten, Trends Cell Biol. 1999; 9: 179-186) (Corynebacterium glutamicum), which promotes cell growth by promoting the expression of c-Myc gene and promotes the carcinogenesis when the activity is excessively maintained (Sawyers et al. Cell 1992; 70: 901-910, Afar et al. Science 1994; 264: 424 -426, Wong et al., Mol Cell Biol 1995; 15: 6535-6544, Furstoss et al., EMBO J 2002, 21: 514-524). In recent years, there have been various attempts to develop a drug that inhibits c-Abl activity worldwide as an anticancer drug.

To date, various anti-cancer drugs have been known and developed, but there remain problems to be solved. One of the ways to overcome this problem is the natural materials that have been used in civilian or traditional medicine for a long time. Plants produce secondary metabolites in small quantities for their defense, one of which is flavonoids. Since the flavonoid derivatives of mannon are already known, the design of flavonoid derivatives with new skeleton is absolutely necessary for the derivation of novel substances.

Van Etten, Trends Cell Biol. 1999; 9: 179-186

The present invention has been made in view of the above needs, and an object of the present invention is to provide a diphenylnaphthylpyrazolinylcarbothioamide derivative having anticancer efficacy.

In order to accomplish the above object, the present invention provides a compound of the formula 1:

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are preferably methoxy or hydrogen,

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are OCH _3, H, H, H, H, H and H; _{OCH 3, H, H, OCH} 3, H, H and H; _{OCH 3, H, H, H} , OCH 3, H and H; _{OCH 3, H, H, H} , H, OCH 3, and H; _{OCH 3, H, H, H} , OCH 3, OCH 3 and OCH _{3; H, OCH 3, OCH 3,} H, H, H and H; _{H, OCH 3, OCH 3,} OCH 3, H, H and H; _{H, OCH 3, OCH 3,} H, OCH 3, H and H; _{H, OCH 3, OCH 3,} H, H, OCH 3 and H; _{H, OCH 3, OCH 3,} H, OCH 3, OCH 3 and OCH _{3; OCH 3, H, OCH 3,} H, H, H and H; _{OCH 3, H, OCH 3,} OCH 3, H, H and H; _{OCH 3, H, OCH 3,} H, OCH 3, H and H; _{OCH 3, H, OCH 3,} H, H, OCH 3 and H; _{OCH 3, H, OCH 3,} H, OCH 3, OCH 3 and OCH _{3; H, H, OCH 3, H} , H, H and H; _{H, H, OCH 3, OCH} 3, H, H and H; _{H, H, OCH 3, H} , OCH 3, H and H; Or _{H, H, OCH 3, H} , H, OCH 3 , and preferably is H _{and, H, OCH 3, OCH 3} , H, OCH 3, H, and H; _{H, OCH 3, OCH 3,} H, OCH 3, OCH 3, and OCH _{3; OCH 3, H, OCH 3,} H, OCH 3, OCH 3, and OCH _{3; H, H, OCH 3, H} , H, H, and H; Or _{H, H, OCH 3, H} , OCH 3, more preferably from H and H a is not limited to this.

The present invention also provides a pharmaceutical composition for anti-cancer comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a compound or a pharmaceutically acceptable salt thereof and / or a pharmaceutical composition for anti-cancer, wherein the compound of the present invention inhibits c-Abl enzyme activity and has anticancer activity.

The present invention also provides a food composition for cancer improvement comprising the compound of the present invention as an active ingredient.

In one embodiment of the present invention, the cancer having the anticancer effect is selected from the group consisting of colon cancer, liver cancer, pancreatic cancer, colon cancer lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, Endometrial carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endometrioid carcinoma, breast cancer, Cancer of the kidney or kidney, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS), pancreatic cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, pancreatic cancer, But are not limited to, cancers selected from the group consisting of central nervous system (CNS) tumors, brain tumors, primary central nervous system lymphoma, spinal cord tumors, brainstem glioma, and pituitary adenomas.

The pharmaceutical composition is characterized in that it comprises at least one pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical composition is characterized by containing a second anti-cancer agent or anti-cancer adjuvant.

Wherein the second anticancer agent is selected from the group consisting of interferon, interleukin-2, paclitaxel, vincristine, vinblastin, doxorrubicin, etoposide, Is at least one selected from the group consisting of irinotecan hydrochloride, cisplatin, amsacrine, cytosine arabinoside, fluoro uracil and taxol. .

The compounds according to the invention can be used in the form of derivatives which are in the form of pharmaceutically acceptable salts.

As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. That is, the compound of the present invention may be formed into a pharmaceutically acceptable acid addition salt according to a conventional method in the art. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, lactic acid, maleic acid, pumaric acid, Sulfonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, calycturonic acid, embonic acid, glutamic acid or aspartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

The derivatives according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

For clinical use, the compounds or their salt forms according to the present invention may be administered alone, but may be formulated with excipients, binders, lubricants, disintegrants, coating materials, emulsifiers, suspending agents, And / or by mixing the ointment base material, in the form of a pharmaceutical preparation formulated to be suitable for the particular use and desired purpose. The mixture may be used for oral, parenteral, rectal or topical administration.

More specifically, as mentioned above, the pharmaceutical anti-cancer composition containing the compound or a salt thereof may be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or Soft gelatine capsules, liquids, emulsions or suspensions. Administration can also be administered rectally, e.g., using suppositories; Topically or transdermally, for example, as ointments, creams, gels or solutions; Or parenterally, e. G., Using a solution for injection.

For the preparation of tablets, coated tablets, dragees, hard or soft gelatine capsules, the compounds of the present invention may be mixed with pharmaceutically inert, inorganic or organic excipients (pharmaceutically acceptable carriers). Examples of suitable excipients for tablets, coated tablets, dragees, hard gelatine capsules include lactose, maize starches or derivatives thereof, talc or stearic acid or their salts. Suitable excipients for use in soft gelatine capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like. However, depending on the nature of the active ingredient, there may be cases where no excipient is needed in the soft gelatine capsules. For the preparation of solutions and syrups, excipients which may be used include, for example, water, polyols, saccharose, invert sugar and glucoses. For the preparation of injectable solutions, excipients which may be used include, for example, water, alcohols, polyols, glycerin and vegetable oils. For suppositories and for the preparation of topical or transdermal applications, excipients which may be used include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

The pharmaceutical composition may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, pigments, fragrances, salts for varying the osmotic pressure, buffers, coatings or antioxidants and they also contain other therapeutically valuable agents You may.

Consequently, pharmaceutical formulations for oral administration may be granules, tablets, sugar coated tablets, capsules, pills, suspensions or emulsions, and may be in the form of parenteral preparations, for example, intravenously, intramuscularly or subcutaneously Forms of sterile aqueous solutions may be used for the formulation, which may include other materials such as salts or glucoses to make an isotonic solution. The antitumor agent may also be administered in the form of a suppository or pessary, or externally applied in the form of a lotion, solution, cream, ointment or dusting powder.

The daily dose of the compound of the present invention is 5 to 2000 mg when administered orally or parenterally. A single dose or two or more divided doses may be appropriate.

It should be understood, however, that the actual dosage should be determined in light of various relevant factors such as the route of administration, the age, sex, and weight of the patient, and the severity of the disease, and accordingly, .

The present invention also provides a health functional food for prevention and improvement of cancer diseases, which comprises the compound of the present invention and a pharmaceutically acceptable food-aid additive.

The health functional food may be in the form of tablet, capsule, pill or liquid.

Hereinafter, the present invention will be described.

The present inventors designed and synthesized a total of 19 diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives.

There are various methods for measuring the anticancer effect. One of them is a method of seeing whether the treatment of cancer cells effectively inhibits growth of cancer cells. Since the clonogenic assay is a method of inhibiting cell line growth of a drug while growing the cancer cell line for about 7 days, it is widely used as a method of measuring anticancer effect in recent years because it can effectively observe cell line growth inhibition effect on derivatives having similar structures (Nature Protocol 1, 2315-2319 (2006)). The present inventors performed clonogenic assays for diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives in human colorectal cancer cell lines and measured their half maximal cell growth inhibitory concentrations (GI50). Eighteen derivatives were tested for human colon cancer cell lines from 421 nM And inhibited growth at a low concentration of 128.8 μM.

In addition, it has been experimentally confirmed that the compound of the present invention inhibits the c-Abl enzyme activity by inhibiting the phosphorylation process of the tyrosine residue of the c-Abl enzyme and has anticancer activity. Thus, the compounds of the present invention have the effect of treating a series of cancers associated with c-Abl enzyme activity.

As can be seen from the present invention, the diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives of the present invention inhibit c-Abl enzyme activity and inhibit the growth of cancer cell lines at low concentrations, and thus can be used as candidate cancer candidates.

Figure 1 shows the preparation of polymethoxylated diphenylnaphthylpyrazolinyl-1-carbothioamide 1-19.
FIG. 2 is a graph showing an important correlation obtained from the COSY (dotted line) and HMBC (solid line) spectra of the derivative 18. FIG.
3A and 3B are photographs showing the colony forming ability of cancer cells treated with diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives in colon cancer cell lines.
FIG. 4 is a graph showing the result of inhibition of phosphorylation of tyrosine 245 residue of c-Abl enzyme by treatment with derivative 10 in HCT116 colon cancer cell line.

The present invention will now be described in more detail by way of non-limiting examples. The following examples are intended to illustrate the present invention and the scope of the present invention is not to be construed as being limited by the following examples.

Example  One. diphenylnaphthylpyrazolinyl -One- carbothioamide  Synthesis of derivatives

diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives were synthesized in the same manner as in FIG.

The structures and names of the 19 diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives obtained by synthesis are shown in Table 1 below.

[Table 1]

Table 1 shows the structure, name, and mass data of polymethoxylated diphenylnaphthylpyrazolinyl-1-carbothioamide 1-19.

Example  2. diphenylnaphthylpyrazolinyl-1- carbothioamide  Of the derivatives Nuclear magnetic resonance spectroscopy  Experiment

Hydrogen and carbon nuclear magnetic resonance spectroscopy experiments were performed to confirm the structure of diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives. Typically, the structure is centered on the derivative 18 (3- (2-hydroxy-4-methoxyphenyl) -N- (3-methoxyphenyl) -5- (naphthalen-1-yl) -4,5- dihydropyrazole-1-carbothioamide Respectively. The instrument used was a Bruker Avance 400 (Bruker, Karlsruhe, Germany). diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives were dissolved in deuterium-dimethylsulfoxide-d6 (DMSO-d6) and placed in a 2.5-mm NMR tube. NMR data were obtained at room temperature. Detailed experimental methods were used [Magn. Reson. Chem. 51: 593]. Two dimensional nuclear magnetic resonance (NMR) experiments were performed to confirm this structure. As a result, the relationship between hydrogen and carbon can be expressed as shown in FIG. The solid line in this figure is the hydrogen-carbon relationship obtained from the HMBC experiment and the dotted line indicates the hydrogen-hydrogen relationship obtained from the COSy experiment.

The results of hydrogen nuclear magnetic resonance spectroscopy of 19 kinds of diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives are shown in Tables 2 and 3 below.

[Table 2]

[Table 3]

Tables 2 and 3 show the 1 H NMR chemical shifts of polymethoxylated diphenylnaphthylpyrazolinyl-1-carbothioamide 1-19, where py refers to pyrazoline and multiplicity and coupling constants are shown in parentheses. Multiplicities, s, d, and m denote a singlet, a doublet, and a multiplet, respectively.

The results of carbon nuclear magnetic resonance spectroscopy of 19 kinds of diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives are shown in Table 4 below.

[Table 4]

Table 4 shows the 13C NMR chemical shift of polymethoxylated diphenylnaphthylpyrazolinyl-1-carbothioamide 1-19, where py refers to pyrazoline.

Example  3. diphenylnaphthylpyrazolinyl -One- carbothioamide  High-resolution mass spectrometry of derivatives

(Waters Corp., Milford, Mass.) was used to analyze the high-resolution mass of diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives. The results were as follows: The left side of the table is the theoretical value (calcd) and the right side is the mass value (found) obtained from the high resolution mass spectrometry.

[Table 5]

Table 5 shows the results of high-resolution mass spectrometry of diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives.

Example  4. diphenylnaphthylpyrazolinyl -One- carbothioamide  Derivatives for the inhibition of human colon cancer cell line growth

HCT116 human colorectal cancer cells were purchased from the American Type Culture Collection (ATTC) and DMEM (Invitrogen Life Technologies) culture medium containing 10% FBS (Fetal Bovine Serum, Invitrogen Life Technologies) and Antibiotic-Antimycotic solution The cells were cultured in a 5% CO2 incubator at 37 ° C in a 100-mm cell culture dish at a seeding density of 1 × 10 6. The effect of inhibiting cell proliferation was measured by analyzing the effect of colony forming assay of cancer cells by diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives. HCT116 cells were divided into 6,000 cells per well in a 24-well culture dish and treated with diphenylnaphthylpyrazolinyl-1-carbothioamide derivative. After 7 days, 6% glutaraldehyde and 0.5% crystal violet solution 1: 1 mixed solution was added to the cells, followed by reaction for 15 minutes to stain the remaining cells. In the cell groups treated with diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives, colony formation of cancer cells was decreased in a dose-dependent manner. These results suggest that the growth of HCT116 colon cancer cells was inhibited by diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives. The colony forming ability of the cancer cells treated with the colon cancer cell line at the concentrations of 0, 0.5, 1, 2.5, and 5 uM is shown in Fig.

[Table 6]

Table 6 shows the result of quantitative analysis of the half maximal cell growth inhibitory concentration (GI50) using the densitometry of the clonogenic assay results.

The diphenylnaphthylpyrazolinyl-1-carbothioamide derivative, which inhibits the growth of human colon cancer cell lines, exhibits a half maximal cell growth inhibitory concentration (GI50) of 420 nM at 10 times and a GI50 value of 128.79 uM at the 12th derivative The diphenylnaphthylpyrazolinyl-1-carbothioamide derivatives of the present invention all exhibited anticancer effects by effectively inhibiting the growth of human colon cancer cell lines.

Example  5. diphenylnaphthylpyrazolinyl -One- carbothioamide  Inhibitory Effect of C-Abl Enzyme on Derivatives

To investigate whether the inhibitory effect of derivative 10, which inhibits the growth of HCT116 colon cancer cells, which is the best diphenylnaphthylpyrazolinyl-1-carbothioamide derivative of the present invention, is due to the inhibitory effect of c-Abl activity, immunoblotting The inhibitory effect of the derivative 10 on c-Abl activity was investigated.

HCT116 human colorectal cancer cells were cultured as described above in a DMEM (Invitrogen Life Technologies) culture medium containing 10% FBS (Fetal Bovine Serum, Invitrogen Life Technologies) and an Antibiotic-Antimycotic solution (Invitrogen Life Technologies). The cultured cells were treated with 20 μM of derivative 10, and cells were harvested after 0, 6, 12, and 24 hours. Cell lysis buffer containing 20 mM HEPES (pH 7.2), 1% Triton X-100, 10% glycerol, 150 mM NaCl, 10 μg / ml leupeptin and 1 mM PMSF was added to the harvested cells for 30 minutes The cells were lysed by high-speed centrifugation, and the cell lysate was harvested. SDS-polyacrylamide gel electrophoresis was performed on the protein lysate prepared to contain the same amount of protein, Were isolated. After transferring the proteins separated by electrophoresis to a polystyrene membrane, the primary antibody (purchased from Cell Signaling Technology) that specifically binds to the phosphorylated c-Abl protein in tyrosine 245 residue and the protein expression as a control (Purchased from Santa Cruz Technology) were reacted for 5 hours each, and then a secondary antibody (purchased from Cell Signaling Technology), which was a primary antibody, was reacted for 1 hour. The change of tyrosine 245 residue phosphorylation degree of c-Abl protein on X-ray film was analyzed using a chemiluminescence detection system (Amersham Pharmacia Biotech, Piscataway, NJ).

As a result, derivative 10 reduced c-Abl tyrosine 245 residue phosphorylation in a time-dependent manner (see FIG. 4). At this time, there was no change in GAPDH protein expression. From this fact, it was judged that the derivative 10 inhibited the tyrosine phosphorylation by acting on the c-Abl enzyme, thereby inhibiting the c-Abl enzyme activity and blocking the cell growth process.

Claims (9)

Claims 1. A compound of the formula (1): < EMI ID =

[Chemical Formula 1]
Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are each independently methoxy (OCH ₃ ) or hydrogen.
The method according to claim 1,
Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are OCH ₃ , H, H, H, H, H and H;
OCH ₃ , _{H, H, OCH 3, H} , H and H;
_{OCH 3, H, H, H} , OCH 3, H and H;
_{OCH 3, H, H, H} , H, OCH 3, and H;
_{OCH 3, H, H, H} , OCH 3, OCH 3 and OCH _{3;
H, OCH 3, OCH 3,} H, H, H and H;
H, OCH _3, OCH _3, OCH ₃ , H, H, and H;
_{H, OCH 3, OCH 3,} OCH 3, H, OCH 3, H and H;
_{H, OCH 3, OCH 3,} H, H, OCH 3 and H;
H, OCH _3, OCH _3, H, OCH _3, OCH ₃ and OCH _3;
OCH ₃ , _{H, OCH 3, H, H} , H and H;
OCH ₃ , _{H, OCH 3, OCH 3,} H, H and H;
OCH ₃ , _{H, OCH 3, H, OCH} 3, H and H;
OCH ₃ , _{H, OCH 3, H, H} , OCH 3 and H;
OCH ₃ , _{H, OCH 3, H, OCH} 3, OCH 3 and OCH _3;
H, H, OCH _3, H, H, H, and H;
_{H, H, OCH 3, OCH} 3, H, H and H;
H, H, OCH _3, H, OCH _3, H and H; or
The compound or a pharmaceutically acceptable salt thereof, characterized in that the _{H, H, OCH 3, H} , H, OCH 3 and H.
The method according to claim 1,
Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, OCH ₃ , OCH ₃ , H, OCH ₃ , H, and H;
_{H, OCH 3, OCH 3,} H, OCH 3, OCH 3, and OCH _{3;
OCH 3, H, OCH 3,} H, OCH 3, OCH 3, and OCH _{3;
H, H, OCH 3, H} , H, H, and H; or
_{H, H, OCH 3, H} , OCH 3, H and a salt thereof characterized by a compound or a pharmaceutically acceptable in which the H.
4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has an anticancer activity.
4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has anticancer activity by inhibiting c-Abl enzyme activity.
A pharmaceutical composition for anticancer therapy comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The method of claim 6, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, pancreatic cancer, colon cancer lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, Cancer of the endocrine system, cancer of the thyroid, papillary cancer, pancreatic cancer, endometrioid cancer, endometrioid carcinoma, endometrial carcinoma, endometrial carcinoma, vulvar carcinoma, vulvar carcinoma, Hodgkin's disease, Neoplasms, kidney or renal cell carcinomas, renal pelvic carcinomas, central nervous system (CNS) tumors, cancer of the central nervous system (CNS), cancer of the central nervous system , Brain tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.
A composition for improving cancer, comprising the compound of any one of claims 1 to 3 as an active ingredient.
9. The method of claim 8, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, pancreatic cancer, colon cancer lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, Cancer of the endocrine system, cancer of the thyroid, papillary cancer, pancreatic cancer, endometrioid cancer, endometrioid carcinoma, endometrial carcinoma, endometrial carcinoma, vulvar carcinoma, vulvar carcinoma, Hodgkin's disease, Neoplasms, kidney or renal cell carcinomas, renal pelvic carcinomas, central nervous system (CNS) tumors, cancer of the central nervous system (CNS), neoplasms, , Brain tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

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