TW201728329A - A pharmaceutical composition comprising pyridino pyrimidine derivatives or medical salt thereof - Google Patents

Abstract

The present invention relates a pharmaceutical composition comprising pyridino pyrimidine derivatives or medical salt thereof. Specifically, the present invention relates a pharmaceutical composition comprising 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin -4-yl) pyridin-2-yl) amino) pyridino [2,3-d] pyrimidin-7(8H)-one or its pharmacologically acceptable salts and disintegrant, the disintegrant is without metallic element, the composition The composition dissolves rapidly. The preparation process of the pharmaceutical composition is simple, and is more suitable for large-scale production.

Description

Medicinal composition containing a pyridopyrimidine derivative or a pharmaceutically acceptable salt thereof

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound containing 6-ethenyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amine A composition of pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmacologically acceptable salt thereof.

Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the progress of the disease is slow. The China Population Association released the "China Breast Diseases Investigation Report" in Beijing on February 1, 2010. The report shows that The mortality rate of breast cancer in urban areas in China has increased by 38.91%. Breast cancer has become the most threatening disease for women. At present, there are at least 156 breast cancer drugs under research and market, of which 68% are targeted therapeutic drugs. Tumors were found to be abnormally associated with the cell cycle. Mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders. At the same time, most tumors have genomic instability (GIN) and genomic instability (CIN). These three basic cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin-dependent protein kinase (CDK, Cyclin Dependent Kinase) inhibitors are increasingly becoming a hot target.

There are many second-generation CDK inhibitors currently under development. The second-generation drugs of greatest concern include the CDK4/6 inhibitor PD-0332991 jointly developed by Pfizer and Onyx, which inhibits the phosphorylation of Rb by inhibiting the activity of CDK4/6. The E2F-Rb complex is retained in the cytosol to block the initiation of the cell cycle. Clinical trial results (NCT00721409) showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas no progress was observed in patients treated with letrozole and PD-0332991. The survival period was extended to 26.1 months, and this significant advantage has received wide attention.

WO2014183520 discloses a series of CDK4/6 inhibitors of the formula (I) which are structurally similar to PD-0332991, have significant inhibitory activity and high selectivity for CDK4/6, and are expected to be useful for a range of tumors. And can be used in combination with a range of existing anti-tumor agents, including the compound of formula A shown below, having the chemical name 6-acetamido-8-cyclopentyl-5-methyl-2-(5 -(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one:

The isethionate of the above compounds and its crystalline form I are described in PCT/CN2016/070636 filed by the applicant.

However, none of the above documents disclose how to obtain rapid and complete dissolution. At the same time, the above-mentioned compounds have poor stability, and therefore it is necessary to conduct intensive studies to find a composition which is well-dissolved and to solve the stability problem.

It is an object of the present invention to provide a pharmaceutical composition which is rapidly and completely dissolved, and which has a simple preparation process and is more suitable for large-scale production. In another aspect, the present invention also provides a pharmaceutical composition having good stability.

The pharmaceutical composition provided by the present invention contains (6-ethenyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl) as an active ingredient) An amino)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmacologically acceptable salt thereof, and a disintegrating agent which is a metal element-free disintegrant. The metal element is an alkali metal or an alkaline earth metal such as sodium, potassium, calcium or magnesium. In a preferred embodiment of the invention, the disintegrant contained in the composition is a low-substituted hydroxypropyl cellulose or a crospovidone. One or more of them are contained, and the content thereof is not particularly limited and may be from about 1 to 30% by weight, preferably from 8% to 15% by weight.

In the pharmaceutical composition provided in the present invention, the pharmacologically acceptable salt of the active ingredient may preferably be selected from the isethionate of the active ingredient. The content of the active ingredient may range from 5% to 50%, preferably from 10% to 35%, more preferably from 25% to 35%, based on the total weight of the composition.

The pharmaceutical composition provided in the present invention further contains a filler containing mannitol. In a preferred embodiment of the present invention, the filler may contain, in addition to mannitol, one or more of microcrystalline cellulose, pregelatinized starch, and calcium hydrogen phosphate, preferably microcrystalline cellulose. In the preferred embodiment In this case, the filler is a mixture of mannitol and microcrystalline cellulose.

In the composition of the present invention, the content of the filler is not particularly limited and may be 20 to 90%, preferably 30% to 70%, more preferably 40% to 65%, based on the total weight of the pharmaceutical composition. It is 45%-60%. Wherein the weight ratio of mannitol to microcrystalline cellulose is from 2:1 to 10:1, preferably from 2.5:1 to 5:1, optimally from 2.5:1 to 3:1. In one embodiment of the invention, the ratio of mannitol to microcrystalline cellulose used is 3:1, which can significantly increase the stability of the sample as well as the rate and extent of dissolution.

The pharmaceutical composition provided in the present invention may further contain a binder, for example, the binder is one or more of polyvinylpyrrolidone, pregelatinized starch, hypromellose, and hydroxypropylcellulose, based on The binder content is from about 0.5% to about 10%, preferably from about 0.5% to about 5%, based on the total weight of the composition.

In the pharmaceutical composition provided in the present invention, the pharmaceutical composition provided by the present invention may further comprise one or more lubricants to facilitate filling of the capsule or tableting. The lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, and the like, based on the total weight of the composition. The lubricant is present in an amount of from about 0.5% to about 5%.

In a particularly preferred embodiment of the invention, there is provided a pharmaceutical composition comprising the following ingredients by weight: 1) 10% to 35% of (6-ethylindenyl-8-cyclopentyl-5-A) Keto-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one or its pharmacologically acceptable Salt; 2) 20%-70% mannitol; 3) 5%-30% microcrystalline cellulose; 4) 8%-15% of a disintegrant selected from one or two of low-substituted hydroxypropylcellulose or crospovidone; 5) 0.5%-5% binder selected from polyethylene One or more of pyrrolidone, pregelatinized starch, hypromellose; 6) optionally 0.5% to 5% of a lubricant selected from magnesium stearate, stearic acid, glyceryl behenate One or several.

The pharmaceutical composition of the present invention can be prepared by a method common in the art, for example, high shear wet granulation, dry granulation, one-step granulation, and the like to prepare granules of the pharmaceutical composition, which are then compressed into tablets.

The composition of the present invention dissolves very rapidly and completely. According to the Chinese Pharmacopoeia 2015 edition two appendix dissolution determination second method (paddle method), purified water is used as the dissolution medium, preferably 1000 ml of purified water, and at 37±0.5 The composition of the present invention was subjected to a dissolution test at a paddle speed of 50 rpm at a rate of 80% or 45 minutes and a dissolution degree of 80% or more, preferably a dissolution rate of 95% or more at 45 minutes or 60 minutes.

On the other hand, the pharmaceutical composition provided by the present invention has improved stability by using a filler containing mannitol, and the composition of the present invention is placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for one month. Then, the content of the relevant substance is not more than 1% as determined by HPLC.

Figure 1 shows the dissolution profiles of the tablets of Examples 1-5 in purified water.

Figure 2 shows the dissolution profiles of the tablets of Examples 6-9 in purified water.

Figure 3 shows the dissolution profiles of the tablets of Examples 1 and 10-12 in purified water.

Figure 4 shows the dissolution profiles of the tablets of Examples 10 and 13-14 in purified water.

The invention is further illustrated in detail by the following examples and experimental examples. The examples and the examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Examples 1-5

6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-ketohydroxyethylsulfonate (hereinafter referred to as Compound A), lactose, microcrystalline cellulose, low-substituted hydroxypropylcellulose or crospovidone, croscarmellose sodium, Sodium carboxymethyl starch, wet granulation using a high-speed shear granulator according to the ratio in Table 1, and 5% aqueous solution prepared with povidone K30 as a wetting agent to wet the wet material The granules are dried and then dried, and the dry granules (less than 3% moisture) are dry granulated, and the prescribed amount of magnesium stearate is added and mixed well. The resulting total mixed granules were compressed into tablets.

Experimental Example 1: Dissolution experiment

The tablets in Examples 1 to 5 were subjected to dissolution measurement according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 2 and 3, the dissolution of Compound A was slow and incomplete; in Example 4, Compound A was completely dissolved. In Example 5, Compound A was completely dissolved, and the dissolution rate was slower than that of the tablet of Example 1. The dissolution data are shown in Table 2 below, and the dissolution curve is shown in Figure 1.

Example 6-9

6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-ketohydroxyethylsulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, according to the ratio in Table 3, using a high-speed shear granulator Wet granulation, 3% aqueous solution prepared with hypromellose E5 as a wetting agent, wet granulation and drying of wet materials, and then dry granules (less than 3% moisture) Add the prescribed amount of magnesium stearate and mix well. The resulting total mixed granules were compressed into tablets.

Experimental Example 2: Dissolution experiment

The dissolution rates of the tablets of Examples 6 to 9 were determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 6 to 9, the dissolution of the compound A was complete. The dissolution data is shown in Table 4, and the dissolution curve is shown in Figure 2.

Example 10~12

6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-ketohydroxyethylsulfonate (hereinafter referred to as Compound A), lactose or mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, according to the ratio in Table 5, using high-speed shearing The granulator is wet granulated, and the 5% aqueous solution prepared by povidone K30 is used as a wetting agent. The wet soft material is wet granulated and dried, and then the dry granules (less than 3% moisture) are dried. Add the prescribed amount of magnesium stearate and mix well. The resulting total mixed granules were compressed into tablets.

Experimental Example 2: Dissolution experiment

The dissolution rates of the tablets of Examples 1 and 10-12 were determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 1 and 10, Compound A was completely dissolved; in Examples 11 and 12, the proportion of microcrystalline cellulose was gradually increased, and the dissolution rate of Compound A was gradually slowed compared with the tablet of Example 1. And the dissolution is not complete. The dissolution data are shown in Table 6 below, and the dissolution curve is shown in Figure 3.

Example 13~14

6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-ketohydroxyethylsulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, according to the ratio in Table 7, using a high-speed shear granulator Wet granulation, a 3% aqueous solution prepared with povidone K30 and a 3% aqueous solution prepared with hypromellose E5 and a 13% aqueous solution prepared with pregelatinized starch as a wetting agent. Wet and soft materials are wet granulated and dried, then dry granules (water content less than 3%) are dry granulated, and the prescribed amount of magnesium stearate is added and mixed uniformly. The resulting total mixed granules were compressed into tablets.

Experimental Example 4: Dissolution experiment

The dissolution rates of the tablets of Examples 10, 13, and 14 were determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 10, Compound A was completely dissolved; in Example 14, Compound A was incompletely eluted; in Example 13, Compound A was completely dissolved. The dissolution data are shown in Table 8 below, and the dissolution curve is shown in Figure 4.

Experimental Example 5: Stability study

The examples 1 and 10 were placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for 1 month, 2 months, and 3 months, and then the changes of the substances were measured by HPLC.

The relevant substance test results indicate that the start of the tablet in Example 1 is related. The total amount of the substance is greater than the total amount of the relevant substance of the tablet in the embodiment 10; after the tablet is placed in the first embodiment, the related substance is increased after being placed for one month; and after the tablet is placed for one month, two months, three months after the implementation There was no significant change in the relevant substances (see Table 9).

Example 15 : 6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin[2,3 -d]Synthesis of pyrimidine-7(8H)-ketohydroxyethyl sulfonate

Step 1: 6-((6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2,3-d]pyrimidine Preparation of 2-butyl)amino)-5',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester

(10g, 29.06mmol) 2-amino-6-(1-butoxyvinyl)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidine-7 under argon (8H)-ketone (prepared according to the method disclosed in WO2014183520), cesium carbonate (14.22g, 43.75 mmol), Pd2(dba)3 (2.12 g, 2.31 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (2.69 g, 4.69 mmol) and 125.00 g of dioxane Put into a three-neck reaction flask, stir evenly, then heat to reflux, and slowly add the raw material 4-(6-chloropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester ( A mixture of 10.34 g, 35.00 mmol, purchased from Yancheng Ruikang Pharmaceutical Chemical Co., Ltd. and dioxane (65.62 g, 0.74 mol) (drip time: about 5 h). After the completion of the dropwise addition, the reaction was stirred for 1 to 1.5 hours, and TLC was used to monitor the starting material 2-amino-6-(1-butoxyvinyl)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidine. The -7(8H)-one reaction was completed (developing solvent: petroleum ether: ethyl acetate = 2:1, starting material Rf = 0.6, product Rf = 0.7), and the reaction was terminated. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane 17. The filtrate was concentrated to dryness under reduced pressure at 65 °C. The residue was dissolved in 137.50 g of dichloromethane, 56.25 g of purified water was added, and the mixture was partitioned and the aqueous phase was extracted with 68.75 g of dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate and filtered, and then filtered and evaporated. Add 150 g of acetone to dissolve, stir at room temperature for about 2 h, and stir in an ice water bath for about 3 h. After filtration, the filter cake was washed with cold acetone 25 g×4, and dried under reduced pressure at room temperature for 8 to 10 hours to obtain a solid of about 14.84 g, yield: 80 to 92%, and the purity of HPLC was not less than 90%. ESI/MS: [M+H] = 601.43.

Step 2: 4-(6-((6-Ethyl-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2,3-d]pyrimidin-2- Of tert-butyl 3-amino)pyridin-3-yl)piperidine-1-carboxylic acid

6-((6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2,3-d]pyrimidine-2 -Amino)-5',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (14.84 g, 24.69 mmol) and 75 g of acetic acid input The three-port reaction bottle is protected by argon gas. Add 10% Pd/C (5g), replace with hydrogen three times, and hydrogenate at 50~60 °C for 30~32h under stirring. The residual amount of the intermediate state (6-((6-(1-butoxyvinyl))-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2, 3-d]pyrimidin-2-yl)amino)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester The intermediate protected by the base but not reduced by the double bond) <0.3%, the reaction was terminated. The reaction solution was cooled to room temperature, the system was replaced with argon and filtered, and the filter cake was washed with 37.50 g of dichloromethane. The filtrate was concentrated to dryness under reduced pressure at 65 °C. The residue was purged with argon gas and refluxed with 50 g of absolute ethanol for 0.5 h, and then cooled to room temperature with stirring, and stirred for about 4 h in an ice bath. Filter and filter cake was washed with cold anhydrous ethanol 12.50 g x 2 . The obtained wet product was stirred with 31.25 g of dichloromethane, and the insoluble matter was filtered. The filtrate was slowly added with 118.75 g of isopropanol, stirred for about 3 hours in an ice bath, filtered and dried under reduced pressure for 8 to 10 hours to obtain a solid of about 8.75 g. Yield: 60 ~72%, the purity of HPLC detection is not less than 98%. ESI/MS: [M+H] = 547.26.

Step 3: 6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin[2,3- Preparation of d]pyrimidin-7(8H)-ketohydroxyethyl sulfonate

4-(6-((6-Ethyl-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydro) Pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (8.75 g, 15.94 mmol) and 56.25 g of anhydrous methanol were placed in a three-reaction reaction flask. Stir well. 80% of isethionic acid (8.81 g, 55.94 mmol) and 0.94 g of water were dissolved in 13.75 g of anhydrous methanol, and added dropwise to the above solution, and the solution became clear. After the dropwise addition, the reaction was stirred under reflux for 3 to 3.5 hours, and the reaction of the starting material was completely confirmed by TLC (petroleum ether: ethyl acetate = 1:1, starting material Rf = 0.3, product Rf = 0), and the reaction was terminated and filtered while hot. Triethylamine (4.00 g, 39.38 mmol) was added dropwise with stirring of the filtrate, and stirring was continued for about 1 hour, and stirred for about 3 hours in an ice bath. Filtration, filter cake washed with cold anhydrous methanol 7.19 g × 2, dried at 40 ° C under reduced pressure for 6 ~ 8h to obtain a solid about 7.97 g, yield: 82 ~ 93%, HPLC detection purity of not less than 98%. TOF-MS: [M+H]=447.2503(6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amine Pyridyl[2,3-d]pyrimidin-7(8H)-one binds to an ion peak of a hydrogen ion).

Since the picture in this case is test data, it is not a representative figure of this case.

Therefore, there is no designated representative map in this case.

Claims (24)

A pharmaceutical composition containing (6-ethenyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino) as an active ingredient Pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmacologically acceptable salt thereof, and a disintegrating agent which is a metal element-free disintegrant. The pharmaceutical composition according to claim 1, wherein the metal element is an alkali metal or an alkaline earth metal. The pharmaceutical composition according to claim 1, wherein the disintegrant is one or more of low-substituted hydroxypropylcellulose or crospovidone. The pharmaceutical composition according to claim 1, wherein the disintegrant is present in an amount of from about 1 to 30% by weight. The pharmaceutical composition according to claim 1, wherein the disintegrant is present in an amount of from about 8% to 15% by weight. The pharmaceutical composition according to claim 1, further comprising a filler containing mannitol. The pharmaceutical composition according to claim 6, wherein the filler further comprises one or more selected from the group consisting of microcrystalline cellulose, pregelatinized starch, and calcium hydrogen phosphate. The pharmaceutical composition according to claim 7, wherein the filler further contains microcrystalline cellulose. The pharmaceutical composition according to any one of claims 6 to 8, wherein the filler is contained in an amount of from 20 to 90% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 9, wherein the filler is contained in an amount of from 30% to 70% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 9, wherein the filler is contained in an amount of from 40% to 65% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 9, wherein the filler is present in an amount of from 45% to 60% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 8, wherein the weight ratio of mannitol to microcrystalline cellulose is from 2:1 to 10:1. The pharmaceutical composition according to claim 13, wherein the weight ratio of mannitol to microcrystalline cellulose is from 2.5:1 to 5:1. The pharmaceutical composition according to claim 13, wherein the weight ratio of mannitol to microcrystalline cellulose is from 2.5:1 to 3:1. The pharmaceutical composition according to claim 1, further comprising a binder selected from the group consisting of polyvinylpyrrolidone, pregelatinized starch, hypromellose, and hydroxypropylcellulose. Several. The pharmaceutical composition according to claim 1, further comprising a lubricant selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmacologically acceptable salt of the active ingredient is isethionate. A pharmaceutical composition comprising the following components by weight: 1) 10% to 35% of (6-acetamido-8-cyclopentyl-5-methyl-2-((5-(piperidin-4) -yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidine -7(8H)-one or a pharmacologically acceptable salt thereof; 2) 20% to 70% mannitol; 3) 5% to 30% microcrystalline cellulose; 4) 8% to 15% disintegration Or one or two selected from the group consisting of low-substituted hydroxypropylcellulose or crospovidone; 5) 0.5% to 5% binder selected from polyvinylpyrrolidone, pregelatinized starch, hyprothenol One or more of cellulose; 6) optionally 0.5% to 5% of a lubricant selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate. A method for producing a pharmaceutical composition according to any one of claims 1 to 19, which is selected from the group consisting of a wet granulation, a dry granulation process, and a direct powder tableting. The method of claim 20, wherein the method is selected from the group consisting of wet granulation. Use of the pharmaceutical composition according to any one of claims 1 to 19 for the preparation of a medicament for treating cancer. The use of the pharmaceutical composition according to claim 22, wherein the cancer is breast cancer. The use of the pharmaceutical composition according to claim 22, wherein the cancer is estrogen receptor positive breast cancer.