WO2022135549A1 - Nk1拮抗剂前药化合物与5-ht3受体拮抗剂的联用用途 - Google Patents
Nk1拮抗剂前药化合物与5-ht3受体拮抗剂的联用用途 Download PDFInfo
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940078646 other antiemetics in atc Drugs 0.000 description 1
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- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- ZSWXMOQFFWMZQH-UHFFFAOYSA-M potassium;ditert-butyl phosphate Chemical compound [K+].CC(C)(C)OP([O-])(=O)OC(C)(C)C ZSWXMOQFFWMZQH-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 235000013555 soy sauce Nutrition 0.000 description 1
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present disclosure belongs to the field of medicine, and relates to the use of a rolapitant prodrug in combination with a 5-HT3 receptor antagonist in the preparation of a medicament for preventing or treating nausea and/or vomiting.
- Tachykinins are peptide ligands for neurokinin receptors.
- Neurokinin receptors such as NK1, NK2 and NK3, are involved in various biological processes. They can be found in the nervous and circulatory systems of mammals as well as in surrounding tissues. Accordingly, modulation of such receptors has been investigated for potential treatment or prevention of various diseases in mammals.
- Typical neurokinin receptor antagonists and their uses include: US5760018 (1998) (pain, inflammation, migraine and vomiting), US5620989 (1997) (pain, nociception and inflammation), WO95/19344 (1995), WO 94/13639 (1994) and WO 94/10165 (1994).
- NK1 receptor antagonists include: Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971- 8981 (2001).
- US7049320 provides a potent, selective, and NK1 antagonist rolapitant with beneficial therapeutic and pharmacological properties and good metabolic stability, which may be in free base form or pharmaceutically acceptable salt form, suitable for preparations for parenteral administration,
- US9101615 provides prodrugs of the formula rolapitant, ie prodrugs of the compound of formula I wherein the free amine (or two amines) hydrogens are replaced by groups selected from -Y, -X, and salts thereof, wherein Y is selected from -P (O)(OH) 2 , -S(O) n1 R 1 , -C(O)(C 1-6 alkyl)X, -C(O)(C 1-6 alkyl)(aryl), -C(O)OR 4 ; X is selected from -NR 2 R 3 , -P(O)(OH) 2 or -S(O) n1 R 1 ; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; n1 is 0-4.
- the prodrug can be used in a suitable liquid formulation (with or without the parenteral
- Drug hemolysis is caused by the massive destruction of red blood cells caused by immune factors after the drug enters the human body.
- hemolytic phenomena such as anemia, jaundice, soy sauce and urine appear.
- Drug-induced hemolytic anemias can be divided into the following three types: (1) drug-induced immunity, which results in antibody-mediated hemolytic reactions; (2) drugs acting on red blood cells with genetic enzyme defects (eg, G6PD deficiency); (3) Hemolytic response of drugs to abnormal hemoglobin.
- the key to the treatment of this disease is to stop the use of related drugs and control the occurrence of hemolysis to prevent the occurrence of complications.
- CN102573475 discloses an improved prescription containing polyethylene glycol 15-hydroxystearate and medium chain triglyceride.
- the hemolysis of the pharmaceutical composition is still not completely resolved, even if the compound of formula I is prepared as a phosphate-containing prodrug.
- PCT/CN2020/098460 provides a new NK1 antagonist prodrug compound that is effective for treating various physiological disorders, symptoms and diseases with less side effects, and its structure is as follows,
- the present disclosure provides a novel NK1 antagonist prodrug compound that is effective for treating various physiological disorders, symptoms and diseases and has less side effects in combination with a 5-HT3 receptor antagonist in the preparation of a medicament for preventing or treating nausea and/or vomiting in use and showed good therapeutic effect.
- the present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with a 5-HT3 receptor antagonist in the preparation of a medicament for preventing or treating nausea and/or vomiting,
- the 5-HT3 receptor antagonist is selected from granisetron, ondansetron, ramosetron, tropisetron, palonosetron and dolasetron, preferably Palonosetron.
- the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 10-500 mg, such as 10 mg, 20 mg, 27.25 mg, 30 mg, 40 mg, 50 mg, 54.5 mg, 60 mg, 70mg, 80mg, 81.75mg, 90mg, 100mg, 109mg, 110mg, 120mg, 130mg, 136.25mg, 140mg, 150mg, 160mg, 163.5mg, 170mg, 180mg, 190mg, 190.75mg, 200mg, 210mg, 218mg, 220mg, 230mg, 40mg , 408.75mg, 410mg, 420mg, 430mg, 436mg, 440mg, 450mg, 460mg, 463.25mg, 470mg, 480mg, 490mg, 490.5mg, 500mg.
- the frequency of administration can be once a day,
- the 5-HT3 receptor antagonist is administered at a dose of 0.075-1 mg, eg, 0.125 mg, 0.25 mg, 0.375 mg, 0.5 mg, 0.625 mg, 0.75 mg, preferably 0.25-0.75 mg .
- the frequency of administration can be once a day, twice a day, three times a day, once a week, and once every two weeks.
- the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 27.25 mg, 54.5 mg, 81.75 mg, 109 mg, 136.25 mg, 163.5 mg, 190.75 mg, 218 mg, 245.25 mg mg, 272.5mg, 299.75mg, 327mg, 354.25mg, 381.5mg, 408.75mg, 436mg, 463.25mg or 490.5mg
- the frequency of administration can be once a day, twice a day, three times a day, once a week, two weeks once.
- the administration dose of the 5-HT3 receptor antagonist is 0.125mg, 0.25mg, 0.375mg, 0.5mg, 0.625mg or 0.75mg, and the administration frequency can be once a day, twice a day, three times a day, Once a week, once every two weeks.
- the pharmaceutically acceptable salts of the medicaments described in the present disclosure can be hydrochloride, phosphate, hydrogenphosphate, sulfate, hydrogensulfate, sulfite, acetate, oxalate, malonate, valerate , glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, mesylate, isethionate, maleate.
- the methods of the present disclosure are used to treat or prevent nausea and/or vomiting caused by a variety of events, including chemotherapy-induced nausea and vomiting ("CINV”), radiation-induced nausea and vomiting from moderately or highly emetic chemotherapy (“RINV”) and postoperative nausea and vomiting (“PONV”).
- CINV chemotherapy-induced nausea and vomiting
- RINV radiation-induced nausea and vomiting from moderately or highly emetic chemotherapy
- PONV postoperative nausea and vomiting
- the method is preferably carried out shortly before the occurrence of the emesis-inducing event (ie, no more than 1 or 2 hours before the event).
- the methods can be used to treat nausea and/or vomiting during the acute phase of nausea or during the delayed phase.
- the modes of administration of the combinations described in this disclosure are selected from simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration.
- the route of administration of the combination described in the present disclosure is selected from oral administration, parenteral administration, and transdermal administration, and the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.
- the present disclosure further relates to a method for preventing or treating nausea and/or vomiting, comprising administering to a patient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a 5-HT3 receptor antagonist.
- the present disclosure further relates to a method of preventing or treating emesis comprising administering a combination of the present disclosure to a patient suffering from or at risk of developing emesis.
- the present disclosure provides methods of preventing or treating emesis by administering one or more of the combinations described herein.
- the combination is preferably administered shortly before the emesis-inducing event (ie, no more than 2 hours before the event).
- the emesis can be acute phase emesis (i.e., vomiting that occurs within about 24 hours after the emesis-inducing event), or delayed emesis (i.e., after the acute phase, but 7 days, 6 days after the emesis-inducing event , vomiting within 5 or 4 days).
- the vomiting may include chemotherapy-induced nausea and vomiting ("CINV”), radiation-induced nausea and vomiting (“RINV”), or postoperative nausea and vomiting (“PONV”) caused by moderately or highly emetic chemotherapy .
- CINV chemotherapy-induced nausea and vomiting
- RINV radiation-induced nausea and vomiting
- PONV postoperative nausea and vomiting
- the combination optionally further includes other components, including but not limited to other antiemetics and the like.
- the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating nausea and/or vomiting, which is used in combination with a 5-HT3 receptor antagonist.
- the present disclosure also provides a 5-HT3 receptor antagonist for preventing or treating nausea and/or vomiting, which is used in combination with the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
- the present disclosure also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a 5-HT3 receptor antagonist, and one or more pharmaceutically acceptable carriers.
- the pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form. For example, it can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injectable solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays agent.
- composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a 5-HT3 receptor antagonist described in the present disclosure can be administered alone or in combination with one or more therapeutic agents.
- the components to be combined can be administered simultaneously or separately in sequence.
- the components to be combined may also be administered in combination in the same formulation or in separate different formulations.
- the present disclosure also provides a pharmaceutical packaging box, in which the pharmaceutical composition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a 5-HT3 receptor antagonist described in the present disclosure is packaged.
- the “combination” in the present disclosure refers to a mode of administration, which refers to the administration of at least one dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and at least one dose of a chemotherapeutic drug within a certain period of time, wherein The administered drugs all showed pharmacological effects.
- Said time period can be within one dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
- the compound of formula (I) or a pharmaceutically acceptable salt thereof and the 5-HT3 receptor antagonist can be administered simultaneously or sequentially.
- This term includes treatment in which the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the 5-HT3 receptor antagonist are administered by the same route of administration or by different routes of administration.
- the modes of administration of the combinations described in this disclosure are selected from simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration.
- PONV postoperative nausea and/or vomiting
- a “therapeutically effective amount” refers to an amount of a therapeutic agent that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount sufficient to treat a disease, disorder, and/or condition when administered according to a regimen to a population having or susceptible to the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of, and/or delays the onset of, one or more symptoms of a disease, disorder, and/or condition. One of ordinary skill in the art will appreciate that the term “therapeutically effective amount” is not actually required to achieve successful treatment in a particular individual.
- a therapeutically effective amount can be that amount that, when administered to a patient in need of such treatment, provides a particular desired pharmacological response in a large number of subjects.
- reference to a therapeutically effective amount can refer to as in one or more specific tissues (eg, tissues affected by a disease, disorder or condition) or fluids (eg, blood, saliva, serum, sweat, tears, urine, etc.).
- tissue e.g, tissues affected by a disease, disorder or condition
- fluids eg, blood, saliva, serum, sweat, tears, urine, etc.
- a therapeutically effective amount of a particular agent or therapy can be formulated and/or administered in a single dose.
- a therapeutically effective agent may be formulated and/or administered in multiple doses, eg, as part of a regimen.
- the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a 5-HT3 receptor antagonist to improve the therapeutic effect of nausea and/or vomiting and other diseases.
- compound 2 (2.8g, 4.53mmol, 1eq), tetrabutylammonium iodide (1.68g, 4.55mmol, 1eq), di-tert-butyl phosphate potassium salt (5.63g) were added to a 500mL there-necked flask , 22.67mmol, 5eq) and dioxane (84mL), heated to 55°C and stirred for 4h.
- reaction solution was cooled, poured into ethyl acetate and water, separated, extracted with ethyl acetate, washed with an aqueous solution of sodium sulfite, then washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.73 g of yellow foam. Yield 107%.
- Rats were given the compound of formula (I), palonosetron or compound of formula (I) + palonosetron by intravenous injection 1 to 2 times a week for 29 consecutive days, and the drug was stopped and recovered for 4 weeks. Observing the nature, degree, dose-effect and time-effect relationship and reversibility of possible toxic reactions, judging toxic target organs or tissues, studying their toxicokinetic characteristics, and understanding the relationship between exposure doses and toxicological results in toxicity studies .
- the content conversion weigh the required amount of the compound represented by the formula (I), add an appropriate amount of 0.02M phosphate buffer (pH is about 7.40) to prepare the required concentration, and the low-concentration administration preparation can be prepared from a high-concentration administration preparation. It is obtained by dilution, and it is used after filtration (PES filter membrane) after preparation. Temporary storage conditions and validity period after preparation: 15 ⁇ 25°C, shading, use within 72 hours.
- the content conversion weigh the required amount of Palonosetron, add an appropriate amount of 0.02M phosphate buffer (pH is about 7.40) to prepare to the required concentration, and the low-concentration preparation can be obtained by diluting the high-concentration preparation. , use after filtration (PES filter membrane) after preparation. Temporary storage conditions and validity period after preparation: 15 ⁇ 25°C, shading, use within 72 hours.
- the compound represented by formula (I) + palonosetron compound group in this experiment was designed as low, medium and high dose groups respectively (the following doses are represented by compound represented by formula (I) + palonosetron) 5+0.0006, 15+0.24, 30+10 mg/kg.
- the compound 5, 20, 40 mg/kg groups and palonosetron 10 mg/kg group represented by formula (I) were set up, and the compound dose of formula (I), the dose of palonosetron and the compound high dose group were Chinese formula
- the dose of compound shown in (I) is the same as that of palonosetron.
- a control group was also set up, and an equal volume of vehicle (0.02M phosphate buffer (pH about 7.40)) was administered intravenously.
- Intravenous infusion administered twice a week in the first 4 weeks, once a week in the 5th week, a total of 9 times of administration, 4 weeks of withdrawal after the last administration, 15 minutes/only/time, administration volume 20ml/ kg.
- Control group before the first and last administration and 2 minutes ( ⁇ 1 minute) after administration;
- CO2-O2 mixed gas (volume ratio 7:3) can be used for anesthesia before blood collection;
- Anticoagulant EDTA-K2;
- Blood sample processing Place the whole blood sample in an ice box before centrifugation, centrifuge at 2-8°C for 10 minutes at a centrifugal force of 1800 ⁇ g, and separate two tubes of plasma, one of which is 50 ⁇ L, and the remaining plasma in another tube. Store below -66°C for inspection.
- Quantitative indicators such as body weight, food intake, hematology, blood biochemistry, urine specific gravity, percentage of each cell line in bone marrow smear and megakaryocyte count (if any), organ weight and coefficient were described by mean ⁇ standard deviation ( ). Routine detection (except urine specific gravity), bone marrow smear nucleated cell proliferation (if any) and other qualitative indicators (two classifications, disordered multi-classification and ordered multi-classification) were described by frequency counts. When the number of samples is less than 3, the data in this group are not statistically compared.
- Quantitative indicators were first tested for homogeneity of variance using the LEVENE test.
- P>0.05 one-way analysis of variance (ANOVA) was used for statistical testing; when the variance was unequal (P ⁇ 0.05), Kruskal was used. -Wallis H rank sum test (K-W method) for statistical analysis.
- K-W method -Wallis H rank sum test
- the Kruskal-Wallis H rank-sum test (K-W method) was used to analyze the ordered multi-category indexes; when the difference was statistically significant (P ⁇ 0.05), the Mann-Whitney U rank-sum test (M-W method) was used to compare the differences between groups.
- the two-category index was analyzed by Fisher's exact probability method (EXACT). When the difference was statistically significant (P ⁇ 0.05), Fisher's exact probability method was used to compare the differences between the two groups.
- Rhesus monkeys were given the compound of formula (I) by intravenous injection 1 or 2 times a week for 29 consecutive days, and the drug was stopped and recovered for 4 weeks.
- Toxic target organs or tissues while studying their toxicokinetic characteristics and understanding the relationship between exposure doses and toxicological results in toxicity studies.
- the content conversion weigh the required amount of the compound represented by the formula (I), add an appropriate amount of 0.02M phosphate buffer (pH is about 7.40) to prepare the required concentration, and the low-concentration administration preparation can be prepared from a high-concentration administration preparation. It is obtained by dilution, and it is used after filtration (PES filter membrane) after preparation. Temporary storage conditions and validity period after preparation: 15 ⁇ 25°C, shading, use within 72 hours.
- the low, medium and high doses of the compound represented by formula (I) in this experiment were 2, 10, and 50 mg/kg, respectively.
- a control group was also set up, and an equal volume of vehicle (0.02M phosphate buffer (pH about 7.40)) was administered in the same manner.
- Intravenous infusion administered twice a week in the first 4 weeks, once a week in the 5th week, 9 times in total, 4 weeks after the last administration, 30 minutes/only/time, administration volume 20ml/ kg.
- Control group 0.25 ( ⁇ 1 minute) hours before the first and last administration and after the end of administration;
- Sampling site saphenous vein of lower extremity or other suitable veins
- Anticoagulant EDTA-K2;
- Blood sample processing Place the whole blood sample in an ice box before centrifugation, centrifuge at 2-8°C for 10 minutes at a centrifugal force of 1800 ⁇ g, and separate two tubes of plasma, one of which is 50 ⁇ L, and the remaining plasma in another tube. Store below -66°C for inspection.
- Quantitative indicators were first tested for homogeneity of variance using the LEVENE test.
- P>0.05 one-way analysis of variance (ANOVA) was used for statistical testing; when the variance was unequal (P ⁇ 0.05), Kruskal was used. -Wallis H rank sum test (K-W method) for statistical analysis.
- K-W method -Wallis H rank sum test
- Ordered multi-category indicators such as urine examination (clarity, glucose, bilirubin, ketone bodies, occult blood, pH, protein, urobilinogen, leukocytes), bone marrow smear nucleated cell proliferation using Kruskal-Wallis H The rank sum test was used for analysis, and when the difference was statistically significant (P ⁇ 0.05), the Mann-Whitney U test (M-W method) was used to compare the differences between groups.
- the two-category (urine nitrite) and disordered multi-category (urine color) indexes were analyzed by Fisher's exact probability method (EXACT). differences between groups.
- Phosphate buffer solution 100ml 2mmol / L NaH2PO4 , 0.1M H3PO4 adjust pH to 3.0.
- Red blood cells were randomly collected from the rabbit jugular vein or central auricular artery (EDTA whole blood) in 10 ml, put into a glass bead Erlenmeyer flask and shaken for 10 minutes to remove fibrinogen to make defibrinated blood. Add about 10 times the amount of sodium chloride injection, shake well, centrifuge at 1500 rpm for 10 minutes, remove the supernatant, and wash the precipitated red blood cells with sodium chloride injection three times as described above until the supernatant is not red. . The obtained red blood cells were prepared into a 2% (v/v) suspension with sodium chloride injection for use.
- test sample compound shown in formula (I)
- PBS pH 7.4 or pH 5
- filter prepare 0.4mg/ml, 0.8mg/ml, 1.2mg/ml, 1.6mg/ml and 2mg/ml, to spare.
- test sample solution was added to the above-mentioned hemoglobin and tested in the supernatant.
- the solution in the test tube is clear red, and no cells or a small amount of red blood cells remain at the bottom of the tube, it indicates that hemolysis has occurred; if all the red blood cells sink, the supernatant liquid is colorless and clear, indicating that no hemolysis has occurred. If there is a brown-red or red-brown flocculent precipitate in the solution, if it is gently inverted for 3-5 times and still does not disperse, it indicates that red blood cell agglomeration may have occurred; it should be further observed under a microscope, if red blood cell aggregation is seen as agglomeration. Compounds provided by the present disclosure employ this method to determine hemolysis.
- rolapitant emulsion (prescription: 4.4% polyethylene glycol-15 hydroxystearate, 1.1% medium chain triglyceride and 0.66% soybean oil), prepare 0.18mg/ml with PBS, 0.09mg/ml, 0.045mg/ml, 0.023mg/ml, 0.011mg/ml, 0.056mg/ml and 0.028mg/ml for use.
- Test Example 4 Pharmacokinetic testing in cynomolgus monkeys
- the bolus injection time is about 30min
- the administration dose is 3.54mg/kg
- the administration concentration is 2mg/ml
- the administration volume is 5ml/kg.
- the content of the compound represented by formula (I) and rolapitant in plasma samples was determined by LC/MS/MS.
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Abstract
Description
pH | 溶解度 | 饱和溶解度 |
7.4 | 26mg/ml | 19.8mg/ml |
9.0 | 28mg/ml | 21.4mg/ml |
Claims (12)
- 根据权利要求1所述的用途,其中所述的5-HT3受体拮抗剂选自格拉司琼、昂丹司琼、雷莫司琼、托烷司琼、帕洛诺司琼和多拉司琼,优选帕洛诺司琼。
- 根据权利要求1或2所述的用途,其中所述式(I)所示化合物或其可药用盐的给药剂量为10-500mg。
- 根据权利要求1-3任意一项所述的用途,其中所述5-HT3受体拮抗剂的给药剂量为0.075-1mg。
- 根据权利要求1-4任意一项所述的用途,其中所述式(I)所示化合物或其可药用盐的给药频次选自一日一次、一日二次、一日三次、一周一次、二周一次。
- 根据权利要求1-5任意一项所述的用途,其中所述5-HT3受体拮抗剂的给药频次选自一日一次、一日二次、一日三次、一周一次、二周一次。
- 根据权利要求1-6任意一项所述的用途,其中所述的恶心和/或呕吐选自化疗诱发的恶心及呕吐、放疗诱发的恶心及呕吐或术后恶心及呕吐。
- 根据权利要求1-7任意一项所述的用途,其中所述的恶心和/或呕吐选自恶心急性期期间或延迟期期间的恶心和/或呕吐。
- 药物组合物,包含式(I)所示化合物或其可药用盐、5-HT3受体拮抗剂,以及一种或多种药用载体。
- 一种药物包装盒,其中包装有式(I)所示化合物或其可药用盐、5-HT3受体拮抗剂的药物组合物。
- 一种预防或治疗恶心和/或呕吐的方法,包括向患者给予式(I)所示化合物或其可药用盐以及5-HT3受体拮抗剂。
- 根据权利要求11的方法,其中式(I)所示化合物或其可药用盐以及5-HT3受体拮抗剂在呕吐事件发生后给予,或在呕吐诱发事件发生前不超过1或2小时给予。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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KR1020237024564A KR20230127252A (ko) | 2020-12-25 | 2021-12-24 | 5-ht3 수용체 길항제와 조합된 nk1 길항제 전구약물화합물의 용도 |
CA3203188A CA3203188A1 (en) | 2020-12-25 | 2021-12-24 | Use of nk1 antagonist prodrug compound in combination with 5-ht3 receptor antagonist |
AU2021407138A AU2021407138A1 (en) | 2020-12-25 | 2021-12-24 | Use of nk1 antagonist prodrug compound in combination with 5-ht3 receptor antagonist |
US18/257,325 US20240016822A1 (en) | 2020-12-25 | 2021-12-24 | Use of nk1 antagonist prodrug compound in combination with 5-ht3 receptor antagonist |
JP2023539378A JP2024501994A (ja) | 2020-12-25 | 2021-12-24 | Nk1拮抗剤プロドラッグ化合物と5-ht3受容体拮抗剤との併用使用 |
MX2023007578A MX2023007578A (es) | 2020-12-25 | 2021-12-24 | Uso del compuesto profarmaco antagonista nk1 en combinacion con un antagonista del receptor 5-ht3. |
EP21909544.5A EP4268818A4 (en) | 2020-12-25 | 2021-12-24 | USE OF AN NK1 ANTAGONIST PRODRUG COMPOUND IN COMBINATION WITH A 5-HT3 RECEPTOR ANTAGONIST |
CN202180071891.8A CN116472048A (zh) | 2020-12-25 | 2021-12-24 | Nk1拮抗剂前药化合物与5-ht3受体拮抗剂的联用用途 |
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CN202011559059.6 | 2020-12-25 | ||
CN202011559059 | 2020-12-25 | ||
CN202111066727.6 | 2021-09-13 | ||
CN202111066727 | 2021-09-13 |
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US (1) | US20240016822A1 (zh) |
EP (1) | EP4268818A4 (zh) |
JP (1) | JP2024501994A (zh) |
KR (1) | KR20230127252A (zh) |
CN (1) | CN116472048A (zh) |
AU (1) | AU2021407138A1 (zh) |
CA (1) | CA3203188A1 (zh) |
MX (1) | MX2023007578A (zh) |
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WO (1) | WO2022135549A1 (zh) |
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-
2021
- 2021-12-24 MX MX2023007578A patent/MX2023007578A/es unknown
- 2021-12-24 CA CA3203188A patent/CA3203188A1/en active Pending
- 2021-12-24 WO PCT/CN2021/141009 patent/WO2022135549A1/zh active Application Filing
- 2021-12-24 US US18/257,325 patent/US20240016822A1/en active Pending
- 2021-12-24 JP JP2023539378A patent/JP2024501994A/ja active Pending
- 2021-12-24 KR KR1020237024564A patent/KR20230127252A/ko unknown
- 2021-12-24 AU AU2021407138A patent/AU2021407138A1/en active Pending
- 2021-12-24 EP EP21909544.5A patent/EP4268818A4/en active Pending
- 2021-12-24 TW TW110148704A patent/TW202233175A/zh unknown
- 2021-12-24 CN CN202180071891.8A patent/CN116472048A/zh active Pending
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Also Published As
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EP4268818A4 (en) | 2024-06-19 |
AU2021407138A1 (en) | 2023-06-29 |
TW202233175A (zh) | 2022-09-01 |
JP2024501994A (ja) | 2024-01-17 |
KR20230127252A (ko) | 2023-08-31 |
CA3203188A1 (en) | 2022-06-30 |
CN116472048A (zh) | 2023-07-21 |
EP4268818A1 (en) | 2023-11-01 |
MX2023007578A (es) | 2023-07-06 |
US20240016822A1 (en) | 2024-01-18 |
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