WO2021045582A1 - 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention provides 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and a pharmaceutical composition comprising same. The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to the present invention not only has superior stability and solubility, but can also be prepared in the form of crystals and thus may be effectively used in a pharmaceutical composition.

Description

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same

The present invention relates to 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and a pharmaceutical composition comprising the same. More specifically, the present invention provides 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride that can be effectively used in pharmaceutical compositions due to excellent stability and solubility, and pharmaceuticals containing the same. It relates to the composition.

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol represented by the following formula (I) is a cyclin-dependent kinase (CDK) inhibitor, including colon cancer, lung cancer, and glioma It is known to be effective in the treatment of cancer and degenerative brain diseases such as Alzheimer's disease [see Korean Patent Registration No. 10-1783642].

[Formula I]

However, the compound represented by Formula I has low solubility in water, and acid addition salts such as trihydrochloride, oxalate, malonate, and sulfate have been developed to improve this, but these acid addition salts have low stability and are difficult to obtain in a crystalline form. There was a problem.

The present inventors have conducted intensive research and review to overcome the problems of the conventional 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol and acid addition salts thereof. As a result, 2,6-bis-( It was found that 2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is excellent in stability and solubility as well as can be prepared in a crystalline form, thereby completing the present invention.

Accordingly, an object of the present invention is to provide 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride having excellent stability and solubility.

Another object of the present invention is to provide a pharmaceutical composition comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

One embodiment of the present invention relates to a 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride represented by the following formula (II).

[Formula II]

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to an embodiment of the present invention may be in a crystalline form, and I/I ₀ ( I: The intensity of the peak at each diffraction angle, I ₀ : The intensity of the largest peak) is 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9± Can be 0.2 and 27.2±0.2.

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form according to an embodiment of the present invention was obtained from a differential scanning calorimetry (DSC) analysis, starting at 147° C. and 150° C. Shows the endothermic peak with the lowest point in.

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to an embodiment of the present invention is 2,6-bis-(2-aminopyrimidin-4-yl) It can be prepared by dissolving pyridin-3-ol in methanol, adding about 45 to 55 equivalents of hydrochloric acid, stirring, filtering, washing, and drying at room temperature. Then, by recrystallization from water and acetone, a crystalline form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride can be obtained.

One embodiment of the present invention is a cyclin-dependent kinase comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride salt together with a pharmaceutically acceptable carrier. kinase, CDK) inhibitory pharmaceutical composition, specifically, to a pharmaceutical composition for the treatment or prevention of cancer or degenerative brain disease.

In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride inhibits CDK, thereby inducing an anticancer effect through cell cycle regulation, Acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma , MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other hematologic cancers and non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer, head and neck squamous It can be usefully used to treat solid cancers such as epithelial cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, and esophageal cancer.

In addition, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride freely passes through the blood brain barrier (BBB) to form an astrocytoma and anaplasticity. Metastasis from glioma such as anaplastic astrocytoma or glioblastoma, brain tumor such as pituitary adenoma, medulloblastoma, meningioma, or lung cancer, breast cancer, melanoma, etc. It can be effectively used for the treatment of metastatic brain tumors.

In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is phosphorylation of tau protein and Aβ, which is the cause of Alzheimer's disease, through CDK5 inhibition. Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multisystem atrophy, It can be usefully used in the treatment of ALS, Huntington's disease, cerebral ischemia or dementia caused by cerebral hemorrhage (Shah K et al., Mol Neurobiol. (2017) 54(3):2255-2268).

The pharmaceutical composition according to the present invention can be administered orally (e.g., ingestion or inhalation) or parenterally (e.g., injection, deposition, implantation, suppository), and the injection is, for example, intravenous , It may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection. According to the route of administration, the pharmaceutical composition according to the present invention is formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc. It can be formulated. The various types of pharmaceutical compositions according to the present invention may be prepared by known techniques using a pharmaceutically acceptable carrier commonly used in each formulation. Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffering agents, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , Suspending agents, stabilizers, colorants, and the like.

The pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.

The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, sex, degree of disease, judgment of a doctor, and the like of the mammal including the person to be treated. Preferably, in the case of oral administration, 0.01 to 50 mg of the active ingredient per 1 kg of body weight per day is administered, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient per 1 kg of body weight per day is administered. The total daily dosage may be administered at once or divided into several times depending on the degree of disease, judgment of a doctor, and the like.

In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is capecitabine, 5-fluorouracil, and Thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide , Tamoxifen, anastrozole, letrozole, exemestein, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eribuline, toremifene, goserelin, megestrol, vinblastine, Bendamustine, Thiotepa, Bleomycin, Topotecan, Leucovorin, Trifluridine, Tipiracil, Mitomycin Seed, Aldesleukin, Temsirolimus, Everolimus, Mitosantron, Mechloretamine, Mesotrec Sate, Pemetrexed, Trastuzumab, Bevacizumab, Cetuximab, Aflibercept, Pertuzumab, Ramucirumab, Panitumumab, Niborumab, Nexitumumab, Pembrolizumab, Semiplimab, Ate Jolizumab, Abelumab, Duvalumab, Ipilimumab, Obinutuzumab, Ofatumumab, Erotinib, Gefitinib, Sorafenib, Lapatinib, Palbociclib, Regorafenib, Imatinib, Sunitinib, Ak From the group consisting of citinib, pazopanib, afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine One or more selected anticancer agents, or donepezil, rivastigmine, galatamine, memantine, aducanumab, levodopa, carbidopa, bencerazide, bromocriptine, ropinirol, pramipexole, rotigotine, trihec Treatment of one or more degenerative brain diseases selected from the group consisting of cifenidyl, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine, rirusol, tetrabenazine, deuterabenazine, and actirase It can be administered in combination with. At this time, the administration time and dose of other drugs may vary.

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to the present invention not only has excellent stability and solubility, but also can be prepared in a crystalline form, so that it can be effectively used in pharmaceutical compositions. have.

1 is an X-ray powder diffraction diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

Figure 2 is a differential scanning calorie analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

3 is a thermogravimetric analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

4 is a dynamic vapor adsorption/desorption curve of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

Hereinafter, the present invention will be described in more detail by examples. These examples are for illustrative purposes only, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: Preparation of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol (10 g, 35.552 mmol) was reacted with hydrochloric acid (150 mL, 1,690 mmol) in methanol solvent (200 mL) at room temperature. It was stirred for 24 hours. The resulting solid was filtered and washed with acetone. The dried compound was dissolved in water (120 ml) and recrystallized with acetone (1,200 ml) to obtain the light brown title compound (11.3 g, 89.8%).

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 14.23 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (br, 4H)

(1) X-ray powder diffraction analysis

X-ray powder diffraction (XRD) analysis was performed under the following conditions using an X-Pert PRO MPD (Philips, Netherlands) analyzer.

Cathode material (Kα): Cu-Kα (1.54056 Å)

Scanning range: 5° to 90°

Generator setting: 40 mA, 40 kV

Scanning speed: 1 second/step

Diver slit: 0.3°

Anti-scatter slit: 0.3°

Temperature: 20 ℃

Step size: 0.02° 2θ

Rotation: use

Fig. 1 shows the XRD results of the obtained 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form. In addition, peaks having a relative intensity of 10% or more in the XRD pattern are shown in Table 1 below.

2θ	d	I/I o (%)	2θ	d	I/I o (%)
6.4	13.9	14.3	23.9	3.7	34.3
6.8	12.9	13.5	24.5	3.6	13.9
9.2	9.6	10.1	25.9	3.4	20.2
10.8	8.2	39.6	26.4	3.4	28.7
11.3	7.9	50.4	27.2	3.3	81.0
12.2	7.3	100	28.8	3.1	17.0
14.6	6.1	54.6	29.6	3.0	14.0
15.2	5.8	14.3	31.1	2.9	14.0
17.9	4.9	14.0	32.6	2.7	10.9
18.7	4.7	10.8	33.2	2.7	10.4
20.9	4.2	19.9	34.6	2.6	13.4
21.7	4.1	20.6	35.6	2.5	16.2
22.7	3.9	23.7	37.1	2.4	13.0

2θ: diffraction angle, d: distance between crystal planes, I/I _o (%): relative intensity

(2) Differential scanning calorie analysis

Differential Scanning Calorimeter (DSC) analysis was performed at 0° C. to 300° C. using DSC204 F1 Phoenix (Netzsch, Germany). Samples were weighed in an amount of 5 mg to 10 mg and added to an aluminum DSC pan, and the aluminum DSC pan was sealed with a perforated aluminum lid in a non-sealing manner. Thereafter, the sample was heated from 0° C. to 300° C. at a scanning rate of 10° C./min, and the generated heat flow reaction was observed by DSC.

Figure 2 shows the DSC analysis results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.

The crystalline form exhibited an endothermic peak having a starting point at about 147° C. and a lowest point at about 150° C.

(3) Thermogravimetric analysis

Thermogravimetric Analysis (TGA) was performed at 30° C. to 350° C. using a TG209 F1 Libra (Netzsch, Germany). The sample was weighed in an amount of 2 mg to 5 mg, and the temperature was measured directly in a vacuum state in a vertical top-loading method in which the sample can be mounted. Thereafter, the sample was heated from 30° C. to 350° C. at a rate of 10° C./min, and the heat weight calculated for exothermic and endothermic reactions occurring in the sample was observed by TGA.

Fig. 3 shows the TGA results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.

The crystalline form was observed to have a weight change in the temperature range of 30° C. to 175° C., which was identified as a weight reduction of about 3.7%.

Experimental Example 1: Long-term storage stability test

The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state at 25±2° C. and 60±5% RH, while initial ( 0 months), 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months later, the changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 2 below.

	0 months	1 month	3 months	6 months	9 months	12 months	18 months	24 months
Individually related substances	0.23% max	0.22% max	0.22% max	0.22% max	0.21% max	0.25% max	0.22% max	0.21% max
Total Related Substances	0.50%	0.54%	0.61%	0.50%	0.66%	0.65%	0.63%	0.61%
content	98.9%	99.9%	98.7%	96.7%	96.4%	99.3%	99.5%	103.3%

As shown in Table 2, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is the maximum individual flexible among the total related substances and the total related substances. It was confirmed that it exhibited excellent stability up to 24 months without an increase in material and without loss of compound content.

Experimental Example 2: Stability test against heat and moisture

The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state under accelerated conditions of 40±2° C. and 75±5% RH. During the initial period (0 months), 1 month, 3 months, and 6 months later, changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 3 below.

	0 months	1 month	3 months	6 months
Individually related substances	0.23% max	0.22% max	0.24% max	0.23% max
Total Related Substances	0.50%	0.54%	0.59%	0.52%
content	98.9%	99.0%	102.7%	100.4%

As shown in Table 3, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is among the total related substances and the total related substances under accelerated conditions. It was confirmed that it exhibited excellent stability up to 6 months without increasing the maximum individual related substances and without losing the compound content.

Experimental Example 3: Solvent Stability Test

The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was dissolved in water, and then stored in a sealed state at 37°C for an initial period (0 hours). , 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, after 24 hours, the purity was analyzed by UPLC. The results are shown in Table 4 below.

	first	1 hours	2 hours	3 hours	6 hours	9 hours	12 hours	24 hours
water	100%	100%	100%	100%	100%	100%	100%	100%

As shown in Table 4, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is stable in water for up to 24 hours without any change in purity. appear.

Experimental Example 4: Solubility Test

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystal form obtained in Example 1 was subjected to a solubility test according to pH, and the results are shown in Table 5. .

aqueous solution depending on pH	Solubility
0.1N HCl aqueous solution [pH 1]	Melts.
0.01N HCl aqueous solution [pH 2]	Melts.
0.15M acetic acid buffer [pH 4]	Melts.
0.15M phosphate buffer [pH 6]	It hardly melts.
0.15M phosphate buffer [pH 8]	Very difficult to melt.

As shown in Table 5, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 exhibited excellent solubility at pH 1 to 4.

Experimental Example 5: Hygroscopicity test

DVS-Advantage Dynamic Vapor Adsorption System (Dynamic Vapor Sorption, Surface Measurement Systems) for the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 Moisture content change was measured by repeating moisture absorption and dehumidification once in a range of 0 to 95% relative humidity (RH) under isothermal conditions of 25°C. The adsorption and desorption behavior of moisture according to the relative humidity is shown in FIG. 4.

4, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is of moisture adsorption or desorption in a section of 80% or less of relative humidity. It can be seen that the change is within 3.6%, and the change in moisture adsorption or desorption in the section exceeding 80% and below 95% relative humidity is within 6.4%. Accordingly, it can be seen that the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is a crystalline form having low hygroscopicity in a normal humidity range.

Claims (10)

1. 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride represented by the following formula (II):

   [Formula II]

   
2. The method of claim 1, wherein in the X-ray powder diffraction analysis, _{the value of the diffraction angle (2θ) at which I/I 0} (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 30% or more is Crystalline 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride in 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9±0.2 and 27.2±0.2 .
3. The crystalline form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridine according to claim 2, which exhibits an endothermic peak having a starting point at 147°C and a lowest point at 150°C in differential scanning calorimetry (DSC) analysis. -3-ol dihydrochloride.
4. Treatment of cancer comprising 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier Or a pharmaceutical composition for prophylaxis.
5. The method of claim 4, wherein acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) ), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer , Head and neck squamous cell cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, or a pharmaceutical composition for the treatment or prevention of esophageal cancer.
6. Degenerative brain disease comprising 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier Pharmaceutical composition for the treatment or prevention of.
7. According to claim 6, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multiple system atrophy, Lou Gehrig's disease, Huntington's disease, a pharmaceutical composition for the treatment or prevention of dementia caused by cerebral ischemia or brain hemorrhage.
8. The method of claim 4, wherein with 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride, capecitabine, 5-fluorouracil, thioguanine, chlorambucil, Oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, Letrozole, exemestein, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eriburin, toremifene, goserelin, megestrol, vinblastine, bendamustine, thiotepa, Bleomycin, Topotecan, Leucovorin, Trifluridine, Tipiracil, Mitomycin Seed, Aldesleukin, Tempsirolimus, Everolimus, Mitosantron, Mechloretamine, Mesotrexate, Pemetrexide, Tra Stuzumab, Bevacizumab, Cetuximab, Aflibercept, Pertuzumab, Ramucirumab, Panitumumab, Niborumab, Nexitumumab, Pembrolizumab, Semipleumab, Atezolizumab, Avelumab, More Valumab, ipilimumab, obinutuzumab, ofatumumab, erotinib, gefitinib, sorafenib, lapatinib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, Concomitant administration of one or more anticancer agents selected from the group consisting of afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine A pharmaceutical composition for the treatment or prevention of cancer.
9. According to claim 6, 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride with donepezil, rivastigmine, galatamine, memantine, aducanumab, levodopa , Carbidopa, bencerazide, bromocriptine, lopinirol, pramipexole, rotigotine, trihexifenidil, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine , Rirusol, tetrabenazine, dutetrabenazine, and at least one degenerative brain disease therapeutic agent selected from the group consisting of actirase is administered in combination, a pharmaceutical composition for the treatment or prevention of degenerative brain disease.
10. The pharmaceutical composition for the treatment or prevention of cancer according to claim 4, wherein temozolomide is administered in combination with 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.

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