CN117427079A - Use of cyano-substituted macrocyclic compounds - Google Patents
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Classifications
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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
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- 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
- A61P35/04—Antineoplastic agents specific for metastasis
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- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Organic Chemistry (AREA)
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- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a cyano-substituted macrocyclic compound. The invention provides application of a substance A in preparation of medicines, wherein the substance A is a compound shown as a formula I or pharmaceutically acceptable salt thereof; the medicine is used for treating and/or preventing intracranial tumor; the compound shown as the formula I has high safety in treating and/or preventing intracranial tumors.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a cyano-substituted macrocyclic compound.
Background
Gliomas (glioma), also known as gliomas, are the most common primary central nervous system tumors, accounting for about half of all intracranial primary tumors. Glioma is a primary tumor of the central nervous system with highest morbidity (annual morbidity is about 3-8 people/10 ten thousand people) and mortality (survival rate of less than 3% -7% in 5 years). Glioma patients may develop symptoms such as headache, personality changes, nausea, stroke-like symptoms, etc., and symptoms often develop rapidly, and severe patients may develop confusion. Gliomas generally recur under full force therapy, with typical survival times of 12-15 months after diagnosis. In untreated cases, the survival is short, typically only 3 months.
All current clinical ROS1 inhibitors are multi-kinase inhibitors, with strong inhibition of ALK and/or Trk kinase, but no highly selective inhibition of ROS 1. Clinically, ALK inhibitors are generally proved to have toxic and side effects related to targets such as pulmonary toxicity (e.g. interstitial lung disease), trk inhibitors are generally proved to have toxic and side effects related to targets such as abnormal taste, cognitive dysfunction, dizziness, ataxia, weight gain, mood disorder, sleep disorder, pain after drug withdrawal and the like (Liu D, flory J, lin A, et al, research of on-target adverse events caused by TRK inhibitor therapy.Annals of oncology.2020,31 (9): 1207-1215). Entritinib has a strong inhibitory effect on Trk kinase, and in STARTRK (355 patients) clinical trials, there are a number of neurological related side effects, the most common of which include loss of taste (44%), dizziness (38%), dysesthesia (34%), cognitive impairment (27%), etc., where more than three levels of cognitive impairment are reached (4.5%) (https:// www.accessdata.fda.gov/drug sada_docs/label/2019/212720 s000lbl. Similar to Entritinib, TPX-0005 in TRIDENT-1 clinical trials, the most common side effects were dizziness (62%) and loss of taste (33%), etc. (B.C.Cho et al MA11.07 Phase 1/2TRIDENT-1Study of Repotrectinib in Patients with ROS1+or NTRK+Advanced Solid Tumors,Journal of Thoracic Oncology Vol.16No.3S). For patients with ROS1 gene fusion, in addition to target-related side effects, additional side effects due to off-target are required, which can affect the therapeutic effect and patient experience.
Therefore, for clinical treatment of ROS1 gene fusion glioma, there is an urgent need for an effective compound that can reduce the side effects of drugs.
Disclosure of Invention
The invention aims to solve the technical problem that the existing medicament for treating ROS1 fusion intracranial tumor has strong side effect. The invention provides application of a cyano-substituted macrocyclic compound, which can treat and/or prevent intracranial tumors. Further, the compounds of the present invention are highly safe for the treatment and/or prevention of intracranial tumors.
The invention provides application of a substance A in preparation of medicines, wherein the substance A is a compound shown as a formula I or pharmaceutically acceptable salt thereof; the medicine is used for treating and/or preventing intracranial tumor;
in such applications, the intracranial tumor can be a ROS1 fused intracranial tumor.
In such applications, the intracranial tumor can be a glioma and/or a non-small cell brain metastasis, such as ROS1 fused glioma or ROS1 fused non-small cell brain metastasis.
In this application, the medicament comprises substance a and a pharmaceutically acceptable carrier.
In such applications, the pharmaceutically acceptable carrier may be a conventional carrier in the art.
In such applications, the frequency of administration of the drug may be 1, 2, or 3 times per day.
In such applications, the medicament may be administered orally.
In such applications, the dosage form of the medicament may be conventional in the art.
In the application, the concentration of the compound shown as the formula I in the medicine can be 0.5-1.5mg/mL; preferably 0.5mg/mL or 1.5mg/mL.
In such applications, the unit dose of the drug may be determined according to the effective amount of the subject/patient, and the unit dose of substance A may be 10-600mg, for example 10mg, 40mg, 100mg, 200mg, 250mg, 300mg, 400mg or 600mg.
In such applications, a single dose of the drug may be determined according to the actual therapeutic effect of the subject/patient each time the drug is administered, preferably the single dose of the drug is the mass ratio of the substance a to the subject/patient, which may be 1.8-30mg/kg, preferably 5-15mg/kg, for example 5mg/kg or 15mg/kg.
In such applications, the daily dose of the drug may be determined according to the actual therapeutic effect of the subject/patient each time the drug is administered, preferably the daily dose of the drug is the mass ratio of the substance a to the subject/patient, which may be 1.8-120mg/kg, preferably 10-30mg/kg, for example 10mg/kg or 30mg/kg.
In the application, the mass fraction of the compound shown as the formula I in the medicine is 5-80%, preferably 5-50%.
The invention also provides a pharmaceutical composition comprising substance a and a pharmaceutically acceptable carrier; the substance A is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
the mass fraction of the compound shown in the formula I is 5-80%.
In the pharmaceutical composition, the mass fraction of the compound shown as the formula I can be 5-50%.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating and/or preventing intracranial tumors.
Preferably, the intracranial tumor is a ROS1 fused intracranial tumor.
Preferably, the intracranial tumor is a glioma and/or a non-small cell brain metastasis, e.g., ROS1 fused glioma or ROS1 fused non-small cell brain metastasis.
The present invention also provides a method of treating and/or preventing an intracranial tumor, the method comprising: administering to the subject/patient a therapeutically effective amount of substance a or a drug comprising substance a and a pharmaceutically acceptable carrier; the substance A is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
in the method, the intracranial tumor can be a glioma and/or a non-small cell brain metastasis, such as ROS1 fused glioma or ROS1 fused non-small cell brain metastasis.
In the method, the intracranial tumor can be a ROS1 fused intracranial tumor.
In the method, the pharmaceutically acceptable carrier may be a conventional carrier in the art.
In the method, the frequency of administration of the drug may be 1, 2, or 3 times per day.
In the method, the medicament may be administered orally.
In the method, the dosage form of the drug may be a conventional dosage form in the art.
In the method, the concentration of the compound shown as the formula I in the medicine can be 0.5-1.5mg/mL; preferably 0.5mg/mL or 1.5mg/mL.
In the method, the unit dose of the drug may be determined according to the effective amount of the subject/patient, and the unit dose of the substance A may be 10 to 600mg, for example, 10mg, 40mg, 100mg, 200mg, 250mg, 300mg, 400mg or 600mg.
In the method, each time the drug is administered, a single dose of the drug may be determined according to the actual therapeutic effect of the subject/patient, preferably, the single dose of the drug is a mass ratio of the substance a to the subject/patient, which may be 1.8-30mg/kg, preferably 5-15mg/kg, for example 5mg/kg or 15mg/kg.
In the method, the daily dose of the drug may be determined according to the actual therapeutic effect of the subject/patient each time the drug is administered, and preferably, the daily dose of the drug is the mass ratio of the substance a to the subject/patient, which may be 1.8 to 120mg/kg, preferably 10 to 30mg/kg, for example 10mg/kg or 30mg/kg.
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For further information on the carrier, reference may be made to Remington, the Science and Practice of Pharmacy,21 st Ed.,Lippincott,Williams&Wilkins (2005), the contents of which are incorporated herein by reference.
The term "treatment" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is about to or has received administration of the compound according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
the compounds of the present invention are capable of treating and/or preventing intracranial tumors. Further, the compounds of the present invention are highly safe for the treatment and/or prevention of intracranial tumors.
Drawings
FIG. 1 is a graph showing survival during in vivo efficacy testing in mice according to example 1;
FIG. 2 is a graph showing the percentage change in body weight of mice during the in vivo efficacy test of mice in example 1.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Test of the efficacy of the Compounds of example 1 in mice
The purpose of the experiment is as follows: the antitumor effect of the test agent on BaF3-GOPC-ROS1 cells in situ in the brain of Balb/c nude mice was evaluated, and the effect on the survival of the mice was studied.
Experimental materials: DMSO (purchased from Sigma), FBS (purchased from GIBCO), PRMI1640 (purchased from GIBCO), trypsin (purchased from GIBCO).
Experimental model: baF3-GOPC-ROS1 cells in vivo model of the intracranial brain in Balb/c nude mice.
The experimental method comprises the following steps:
cell culture: in vitro monolayer culture of cells under the conditions of adding 10% fetal bovine serum, 100U/mL penicillin and 100ug/mL streptomycin in RPMI1640 medium, 37deg.C, 5% CO 2 Culturing under 95% relative humidity, digesting and passaging twice a week with pancreatin, and when the cells are in logarithmic growth phase, digesting the cells for inoculation.
Experimental animals: BALB/c nude mice (Beijing Fukang Biotechnology Co., ltd.) were female, 6-8 weeks (the week age of mice at the time of tumor cell inoculation), and had a weight of 18-20g, for a total of 32.
Tumor inoculation: the treated cells were concentrated at a concentration of 2.5X10 7 cell/mL BAF3-GOPC-ROS1 cell suspension 0.2mL, placing on ice, blowing to uniformity, fixing the mice on a mouse brain stereotactic apparatus, inoculating 2 μl cell suspension, 5×10 with microinjector 4 Cell-
Only. The treatment for post-group dosing was as follows in table 1, with random grouping after the seventh day of inoculation.
Table 1 dosing of mice
Remarks:
a solvent: 10% DMSO (DMSO volume percent of volume of solution) +10% solutol (polyethylene glycol-15 hydroxystearate volume percent of volume of solution) +80% water;
experimental results:
1) Compound i had an average median survival of greater than 49 days at doses of 5mg/kg and 15mg/kg, both significantly prolonged median survival in mice (p=0.032 and p=0.007) compared to the control group.
2)TPX-0005The mean median survival of the group was 45 days, with a trend to extend median survival in mice compared to the solvent control group, but not statistically significant (0.177). In addition, median survival in mice treated with Compound I was longer than in mice treated with TPX-0005, and the median survival for mice in each of the treatment group and the solvent control group is shown in Table 2.
3) At the end of dosing, mice body weight significantly decreased after TPX-0005 treatment compared to control, with a mean percent body weight change of-11.48% (P < 0.05), whereas mice treated with compound i (5 mg/kg and 15 mg/kg) had little body weight decrease, with mean percent body weight change of-4.99% (p=0.254) and-0.81% (P < 0.05), respectively. Compound i significantly prolonged the minimum survival and increased survival of mice at the end of the experiment compared to TPX-0005. As shown in table 2.
TABLE 2 median survival in mice
TABLE 3 rate of weight change in mice
Conclusion of experiment: the tested compound I has a remarkable inhibition effect on the growth of BAF3-GOPC-ROS1 intracranial brain in-situ transplantation tumor of a nude mouse, and remarkably prolongs the survival median period of the mouse. In this brain in situ mouse model, compound I has a better cancer inhibition trend than TPX-0005.
Compound i showed little decrease in body weight from the percent change in body weight of mice at two doses (5 mg/kg and 15 mg/kg); whereas the control compound TPX-0005 showed a gradual decrease in body weight and intolerance trend at the dose of 3 mg/kg. The results showed that compound I was safer than TPX-0005 (3 mg/kg). As shown in fig. 2.
From the shortest survival time and the number of surviving mice at the end of the experiment, compound i survived significantly longer than the solvent control and TPX-005 at both doses (5 mg/kg and 15 mg/kg), and the survival rate of mice at the end of the experiment was much higher than that of the control, as shown in fig. 1. The compound I has obvious inhibition effect on the growth of BAF3-GOPC-ROS1 intracranial brain in-situ transplantation tumor of nude mice.
Example 2
One lung adenocarcinoma patient with clear pathology diagnosis, NGS detection was clear as ROS1 gene fusion mutation. The patient is treated for drug resistance through multiple lines in the past, such as first-line Ecotinib, second-line Kzotinib, three-line-PEMEITIACESS combined carboplatin and four-line succinic acid compound critinib, wherein the Kzotinib and the succinic acid compound critinib are inhibitors for targeting ROS 1. Subjects were enrolled in clinical trials of a phase I clinical study of safety, tolerability, pharmacokinetic profile and primary efficacy of compound I in ROS1 gene fusion positive locally advanced/metastatic solid tumor patients after multi-line treatment of drug resistance. The tests of vital signs, physical examination, ECOG physical scores, infectious disease markers, blood routine, urine routine, blood coagulation function, liver function, kidney function, electrolyte, fasting blood glucose, blood fat, 12-lead electrocardiogram and the like are carried out in the baseline period, and the conditions of group inclusion are met. Before group entry, imaging to determine the position and the size of a target focus, wherein the diameter of the target focus is 15mm (1) for the right upper lung and 15.5mm for the left upper lung; (3) Lymph node (right neck), diameter 25.4mm, (4) lymph node (anterior superior vena cava), diameter 28.5mm, (5) brain (left frontal lobe), 13.6mm, total diameter 97.8mm.
Following single drug treatment of the subject with compound i, the specific dosing regimen is as follows: compound I tablet is orally administered orally on an empty stomach, 1 time a day, 300mg each time, and continuously. And the medicine is subjected to vital sign, physical examination, blood routine examination, urine routine examination, liver function, kidney function, electrolyte, fasting blood glucose, blood fat, 12-lead electrocardiogram and other examinations every week (within the first month after taking medicine) or every two weeks (after the first month after taking medicine), and no serious side effects occur during taking medicine; imaging tumor evaluation after single drug treatment of compound I, (1) upper right lung with diameter of 8.5mm, (2) upper left lung with diameter of 10.5mm; (3) Lymph node (right neck), diameter 19.9mm, (4) lymph node (anterior superior vena cava), diameter 26.5mm, (5) brain (left frontal lobe), 8.7mm, total diameter 74.1mm. Compared with the baseline, the overall diameter of the tumor is reduced by 24.2 percent, and the overall diameter of the brain tumor metastasis is reduced by 36 percent.
The study shows that the compound I can reduce the overall tumor volume of patients suffering from brain metastatic lung adenocarcinoma, in particular the brain. Furthermore, the patient did not show any serious side effects. Taken together, the treatment of compound i has clinical benefit (demonstrated efficacy and high safety) for lung adenocarcinoma patients with brain-transferred ROS1 fusion mutations.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.
Claims (10)
1. The application of a substance A in preparing medicines is characterized in that the substance A is a compound shown as a formula I or pharmaceutically acceptable salt thereof; the medicine is used for treating and/or preventing intracranial tumor;
2. the use according to claim 1, wherein,
the intracranial tumor is ROS1 fusion intracranial tumor,
and/or, the intracranial tumor is a glioma and/or a non-small cell brain metastasis.
3. The use according to claim 2, wherein,
the intracranial tumor is ROS1 fused glioma or ROS1 fused non-small cell brain metastasis.
4. The application of claim 1, wherein the application satisfies one or more of the following conditions:
(1) the medicament comprises a substance A and a pharmaceutically acceptable carrier;
(2) the frequency of administration of the drug is 1, 2 or 3 times/day;
(3) the medicament is administered orally;
(4) the unit dose of the substance A is 10-600mg;
and (5) the concentration of the compound shown as the formula I in the medicine is 0.5-1.5mg/mL.
5. The application of claim 4, wherein the application satisfies one or both of the following conditions:
(1) the unit dose of the substance A is 10mg, 40mg, 100mg, 200mg, 250mg, 300mg, 400mg or 600mg;
and (2) the concentration of the compound shown as the formula I in the medicine is 0.5mg/mL or 1.5mg/mL.
6. The use according to any one of claims 1-5, wherein in the use,
a single dose of the medicament is a mass ratio of the substance a to the subject/patient of 1.8-30mg/kg, preferably 5-15mg/kg, for example 5mg/kg or 15mg/kg;
preferably, in said application, the daily dose of said medicament is the mass ratio of said substance a to the subject/patient, said mass ratio being between 1.8 and 120mg/kg, preferably between 10 and 30mg/kg, for example 10mg/kg or 30mg/kg.
7. The use according to any one of claims 1 to 5, wherein the compound of formula i represents 5 to 80%, preferably 5 to 50% by mass of the medicament.
8. A pharmaceutical composition comprising substance a and a pharmaceutically acceptable carrier; the substance A is a compound shown in a formula I or pharmaceutically acceptable salt thereof;
the mass fraction of the compound shown in the formula I is 5-80%.
9. The pharmaceutical composition according to claim 8, wherein the mass fraction of the compound of formula i is 5-50%.
10. The use of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment and/or prophylaxis of intracranial tumours,
preferably, the intracranial tumor is a ROS1 fused intracranial tumor;
and/or, the intracranial tumor is a glioma and/or a non-small cell brain metastasis, such as ROS1 fused glioma or ROS1 fused non-small cell brain metastasis.
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