CN116672345A - Combination of PARP inhibitors and cytotoxic agents and uses thereof - Google Patents
Combination of PARP inhibitors and cytotoxic agents and uses thereof Download PDFInfo
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- CN116672345A CN116672345A CN202210160263.3A CN202210160263A CN116672345A CN 116672345 A CN116672345 A CN 116672345A CN 202210160263 A CN202210160263 A CN 202210160263A CN 116672345 A CN116672345 A CN 116672345A
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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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- 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
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a combination product of a PARP inhibitor and a cytotoxic agent and application thereof, in particular to a pharmaceutical composition containing a compound of 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridine-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) ketone, the combination product and a pharmaceutical kit and application thereof in preparing medicines for preventing or treating diseases improved by PARP activity inhibition.
Description
Technical Field
The present invention relates to a combination of a PARP inhibitor and a cytotoxic agent and uses thereof, and methods of treating diseases using such a combination. In particular to a pharmaceutical composition, a combination product and a pharmaceutical kit containing a compound of 4- (3- (4- (1-hydrogen-imidazo [4,5-b ] pyridine-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daidzin-1 (dihydro) ketone.
Background
Poly ADP-ribose polymerase (PARP) plays an essential role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. PARP inhibitors can inhibit DNA damage repair of tumor cells, promote apoptosis of tumor cells, and have shown efficacy in a variety of cancer models, such as breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, liver cancer, and the like.
The prior art reports that the PARP inhibitor can enhance the curative effects of radiotherapy, alkylating agents, cytotoxic drugs, platinum drugs and the like, so that considerable interest is brought to the development of PARP inhibitors combined with radiotherapy and chemotherapy drugs for cancer treatment.
Document 1 discloses a combination of a PARP inhibitor and temozolomide for the treatment of leukemia, CNS tumors, melanoma. The combination of valipanib with carboplatin and cisplatin is used for the treatment of breast cancer. For example, treatment of MX-1 breast cancer xenograft mice, subcutaneously administered the PARP inhibitor at a dose of 25 mg/kg/day for 14 consecutive days, significantly enhanced the anti-tumor effect of carboplatin following use with carboplatin.
Document 2 discloses the use of PARP inhibitors in combination with TMZ for the treatment of colon cancer, breast cancer. For the treatment of a mouse model with human colon cancer SW620 cells or human triple negative breast cancer MDA-MB-436 transplanted tumor, the PARP inhibitor is administered after being combined with TMZ at the dosage of 30 mg/kg/day, so that the tumor inhibition rate is remarkably improved.
Document 3 discloses the use of PARP inhibitors in combination with TMZ for the prevention or treatment of cancer. Wherein the PARP inhibitor is administered twice daily at a dose of 60 mg.
Although the prior art discloses more trials of PAPR inhibitors in combination with cytotoxic agents for the treatment of cancer, there is still a need to develop new combinations of PARP inhibitors with cytotoxic drugs in order to obtain better efficacy.
Reference is made to:
document 1 C.sub.N.101370497A
Document 2cn 102762549A
Document 3 CN110891576A
Disclosure of Invention
In a first aspect, the invention provides a pharmaceutical composition comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) endorphin-1 (dihydro) ketone or a salt thereof (alternatively referred to as "compound" or "compound a"). The content of the compound or the pharmaceutically acceptable salt thereof is 0.1-50mg, or the compound or the salt thereof is administered in a daily dose of 0.1-50mg; preferably, the amount of the compound or salt thereof in the composition or the dosage to be administered is 0.1 to 30mg; it is further preferred that the amount of the compound or salt thereof in the composition or the dosage to be administered is 0.1 to 15mg.
In the present invention, the content or administration dose of the compound may optionally be 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, etc. The content or the administration dose can be administered once daily, twice daily, multiple times daily, once every two days, once weekly, etc. according to the needs of the patient. The administration dosage can be further based on the weight (kg) or body surface area (m 2 ) Is increased or decreased according to the difference.
In a second aspect the invention provides a combination comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof; and at least one cytotoxic agent.
Suitable cytotoxic agents of the present invention are selected from any one of temozolomide, platinum, etoposide, dacarbazine, topotecan, kemptide, gemcitabine, albumin paclitaxel, bevacizumab, or combinations thereof. Platinum-based cytotoxic agents include cisplatin, carboplatin, oxaliplatin, or combinations thereof.
The preferred cytotoxic agent is any one or a combination of temozolomide, platinum, etoposide, open, gemcitabine, albumin paclitaxel.
More preferred cytotoxic agents are one or a combination of temozolomide, cisplatin, carboplatin, etoposide, gemcitabine, albumin paclitaxel.
In one embodiment of the invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and the cytotoxic agent temozolomide.
In another embodiment of the present invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) endoriboxazin-1 (dihydro) one or a salt thereof and the cytotoxic agent carboplatin or cisplatin.
In another embodiment of the present invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and the cytotoxic agent is developed.
In another embodiment of the present invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and the cytotoxic agent gemcitabine.
In another embodiment of the present invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, together with the cytotoxic agents gemcitabine and albumin paclitaxel.
In another embodiment of the invention, the combination product comprises the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, and the cytotoxic agents cisplatin and etoposide.
The compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) ketone or a salt thereof and a cytotoxic agent are administered in combination, which can achieve a significant synergistic effect, such as a significantly reduced dosage of the compound and a better tumor suppression effect compared to the administration of the compound alone.
In the combination product of the invention, the cytotoxic agent is contained or administered in an amount of 0.1 to 1500mg. Specifically, it includes, but is not limited to, 0.1mg, 0.5mg, 1mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 300mg, 350mg, 400mg, 500mg, 600mg, 700mg, 800mg, 1000mg, 1250mg, 1500mg.
The content or the administration dose can be administered once daily, twice daily, multiple times daily, once every two days, once weekly, etc. according to the needs of the patient. The daily dosage can be further controlled according to the weight (kg) or body surface area (m 2 ) For example, the dosage may be 0.1-1500 mg/kg/day calculated on the basis of the weight of the patient; for example, by body surface areaCalculated, the administration dosage can be 0.1-1500mg/m 2 Day/day.
The preferred cytotoxic agent is present in an amount or dosage of 1-500mg (/ kg/day, or/m) 2 Day), further preferred cytotoxic agent content or dosage is 1-250mg; further preferred amounts or doses of cytotoxic agent are 1-200mg.
In the combination of the invention, the compound or salt thereof is present in an amount of 0.1 to 50mg, or the compound or salt thereof is administered in a daily dose of 0.1 to 50 mg.
In the combination of the present invention, the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) polypeptide-1 (dihydro) ketone or a salt thereof and a cytotoxic agent can be administered simultaneously, sequentially or at intervals. The effect of the invention can be achieved by all three administration modes. Modes of administration include, but are not limited to, oral administration, parenteral administration, intravenous drip administration, subcutaneous administration, intramuscular administration, and the like.
In a third aspect, the invention provides a pharmaceutical composition comprising a combination product according to the invention. The compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and a cytotoxic agent are administered in the form of a pharmaceutical composition. Specifically, the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) polypeptide-1 (dihydro) ketone or a salt thereof and a cytotoxic agent can be prepared into unit dosage forms such as tablets, capsules, dispersing agents, granules, injections, freeze-dried preparations for injection and the like by adding conventional pharmaceutically acceptable auxiliary materials by a conventional method of a person skilled in the art. Preferably, the pharmaceutical composition of the invention is a tablet, a capsule, an injection, a freeze-dried preparation for injection, and the like.
Alternatively, the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof of the present invention may be prepared separately from a cytotoxic agent in the form of a pharmaceutical composition. For example, the compound of the present invention may be formulated into a solid dosage form, and the cytotoxic agent may be formulated into an injection or lyophilized preparation for injection. The two pharmaceutical compositions may be administered simultaneously, sequentially or separately.
In solid form pharmaceutical compositions, suitable pharmaceutically acceptable excipients include diluents, disintegrants, lubricants, surfactants, coating agents, and the like. The specific components may be identified according to conventional methods by those skilled in the art. In the injection, suitable pharmaceutically acceptable auxiliary materials include water for injection, osmotic pressure regulator, pH regulator, preservative and the like. The pharmaceutical composition contains 0.1-50mg of 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) ketone or a salt thereof; the preferred compound or salt thereof is contained in an amount of 0.1 to 30mg; it is further preferred that the amount of the compound or salt thereof in the composition or the dosage to be administered is 0.1 to 15mg.
In a fourth aspect, the invention provides a pharmaceutical kit. The pharmaceutical kit may contain the first composition, the second composition, the third composition or the pharmaceutical composition described above. The first composition of the pharmaceutical kit of the invention contains the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, and pharmaceutically acceptable excipients conventional in the art. The second composition contains a cytotoxic agent and pharmaceutically acceptable excipients conventional in the art. The third composition may contain another cytotoxic agent different from the second composition, and pharmaceutically acceptable excipients conventional in the art.
The first composition of the pharmaceutical kit of the invention contains 0.1-50mg of the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) endorphin-1 (dihydro) ketone or a salt thereof; preferably 0.1-15mg of the compound or salt thereof; the second composition contains 0.1-1500mg of cytotoxic agent; preferably, the composition contains 0.5-250mg of the cytotoxic agent, and more preferably 1-200mg of the cytotoxic agent.
In the pharmaceutical kit, the first composition, the second composition and/or the third composition can be independently prepared into the same or different dosage forms according to the property of the medicine, such as tablets, capsules, injections, granules, freeze-drying agents and the like.
In a fifth aspect the invention provides a therapeutic use for a disease. The disease is ameliorated by inhibition of PARP activity, or the disease lacks Homologous Recombination (HR) -dependent DNA double strand break (DBS) repair, or the cancer is a cancer with BRCA1 or BRCA2 defects, mutations.
In a preferred aspect of the present invention, there is provided the use of a compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof in an amount of 0.1 to 50mg in the manufacture of a medicament for the prevention or treatment of a disease ameliorated by the inhibition of PARP activity.
In a preferred aspect of the present invention there is provided the use of a combination comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, and a cytotoxic agent, in a medicament for the prevention or treatment of a disease ameliorated by PARP activity inhibition.
In a preferred aspect of the present invention, there is provided a use of a pharmaceutical composition comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) propanazin-1 (dihydro) one or a salt thereof, and a cytotoxic agent, in a medicament for the prevention or treatment of a disease ameliorated by the inhibition of PARP activity.
In a preferred aspect of the present invention, there is provided the use of a pharmaceutical kit comprising a first composition of the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) propanazin-1 (dihydro) one or a salt thereof, together with pharmaceutically acceptable excipients conventional in the art, in a medicament for the prevention or treatment of a disease ameliorated by the inhibition of PARP activity. The second composition contains a cytotoxic agent and pharmaceutically acceptable excipients conventional in the art. The third composition may contain another cytotoxic agent different from the second composition, and pharmaceutically acceptable excipients conventional in the art.
In a preferred aspect of the invention there is provided the use of a combination product, pharmaceutical composition or pharmaceutical kit comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and a cytotoxic agent for the manufacture of a medicament for the treatment of a DNA double strand break (DBS) repair lacking Homology Recombination (HR) dependence or a disease having BRCA1 or BRCA2 defects, mutations.
In such therapeutic uses, the compounds of the present invention and the cytotoxic agent may be formulated in unit dosage forms or separate identical or different dosage forms and may be administered simultaneously, sequentially or at intervals.
The diseases according to the invention include in particular cancer, vascular diseases, septic shock, ischemic injury, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis. Preferably cancer, including small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, fallopian tube cancer, peritoneal cancer, melanoma, glioblastoma or lymphoma. Further preferred cancers are small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, breast cancer.
Drawings
FIG. 1 shows the effect of compound A alone or in combination with Temozolomide (TMZ) on H2AX phosphorylation of MDA-MB-436 cells.
Detailed Description
Term interpretation:
by "compound or salt thereof" is meant a compound of the present invention with which it is capable of forming a pharmaceutically acceptable salt, such salts including, but not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like. The compounds of the present invention or salts thereof may be prepared with reference to the process described in patent CN107428757a or the process described in CN 109843885A.
TMZ refers to the cytotoxic agent Temozolomide (Temozolomide); AZD2281 refers to Olaparib, chemical name 1- (cyclopropanecarbonyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine; the kemptuo refers to irinotecan hydrochloride injection.
The dosage of the compound of the invention or the cytotoxic agent,when calculated as body weight, 0.1-50mg is expressed as a dosage of 0.1-50mg/kg; when calculated as body surface area, 0.1-50mg represents administration dosage of 0.1-50mg/m 2 . The content of the compound or cytotoxic agent of the present invention means the content of the corresponding drug in a unit preparation.
In the route of administration, i.v. means intravenous injection; i.p. represents intraperitoneal injection; i.g. means intragastric administration.
In the dosing frequency, D0 represents the first dosing time after the mice completed grouping, i.e., day 1; d0-n (n is 4, 9, 10, 16) represents continuous administration once daily starting from D0 to day n+1th;
dn (n is 17, 21, 54) represents day n+1 from D0;
d1,5,8 represent dosing at day 2, day 6 and day 9 intervals; d0,4 represents administration at 1 day and 5 day intervals.
Example 1
Effect of combination of compound a and temozolomide on H2AX phosphorylation in MDA-MB-436 cells.
The cell DNA contains histone H2AX, when DNA double strand break, the C terminal serine residue of histone H2AX near the break point is phosphorylated to form phosphorylated histone gamma-H2 AX, so gamma-H2 AX is the marker of DNA damage. We examined the effect of compound A and temozolomide on DNA damage repair, alone and in combination, respectively, in BRCA1 mutated MDA-MB-436 cells. Through immunoblotting research, the compound A can obviously enhance the phosphorylation of H2AX after being combined with temozolomide, further weaken the repair capability of PARP on DNA damage, and the effect shows obvious dose dependency.
The results in FIG. 1 show that compound A (100 nM) when used in combination with temozolomide (1 mM) induced greater phosphorylation of cellular H2AX than either compound A (10000 nM) or temozolomide (1 mM) alone.
Example 2
Combination of compound a and temozolomide was tested for inhibition of tumor cell proliferation in vitro.
The inhibition of proliferation of tumor cells in vitro was examined by SRB (Sulfonyl rhodamine B staining) on PARP inhibitor compound A (0.3, 1, 2 nM), AZD2281 (10, 30, 100 nM) alone or in combination with the cytotoxic drug temozolomide (10, 30. Mu.M) for 120hrs by selecting BRCA1 mutated MDA-MB-436 cells.
Inhibition of proliferation of MDA-MB-436 cells by the combination of Compound A, AZD2281 and TMZ of Table 1 (% n=2)
The research result shows that the compound A can obviously enhance the proliferation inhibition effect of TMZ on tumor cells, and the effective concentration of the compound A is obviously lower than that of AZD 2281.
Example 3
In vivo test of Compound A in combination with temozolomide.
The compound A and temozolomide are combined to treat the human breast cancer cell MDA-MB-436 nude mice subcutaneous transplantation tumor model. BALB/c nude mice were subcutaneously inoculated with human breast cancer MDA-MB-436 cells until the tumor grew to 100-200mm 3 Animals were then randomized into solvent and treatment groups, with 12 mice in the solvent group and 6 mice in the other treatment groups. The mice were dosed according to the dosing schedule of table 2, followed by the first dose, D0. The administration volume is 10ml/kg; the solvent group given the same volume of solvent. D21 was measured separately for each tumor volume and the results are shown in table 2.
Table 2 curative effects of Compound A in combination with temozolomide on human breast cancer MDA-MB-436 nude mice transplantation tumor
Compound a significantly inhibited the growth of human breast cancer MDA-MB-436 nude mice with subcutaneous engraftment tumors, 1mg/kg group had 1/6 tumor partial regression and 5/6 tumor complete regression at D21, and 6/6 tumors all completely resolved by the end of the experiment (D54) without recurrence.
The compound a significantly inhibited tumor volume after combination with temozolomide, and at D21, the compound a combination had partial regression of 2/6 tumors and complete regression of 4/6 tumors, and by the end of the experiment (D54), all tumors in the combination were completely resolved without recurrence.
It can be seen that compound A significantly enhances the efficacy of TMZ in inhibiting MDA-MB-436 tumor proliferation. The compound A and temozolomide are combined, so that the curative effect is enhanced, and the administration dosage can be obviously reduced.
Example 4
Therapeutic effect of compound A in combination with carboplatin on subcutaneous transplantation tumor in MX-1 nude mice.
BALB/c nude mice were subcutaneously inoculated with breast cancer MX-1 tumor tissue until the tumor grew to 100-150mm 3 Animals were then randomly grouped. The mice were divided into solvent group and treatment group, wherein the number of mice in solvent group was 12, and the number of mice in other treatment group was 6. The mice were dosed according to the dosing schedule of table 3, followed by the first dose, D0. The administration volume is 10ml/kg; the solvent group given the same volume of solvent. D21 was measured separately for each tumor volume and the results are shown in table 3.
Table 3 efficacy of Compound A alone or in combination with carboplatin on subcutaneous transplantation tumor in nude mice with human breast cancer MX-1
The research result shows that the compound A can obviously enhance the inhibition effect of carboplatin on proliferation of subcutaneous transplantation tumor of a human breast cancer MX-1 nude mouse, and cause complete tumor regression.
Example 5
The compound A and the open pioneering are used for treating the subcutaneous transplantation tumor of the SW620 nude mice.
BALB/c nude mice were subcutaneously inoculated with human colon cancer SW-620 cells until tumors grew to 100-150mm 3 Animals were then randomly grouped. Mice were divided into solvent group and treatment group, wherein the solvent group mice were 12 and the other treatment group mice were 6 each. The dosing regimen was as set forth in table 4 below,mice were grouped and given the first dose, D0. The administration volume is 10ml/kg; the solvent group given the same volume of solvent. D17 was measured separately for each tumor volume and the results are shown in table 4.
Table 4 curative effects of Compound A alone or in combination with Kappy application on subcutaneous transplantation tumor in nude mice of human colon cancer SW620
Compound a (1 mg/kg) had no significant inhibitory effect on the growth of human colon cancer SW620 nude mice subcutaneous transplantation tumor; compound a (0.1, 0.3, 1 mg/kg) was combined with kemption (10 mg/kg), significantly inhibiting tumor volume; the tumor-bearing mice can better tolerate the drugs, and no symptoms such as weight loss and the like occur. The combination of compound a with the open cell can significantly enhance the efficacy.
Claims (11)
1. A pharmaceutical composition comprising the compound 4- (3- (4- (1 hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, said compound or pharmaceutically acceptable salt being present in said pharmaceutical composition in an amount of 0.1-50mg, or said compound or pharmaceutically acceptable salt being administered in a daily dose of 0.1-50 mg.
2. The pharmaceutical composition according to claim 1, wherein the content of the compound or salt thereof in the pharmaceutical composition is 0.1-30mg, or the compound or salt thereof is administered in a daily dose of 0.1-15mg.
3. A combination product comprising the pharmaceutical composition of claim 1; and at least one cytotoxic agent.
4. The combination product of claim 3, wherein the cytotoxic agent is selected from one of temozolomide, cisplatin, carboplatin, etoposide, dacarbazine, topotecan, open-plakom, gemcitabine, albumin paclitaxel, and bevacizumab, and combinations thereof.
5. A combination product according to claim 3, wherein the cytotoxic agent is present in an amount or dose of 0.1-1500mg.
6. A combination product according to claim 3, wherein the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof and the cytotoxic agent are administered simultaneously, sequentially or separately.
7. A pharmaceutical composition comprising the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daizin-1 (dihydro) one or a salt thereof, and at least one cytotoxic agent, together with pharmaceutically acceptable excipients.
8. The pharmaceutical composition according to claim 7, wherein the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) daiamid-1 (dihydro) ketone or a salt thereof is contained in an amount of 0.1-50mg and the cytotoxic agent is contained in an amount of 0.1-1500mg.
9. A pharmaceutical kit comprising a first composition and a second composition, the first composition comprising 0.1-15mg of the compound 4- (3- (4- (1-hydro-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) propanazin-1 (dihydro) one or a salt thereof and a pharmaceutically acceptable adjuvant; the second composition contains a cytotoxic agent and pharmaceutically acceptable excipients.
10. Use of a combination product according to claim 3, a pharmaceutical composition according to claim 7 or a pharmaceutical kit according to claim 9 for the manufacture of a medicament for the prevention or treatment of cancer ameliorated by PARP activity inhibition.
11. The use of claim 10, wherein the cancer is small cell lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, fallopian tube cancer, peritoneal cancer, melanoma, glioblastoma or lymphoma.
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| WO2024183794A1 (en) * | 2023-03-07 | 2024-09-12 | 中国科学院分子细胞科学卓越创新中心 | Use of parp inhibitor in combination with chemotherapy in treatment of cxorf67 high-expression tumors |
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| WO2024183794A1 (en) * | 2023-03-07 | 2024-09-12 | 中国科学院分子细胞科学卓越创新中心 | Use of parp inhibitor in combination with chemotherapy in treatment of cxorf67 high-expression tumors |
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