CN112870198A - Application of luccotinib in preparation of medicine for treating chronic secondary myelofibrosis - Google Patents

Application of luccotinib in preparation of medicine for treating chronic secondary myelofibrosis Download PDF

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CN112870198A
CN112870198A CN202011636145.2A CN202011636145A CN112870198A CN 112870198 A CN112870198 A CN 112870198A CN 202011636145 A CN202011636145 A CN 202011636145A CN 112870198 A CN112870198 A CN 112870198A
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myelofibrosis
luccotinib
tyrosine kinase
treating
mixture
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夏永寿
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Chang'an Hospital Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention provides the application of the luccotinib and the tyrosine kinase inhibitor in preparing a mixture, a pharmaceutical composition or a kit for treating the secondary myelofibrosis of the chronic myelocytic leukemia, protects the combined medication scheme of the luccotinib and the tyrosine kinase inhibitor, and clinical experiment results show that the combined medication of the luccotinib and the tyrosine kinase inhibitor has synergistic effect, has obvious effect on treating the chronic myelofibrosis of patients with the secondary myelofibrosis of the chronic myelocytic leukemia and simultaneously improving the myelofibrosis, and has great clinical significance.

Description

Application of luccotinib in preparation of medicine for treating chronic secondary myelofibrosis
Technical Field
The invention relates to the technical field of medicines, in particular to application of luccotinib in preparing a medicine for treating chronic granulocytic leukemia secondary myelofibrosis.
Background
Chronic myelogenous leukemia (abbreviated as lentil/CML) is a hematological malignancy that originates in hematopoietic stem cells and is characterized by clonal myelogenous hyperproliferation. The incidence of CML accounts for 15% -20% of adult leukemia. 95% of CML patients have characteristic Ph chromosome, i.e. 9 chromosome ABL proto-oncogene is transferred to BCR fragmentation aggregation region of 22 chromosome to form BCR-ABL fusion gene, and its coded BCR-ABL protein has strong tyrosine kinase activity, can stimulate abnormal proliferation of granulocyte and inhibit its apoptosis by interfering normal cell signal transduction, and is the molecular basis of CML pathogenesis. CML can be divided into chronic, accelerated and acute stages according to the course of disease. The study suggested that the prognosis varied among these 3 patients at different stages, and that their prognosis was influenced by a number of factors. Myelofibrosis (MFP) can occur in many hematopoietic diseases, and many studies have shown that in the late stages of CML there is often MFP or even secondary Myelofibrosis (MF). Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) caused by clonal proliferation of hematopoietic stem cells, and comprises primary myelofibrosis and secondary myelofibrosis, wherein the secondary myelofibrosis can be caused by various factors such as acute leukemia, chronic leukemia, lymphocytic leukemia, multiple myeloma, lymphoma, breast cancer, chemical substances (benzene, chlorine and the like), tuberculosis systemic lupus erythematosus, virus infection and the like, and the secondary myelofibrosis is most common in terms of lentil. It was found that 90% of patients with chronic granuloses were associated with myelofibrosis.
The lucocotinib (Ruxolitinib) is a selective JAK1/JAK2 tyrosine kinase inhibitor cooperatively developed by Incyte and Novartis companies, is approved as the first medicament for treating myelofibrosis by the US FDA in 11 months in 2011 (the trade name is Jakafi), and is applicable to intermediate or high-risk myelofibrosis including primary myelofibrosis, secondary polycythemia myelofibrosis and primary thrombocythemia myelofibrosis; in 12 months 2014, FDA approved a new indication as polycythemia vera with an inadequate or intolerant response to hydroxyurea. Approval to market in the European Union at 8 months 2012 (under the trade name Jakavi); approved for sale in japan in 7 months 2014. The chemical name of the luccotinib is (R) -3-cyclopentyl-3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile, and the structural formula of the luccotinib is shown as a formula I:
Figure BDA0002876322870000021
in the prior art, there is no effective treatment means and medicine for CML secondary MF, and the medicine for treating CML is mostly adopted to control the disease progress. The chronic stage of CML mainly treats Tyrosine Kinase Inhibitors (TKI), the acute-phase treatment mainly treats TKI in combination with chemotherapy, and the adjuvant treatment is heterogenic hematopoietic stem cell transplantation. Therefore, the search for an effective therapeutic agent for treating the secondary myelofibrosis of chronic myelogenous leukemia is a problem to be solved in the field.
Disclosure of Invention
Therefore, in order to overcome the problems in the prior art, the invention provides the following technical scheme:
the first aspect of the invention provides a mixture for treating secondary myelofibrosis of chronic myelogenous leukemia, which comprises luccotinib and a tyrosine kinase inhibitor, wherein the mass ratio of luccotinib to the tyrosine kinase inhibitor is 1: 30-80;
further preferably, the mass ratio of the luccotinib to the tyrosine kinase inhibitor is 1: 60;
further, the tyrosine kinase inhibitor is any one or more of nilotinib, imatinib, dasatinib, bosutinib and panatinib; preferably, the tyrosine kinase inhibitor is nilotinib;
the second aspect of the present invention provides a pharmaceutical composition for treating myelofibrosis secondary to chronic myelogenous leukemia, comprising any one of the above mixture and a pharmaceutically acceptable carrier or excipient;
further, the pharmaceutical composition is a tablet, a capsule or a pill;
in a third aspect, the present invention provides a kit for treating myelofibrosis secondary to chronic myelogenous leukemia, comprising any one of the above mixtures or pharmaceutical compositions;
further, the kit further comprises: instructions for use describe a method of treating myelofibrosis secondary to chronic myelogenous leukemia;
in a fourth aspect, the invention provides the use of luccotinib for preparing any one of the above-mentioned mixtures, pharmaceutical compositions or kits for the treatment of secondary myelofibrosis in chronic myelogenous leukemia.
Advantageous effects
Clinical experiment results show that the drug combination of the reed cotinib and the tyrosine kinase inhibitor nilotinib has a synergistic effect: (1) the data of white blood cells, hemoglobin and blood platelets tend to be normal; (2) spleen volume is reduced by more than 50%; (2) the megakaryocyte quantity is increased, and the myelofibrosis degree is greatly reduced.
Drawings
FIG. 1 shows the results of bone marrow aspiration before treatment of patients in 3.2 cases
FIG. 2 is the results of bone marrow aspiration after treatment of patients in 3.2 cases
Detailed Description
All of the starting materials used in the examples of the present invention are commercially available.
The lucocotinib (Ruxolitinib) is a selective JAK1/JAK2 tyrosine kinase inhibitor cooperatively developed by Incyte and Novartis companies, is approved as the first medicament for treating myelofibrosis by the US FDA in 11 months in 2011 (the trade name is Jakafi), and is applicable to intermediate or high-risk myelofibrosis including primary myelofibrosis, secondary polycythemia myelofibrosis and primary thrombocythemia myelofibrosis; in 12 months 2014, FDA approved a new indication as polycythemia vera with an inadequate or intolerant response to hydroxyurea. Approval to market in the European Union at 8 months 2012 (under the trade name Jakavi); approved for sale in japan in 7 months 2014. The chemical name of the luccotinib is (R) -3-cyclopentyl-3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) propionitrile, and the structural formula of the luccotinib is shown as a formula I:
Figure BDA0002876322870000041
tyrosine kinase inhibitors (TKI for tyrosinase inhibitors) are compounds which can inhibit Tyrosine kinase activity. Tyrosine kinases (Tyrosinekinase) are kinases which catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, can catalyze the phosphorylation of various substrate protein tyrosine residues, and have important functions in cell growth, proliferation and differentiation. Most of the protein tyrosine kinases discovered to date are oncogene products belonging to oncogenic RNA viruses, and can also be produced from vertebrate proto-oncogenes. Tyrosine kinase inhibitors can be used as competitive inhibitors of combination of Adenosine Triphosphate (ATP) and tyrosine kinase, can also be used as tyrosine analogues, block the activity of tyrosine kinase, inhibit cell proliferation, and have been developed into a plurality of antitumor drugs. The action mechanism of the tyrosine kinase inhibitor is mainly to inhibit the growth and proliferation of tumor cells and promote the apoptosis by inhibiting cell signal transduction. For example, the most common tyrosine kinase small molecule inhibitors (small molecule TKIs) aiming at the BCR-ABL fusion gene in clinic at present comprise first generation drugs of imatinib, second generation drugs of dasatinib and nilotinib. Tyrosine kinase inhibitors exert an anti-leukemia effect mainly by inhibiting BCR-ABL fusion proteins.
Nilotinib (Nilotinib), also known as Nilotinib, is a chemical that is an off-white solid. Molecular formula C28H22F3N7O, molecular weight 529.51600. Nilotinib is obtained by improving the molecular structure of imatinib, has stronger selectivity on BCR-ABL kinase activity, has 30 times stronger inhibition effect on tyrosine kinase than imatinib, and can inhibit the kinase activity of imatinib-resistant BCR-ABL mutant. And simultaneously can inhibit KIT and PDGFR kinase activity. Nilotinib is an antitumor drug, is mainly used for clinically treating imatinib-resistant chronic myelocytic leukemia, and has a structure shown as the following formula II:
Figure BDA0002876322870000051
in the present invention, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
The effective dosage of nilotinib and lucotinib used may vary with the mode of administration and the severity of the condition being treated. In a specific embodiment, the mixture for treating myelofibrosis secondary to chronic myelogenous leukemia comprises the luctinib and a tyrosine kinase inhibitor, wherein the luctinib is used in an amount of 10-20 mg/day, and the TKI is used in an amount of 600-800 mg/day; preferably 1-2 (preferably 2) divided doses per day, or in a sustained release form.
Preferably, the dosage of the luccotinib is 10 mg/day;
preferably, the TKI is used in an amount of 600 mg/day.
In the present invention, a "pharmaceutically acceptable" component is a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
In the present invention, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering nilotinib and lucotinib of the present invention to an animal or human. The carrier may be a liquid or a solid. The pharmaceutical composition or mixture of the present invention can be prepared into any conventional formulation form by a conventional method. The dosage form may be various, as long as it is a dosage form that enables the active ingredient to efficiently reach the body of a mammal. Such as may be selected from: tablets, capsules, pills.
The invention also provides a medicine box for treating secondary myelofibrosis of chronic myelocytic leukemia, which comprises the following components: a container 1, and an luccotinib component disposed in the container 1; and container 2 and a nilotinib component disposed in container 2;
or, the kit only comprises one container, and the mixture of the reecotinib and the nilotinib is contained in the content of the reecotinib and the nilotinib;
or, the kit comprises a pharmaceutical composition comprising the mixture, wherein the content of the luccotinib and nilotinib is as described above;
in addition, the kit can also contain an instruction manual for treating the secondary myelofibrosis of the chronic granulocytic leukemia.
Example (A)
Example 1:
a mixture of nilotinib and lucotinib is provided, wherein nilotinib is 600 mg/day, and lucotinib is 5 mg/day.
Example 2:
a mixture of nilotinib and lucotinib is provided, wherein nilotinib is 800 mg/day, and lucotinib is 5 mg/day.
Example 3:
a mixture of nilotinib and lucotinib is provided, wherein nilotinib is 800 mg/day, and lucotinib is 10 mg/day.
Example 4:
a mixture of nilotinib and lucotinib is provided, wherein nilotinib is 600 mg/day, and lucotinib is 10 mg/day.
(II) comparative example
Comparative example 1:
nilotinib 600 mg/day.
Comparative example 2: lucotinib
The dose of the luccotinib is 10 mg/day.
Comparative example 3:
a mixture of imatinib and luccotinib, wherein imatinib is 600 mg/day and luccotinib is 10 mg/day.
Comparative example 4:
a mixture of dasatinib and luccotinib is provided, wherein dasatinib is 600 mg/day, and luccotinib is 10 mg/day.
Comparative example 5: nilotinib + lucotinib + prednisone
A mixture consisting of nilotinib, lucotinib and prednisone, wherein the nilotinib accounts for 600 mg/day, the lucotinib accounts for 10 mg/day and the prednisone accounts for 0.5 mg/kg/day (estimated according to the weight of 50-80 kg of an adult, the dosage of the prednisone is 25-40 mg/day).
(III) examples of the experiments
3.1 clinical experiments
Of 30 patients with secondary myelofibrosis of chronic myelocytic leukemia collected so far in 2018 of our hospital, 17 men and 13 women; age 21-62 years; the course of chronic granulocytic leukemia is 2-7 years. Patients all have anemia symptoms aggravated and extensive bones in the process of CML treatment and maintenance and reliefPain, progressive enlargement of the spleen (giant spleen) and the like. The clinical manifestations are as follows: the abdomen is raised and the patient cannot lie flat, and the patient has difficulty in breathing. Blood routine examination: hemoglobin (Hb) 15-50 g/L, total white blood cell count (WBC) 0.5-2.5 × 109L; the classification shows that the number of the juvenile grains and the juvenile red blood cells is different (the highest juvenile red blood cells reach about 40 percent); the bone marrow puncture is characterized in that repeated multi-part 'dry suction' is performed, bone marrow biopsy Gomori staining proves that fibrous tissue hyperplasia exists, patients accord with the diagnosis standard of MF, the biochemical indexes of liver and kidney functions, blood sugar, blood fat and the like and the cardiac function of the patients are not abnormal before treatment, the patients are randomly divided into 6 groups, 5 persons in each group are treated by taking medicines according to the treatment scheme shown in table 1, and after 3 months, the blood routine (the blood routine normal value range: 54-80g/L of hemoglobin and 2.5-4.0 multiplied by 10 of the total number of white blood cells) is rechecked9The total number of hemoglobin and leucocyte is increased, namely the conventional improvement of blood is obtained, the conventional improvement rate of blood is counted, and the conventional improvement rate is counted in a table 1; checking the size of the spleen: patient spleen volume reduction of 50% is included in table 1; bone marrow biopsy: the decrease in the degree of fibrosis (increase in the number of megakaryocytes and decrease in the area of fibrosis) was calculated as the rate of decrease in fibrosis (improvement in both indices), and the specific results are shown in Table 1.
TABLE 1
Figure BDA0002876322870000081
3.2 cases exemplified
The treatment scheme comprises the following steps: example 4
The treatment time is as follows: for 12 weeks
Blood routine examination data: (1) before treatment: leukocyte 0.8X 109/L, hemoglobin 17g/L, platelets 17X 109L; (2) after treatment: white blood cell 3.0X 109/L, hemoglobin 53g/L, platelets 120X 109/L
Spleen size: the spleen volume is reduced by more than 50 percent
Degree of myelofibrosis: the fibrous tissue in the bone marrow stroma was significantly hyperplastic (fig. 1) to scattered (fig. 2): fig. 1 (10 × 10 for both a and b magnifications), fig. 2 (10 for a)
10; b magnification of 10 × 40) reflects the results of bone marrow aspiration of a patient before and after treatment with the protocol of example 3, and the results of bone marrow biopsy of a patient before treatment are: (1) the hematopoietic tissue proliferation is extremely active, the volume is more than 90 vol%, the adipose tissue is rare, and the grain-red ratio is increased; (2) the granulosa is proliferated actively, the proportion is increased, the juvenile precursor cells are scattered, the proportion of the cells in the middle and late juvenile stages is high, the eosinophilic granulocytes are scattered, and a few cells can be subjected to similar macromutation; (3) erythroid hyperplasia, mainly including middle-late juvenile erythroid, with a few cells showing megaloblastic change; (4) megakaryocyte hyperplasia (0-10 pieces/HPF) is scattered, and the polymorphism is obvious; (5) lymphocytes and histiocytes are scattered; (6) the trabecula is increased, and the fibrous tissues in the stroma are obviously proliferated; and (4) conclusion: myelofibrosis, in combination with clinical history, considering incomplete remission/relapse myeloid picture; the results of bone marrow biopsy of patients after treatment were: (1) the hematopoietic tissue proliferation is extremely active, the volume is more than 90 vol%, the adipose tissue is rare, and the grain-red ratio is increased; (2) the proliferation of the grain system is active, the proportion is increased, the proliferation of the immature precursor cells is dispersed or focally distributed, the medium and late stage and the above stage are taken as main, and partial cells can be seen in the similar giant change; (3) the red-line hyperplasia is reduced, but is rare; (4) megakaryocyte hyperplasia (0-20 pieces/HPF) scattered, and cell body micronucleus, lobular oligomegakaryocytes visible; (5) the powder is scattered on the visible fibrous tissues to obviously proliferate (the nucleated cells in the auxiliary tablet are rarely seen). And (4) conclusion: after the treatment of the chronic granulocytic leukemia in the accelerated stage, the proliferation of hematopoietic tissues is extremely active, the granulosa juvenile precursor cells are proliferated and distributed dispersedly or focally, the erythroid proliferation is reduced, the megakaryocytes are easy to see, the scattered fibrocytes are obviously proliferated, and the fibrosis is obviously improved.
And (4) conclusion: partial hematological remission, spleen retraction greater than 50%, and obvious reduction in myelofibrosis. Therefore, the composition prepared by the embodiment of the invention can obviously improve the secondary myelofibrosis of the patient with chronic myelogenous leukemia.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (9)

1. The mixture for treating secondary myelofibrosis of chronic granulocytic leukemia is characterized by comprising the reed cotinib and a tyrosine kinase inhibitor, wherein the mass ratio of the reed cotinib to the tyrosine kinase inhibitor is 1: 30-80.
2. The mixture for treating myelofibrosis secondary to chronic myelogenous leukemia according to claim 1, wherein the mass ratio of the luccotinib to the tyrosine kinase inhibitor is 1: 60.
3. The mixture for treating myelofibrosis secondary to chronic myelogenous leukemia according to claim 1 or 2, wherein the tyrosine kinase inhibitor is any one or more of nilotinib, imatinib, dasatinib, bosutinib, panatinib.
4. The composition for treating myelofibrosis secondary to chronic myelogenous leukemia according to claim 3, wherein the tyrosine kinase inhibitor is nilotinib.
5. A pharmaceutical composition for treating myelofibrosis secondary to chronic myelogenous leukemia, comprising the mixture of any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is a tablet, capsule or pill.
7. A kit for the treatment of secondary myelofibrosis of chronic myelogenous leukemia comprising the mixture of any one of claims 1 to 4 or the pharmaceutical composition of any one of claims 5 to 6.
8. The kit according to claim 7, further comprising instructions for use in a method for treating myelofibrosis secondary to chronic myelogenous leukemia.
9. Use of luccotinib for the preparation of a mixture for the treatment of secondary myelofibrosis in chronic myelogenous leukemia as claimed in any one of claims 1 to 4, a pharmaceutical composition for the treatment of secondary myelofibrosis in chronic myelogenous leukemia as claimed in any one of claims 5 to 6 or a kit for the treatment of secondary myelofibrosis in chronic myelogenous leukemia as claimed in any one of claims 7 to 8.
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Citations (2)

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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109310768A (en) * 2015-12-29 2019-02-05 得克萨斯大学体系董事会 The inhibition of P38 MAPK for treating cancer
CN110062626A (en) * 2016-11-18 2019-07-26 纽维制药有限公司 Purposes of the sanglifehrin Macrocyclic analogs as anticancer compound

Non-Patent Citations (4)

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Title
ALICIA ARENAS CORTES ET AL.: "Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms", 《HAEMATOLOGICA》 *
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Application publication date: 20210601