[go: up one dir, main page]

WO2020143779A1 - Sel de promédicament de pomalidomide - Google Patents

Sel de promédicament de pomalidomide Download PDF

Info

Publication number
WO2020143779A1
WO2020143779A1 PCT/CN2020/071472 CN2020071472W WO2020143779A1 WO 2020143779 A1 WO2020143779 A1 WO 2020143779A1 CN 2020071472 W CN2020071472 W CN 2020071472W WO 2020143779 A1 WO2020143779 A1 WO 2020143779A1
Authority
WO
WIPO (PCT)
Prior art keywords
valine
amino
dioxopiperidin
methyl ester
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/071472
Other languages
English (en)
Chinese (zh)
Inventor
刘飞
赵欣
吴刚
蔡璇
刘伟
祁智
杨许东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Noratech Pharmaceuticals Co Ltd
Original Assignee
Nanjing Noratech Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Noratech Pharmaceuticals Co Ltd filed Critical Nanjing Noratech Pharmaceuticals Co Ltd
Publication of WO2020143779A1 publication Critical patent/WO2020143779A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicine, in particular to L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- Base) methyl ester salts and pharmaceutical compositions containing the above salts, and their use in the preparation of medicaments for the treatment of cancer.
  • L-valine 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- Base
  • methyl ester salts and pharmaceutical compositions containing the above salts, and their use in the preparation of medicaments for the treatment of cancer.
  • Pomalidomide (Formula A structure) was developed by Cell Genetics of the United States and was first approved for listing in the United States in February 2013. Pomalidomide is the third immunomodulator on the market after thalidomide and lenalidomide. It can enhance the immune response mediated by T cells and natural killer cells, while inhibiting the production of proinflammatory cells by monocytes. Factors (such as TNF- ⁇ , IL-6, etc.). In addition, pomalidomide can inhibit tumor cell proliferation and induce apoptosis, and also has a strong proliferation inhibitory effect on lenalidomide-resistant multiple myeloma cell lines.
  • pomalidomide Common adverse reactions of pomalidomide include neutropenia, fatigue and weakness, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infection, back pain and fever, and may also cause thrombosis and may cause serious birth defects in the fetus.
  • pomalidomide is a poorly soluble drug. Its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1mol/L hydrochloric acid was measured. The results were 17.8, 17.0, 18.7 and 18.9 ⁇ g/mL.
  • the low solubility of pomalidomide not only increases the difficulty of the formulation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, which in turn affects oral bioavailability.
  • the structure of formula (B) is a prodrug of pomalidomide with good solubility and capable of significantly improving bioavailability.
  • this structure has poor stability and is easily degraded when placed at room temperature.
  • the purpose of the present invention is to provide novel L-valine (3-(4-amino-1,3-dioxo) with high stability, good solubility, improved bioavailability, low toxicity and side effects or long-term potential Salt of isoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester.
  • the first aspect of the present invention provides L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 -Acid addition salts of methyl) methyl esters (structure B).
  • the acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, citrate, malate, oxalate, salicylate Acid salt, p-toluenesulfonate, 1,5-naphthalene disulfonate, 2-naphthalene sulfonate, or sulfonate.
  • the acid addition salt is selected from hydrochloride, p-toluenesulfonic acid monosalt, dip-toluenesulfonic acid salt, p-toluenesulfonic acid 1.5 salt, naphthalene disulfonic acid half salt or male Acid monosalt.
  • the solubility of the acid addition salt in water is not less than 24 mg/ml; preferably, not less than 40 mg/ml; more preferably, not less than 45 mg/ml.
  • the purity of the acid addition salt stored at 40°C for 5 days is less than 1%; preferably less than 0.7%; more preferably less than 0.2%; or
  • the acid addition salt stored at 40°C for 10 days has a purity change of less than 0.8%; preferably less than 0.5%; more preferably less than 0.4%; or
  • the acid addition salt stored at 60°C for 5 days has a purity change of less than 1%; preferably less than 0.9%; more preferably less than 0.3%; or
  • the acid addition salt stored at 60°C for 10 days has a purity change of less than 1.5%; preferably less than 1%; more preferably less than 0.5%.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and L-valine (3-(4-amino-1,3-dioxoisoindoline Acid addition salt of -2-yl)-2,6-dioxopiperidin-1-yl) methyl ester.
  • the acid addition salt is selected from L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-di Hydrochloride of oxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Sulfate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Phosphate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Maleate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxois
  • the acid addition salt is selected from L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Dihydropiperidin-1-yl) methyl ester hydrochloride, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 -P-toluenesulfonic acid monosalt of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl) -2,6-dioxopiperidin-1-yl) methyl bis-p-toluenesulfonate, L-valine (3-(4-amino-1,3-dioxoisoindoline- 2-yl)-2,6-dioxopiperidin-1-yl) methyl ester of p
  • the third aspect of the present invention provides L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 -The use of acid addition salts of methyl) methyl esters and pharmaceutical compositions containing said salts in the preparation of medicaments for the treatment of cancer.
  • the cancer includes but is not limited to multiple myeloma, prostate cancer, and the like.
  • the fourth aspect of the present invention provides the acid addition salt or the pharmaceutical composition for treating cancer.
  • the cancer is multiple myeloma or prostate cancer.
  • a medicament for treating cancer containing the acid addition salt or the pharmaceutical composition.
  • the cancer is multiple myeloma or prostate cancer.
  • a method for treating cancer comprising administering the acid addition salt or the pharmaceutical composition to a subject in need of treatment for cancer.
  • the cancer is multiple myeloma or prostate cancer.
  • the compounds described in the present invention include two asymmetric centers, and thus can exist in various isomeric forms, for example, enantiomers and/or diastereomeric forms.
  • the compounds described in the present invention may be individual enantiomers, diastereomers or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and rich in one A mixture of one or more stereoisomers.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • the invention additionally includes the compounds described herein as individual isomers that are substantially free of other isomers, or as a mixture of multiple isomers.
  • the acid addition salt of the present invention is the compound of formula (B) described above, ie, L-valine (3-(4-amino-1,3-dioxoisoind Indoline-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester and acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid , Salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2-naphthalene sulfonic acid or sulfamic acid salt.
  • acid such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid , Salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2-na
  • the "p-toluenesulfonic acid monosalt” described herein means that each molecule of the single salt is composed of an equimolar amount of the free base of formula B and p-toluenesulfonic acid; the "bis-p-toluenesulfonate” described herein It means that the double salt per molecule is composed of a single mole of free base and two moles of p-toluenesulfonic acid; "p-toluenesulfonic acid 1.5 salt” as used herein means that 1.5 salts per molecule is composed of two moles of free base and three moles of p-toluene Sulfonic acid composition; "Naphthalene disulfonic acid half salt” described herein means that each molecule of half salt is composed of two moles of free base and a single mole of naphthalene disulfonic acid.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen and sulfur involved in the groups and compounds of the present invention, Nitrogen or halogen, optionally further replaced by one or more of their corresponding isotopes, where carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H) and deuterium (D, also known as Heavy hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N And 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include protium (H
  • the pharmaceutical composition refers to a composition containing the acid addition salt according to the present invention and a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism such as a human or other mammal.
  • a pharmaceutically acceptable carrier means that it can form a pharmaceutical composition together with a specific agent, and can be solid or liquid.
  • Subjects described herein include but are not limited to humans and other mammals; preferably humans.
  • solubility of the salt of the present invention in water is significantly higher than that of pomalidomide, so that it can have excellent drug forming properties;
  • the salt of the present invention can have excellent stability, thereby facilitating storage and transportation;
  • the salt of the present invention has better oral bioavailability than pomalidomide.
  • Figure 1 shows the relationship between drug concentration and time in rat plasma after administration.
  • Figure 2 shows the relationship between drug concentration in dog plasma and time after administration.
  • FIG 3 shows the plasma metabolism of Compound A and Compound 1 of the present invention in rats after administration.
  • the inventor selected a variety of acids (including sulfuric acid, phosphoric acid, hydrochloric acid, formic acid, acetic acid, oxalic acid, oleic acid, lactic acid, nicotinic acid, tartaric acid, methanesulfonic acid, maleic acid, citric acid, fumaric acid, benzenesulfonic acid Acid, malic acid, lactobionic acid, hippuric acid, benzoic acid, cinnamic acid, adipic acid, stearic acid, orotic acid, glycolic acid, salicylic acid, citric acid, L-tartaric acid, p-toluenesulfonic acid, 4 -Chlorobenzenesulfonic acid, D-glutamic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene disulfonic acid), a variety of solvent systems (including ethyl acetate, isopropanol, acetonitrile,
  • hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid, salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2 -Naphthalene sulfonic acid and fipronil can form salts and have solid shapes.
  • Step1 Under the protection of nitrogen, add S.M.B (20g, 73.2mmol, 1.00eq) and DMF (400ml) to a 1000mL three-necked reaction flask, and stir electromagnetically. Then sodium hydride (3.5g, 87.5mmol, 1.2eq) was slowly added, and after stirring for 30min, potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9mmol, 0.15) were added eq), after stirring for 15 min, SM1 (23.8 g, 72.8 mmol, 0.99 eq) was added and stirred for 12 h.
  • S.M.B 20g, 73.2mmol, 1.00eq
  • DMF 400ml
  • Step2 Under nitrogen protection, add Int 1-01 (500mg, 1mmol, 1.00eq), 5ml of DCM to a 100ml three-necked reaction flask, after stirring at room temperature for 10min, add HCl/EA (10ml, 10mmol, 10.0eq) at one time. Continue stirring for 40 min. Stop the reaction, filter and dry to obtain 380mg of yellow solid product, yield 86.9%
  • Step3 In a 200mL three-necked bottle, add 4g of L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine -1-yl) methyl ester hydrochloride (Int 1-02), 40mL ethyl acetate, stirred for 5min under ice-water bath conditions, then poured into 30mL of ice water, continue to add 30mL of saturated sodium bicarbonate, stirred for 5-10min, water The phase was extracted once more with ethyl acetate (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain L-valine (3-(4-amino-1,3-dioxoiso Indoline-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester 3g for use.
  • L-valine 3-(
  • tert-butoxycarbonyl-L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine -1-yl) methyl ester (Int 1-01) was suspended in 139 mL of methylene chloride and stirred at 0°C. 139mL of hydrochloric acid ethyl acetate solution was added, and the temperature was naturally raised to room temperature for 1 hour. Filter and dry the filter cake in vacuo. The dried solid was slurried with 100 mL of methylene chloride at room temperature for 2 hours. Filter and dry the filter cake in vacuo. The target product 4.58g was obtained.
  • the saturated solubility of the sample is not determined, but an appropriate amount of sample is selected to test the solubility of the sample.
  • the solubility of the salt of the present invention is not less than 24mg/ml.
  • the solubility of pomalidomide in water is about 0.01 mg/ml, which is far lower than the solubility of the salt of the present invention.
  • the free base structure of formula (B) has poor structural stability and is easily degraded when left at room temperature, while the salt of the present invention has significantly improved stability.
  • the male SD rats (SPF grade) used in this example weighing 250-330g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were more than 8 weeks old. In carbonate cages (up to 5 animals/sex/cage). Drink water freely and freely eat qualified feed 5CC4 (same as 5CR4, PMI Nutrition International LLC, USA).
  • the SD rats were divided into NORA0310 group (hydrochloride) and NORA0312 group (pomadimide) by using randomized group design. Each group was administered by gavage (i.g.), and the dose was set at 2 mg/kg (calculated as pomalidomide).
  • Test method Before administration, blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after administration, and the whole blood samples were collected into anticoagulation tubes containing EDTA-2K Blood was stored on wet ice and centrifuged at 3500 rpm and 4°C for 5 minutes within 30 minutes to obtain plasma samples. The separated plasma samples were immediately placed in dry ice for temporary storage and then transferred to the refrigerator at -60 to -80°C. LC/MS/MS was used for detection, and the non-compartment model of software WinNonlin was used to calculate the pharmacokinetic parameters of rats after administration. The data is shown in Table-3.
  • Beagle dogs weighing 8.6-10.6 kg, were purchased from Beijing Mas Biotechnology Co., Ltd.
  • the test animals are all over 1 year old, and the animals are at least two weeks apart from the last test.
  • the three dogs adopt a cross-over design, and the cleaning interval is at least three days.
  • NORA0310A4 di-p-toluenesulfonate
  • NORA0312 pomadolamine
  • Oral capsules POMALID, manufactured by Natco Pharma Limited.
  • Each cycle was given a capsule by oral administration with 50mL of water to assist swallowing.
  • Test method Before administration, blood samples were collected 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours after administration, and whole blood was collected in anticoagulation tubes containing EDTA-2K and stored on wet ice , And centrifuged at 1800 ⁇ g, 4°C for 5 minutes within 1 hour to obtain plasma samples. The separated plasma sample will be added with 2% formic acid in a 4:1 ratio and shaken evenly, immediately placed on dry ice for temporary storage and then transferred to a -20°C refrigerator. LC/MS/MS was used for detection, and the non-compartment model of the software WinNonlin was used to calculate the pharmacokinetic parameters of dogs after administration. The data is shown in Table-4.
  • the salt of the present invention has a Cmax value that is more than 4 times higher than that of pomalidomide, and an AUC last that is more than 1.5 times higher, indicating that the salt of the present invention is better than pomalidomide. Oral bioavailability.
  • the present inventors prepared other pomalidomide prodrugs (compound A) according to the prior art literature, for example, as described in US20080051432/WO2006105697.
  • the structure of the prodrug and Compound 1 of the present invention are shown below:
  • compound 1 can be rapidly metabolized to pomalidomide, which can reduce the side effects caused by the prodrug itself.
  • Table 5 and Figure 3 The specific results are shown in Table 5 and Figure 3.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un sel d'un ester de L-valine (3- (4-amino-1,3-dioxoisoindoline-2-yl)-2,6-dioxopipéridin-1-yl) méthyle, et son utilisation en tant qu'immunomodulateur.
PCT/CN2020/071472 2019-01-11 2020-01-10 Sel de promédicament de pomalidomide Ceased WO2020143779A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910025245.2A CN111434659A (zh) 2019-01-11 2019-01-11 泊马度胺前体药物的盐
CN201910025245.2 2019-01-11

Publications (1)

Publication Number Publication Date
WO2020143779A1 true WO2020143779A1 (fr) 2020-07-16

Family

ID=71520652

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/071472 Ceased WO2020143779A1 (fr) 2019-01-11 2020-01-10 Sel de promédicament de pomalidomide

Country Status (2)

Country Link
CN (1) CN111434659A (fr)
WO (1) WO2020143779A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735276A (zh) * 2009-12-17 2010-06-16 廖国超 水溶性磷酸单酯衍生物及其应用
WO2011160042A2 (fr) * 2010-06-18 2011-12-22 Makoto Life Sciences, Inc. Modulateurs de prpk-tprkb et leurs utilisations
US20140179737A1 (en) * 2005-04-07 2014-06-26 Tianjin Hemay Bio-Tech Co., Ltd. Piperidine-2, 6-dione derivatives and their use as tumor necrosis factor inhibitors
WO2019036839A1 (fr) * 2017-08-21 2019-02-28 诺瑞特国际药业股份有限公司 Dérivé de pomalidomide et son procédé de préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140179737A1 (en) * 2005-04-07 2014-06-26 Tianjin Hemay Bio-Tech Co., Ltd. Piperidine-2, 6-dione derivatives and their use as tumor necrosis factor inhibitors
CN101735276A (zh) * 2009-12-17 2010-06-16 廖国超 水溶性磷酸单酯衍生物及其应用
WO2011160042A2 (fr) * 2010-06-18 2011-12-22 Makoto Life Sciences, Inc. Modulateurs de prpk-tprkb et leurs utilisations
WO2019036839A1 (fr) * 2017-08-21 2019-02-28 诺瑞特国际药业股份有限公司 Dérivé de pomalidomide et son procédé de préparation

Also Published As

Publication number Publication date
CN111434659A (zh) 2020-07-21

Similar Documents

Publication Publication Date Title
CA2669736C (fr) Composes heterocycliques utiles comme modulateurs des tyrosine kinases
JP7295833B2 (ja) Ｏｌｉｇ２活性の阻害
WO2010031266A1 (fr) Sels de n-[4-(1-cyanocyclopentyl)phényl]-2-(4-pyridylméthyl)amino-3-pyridinecarboxamide
KR20110111472A (ko) 3-（1-｛3-［5-（1-메틸-피페리딘-4일메톡시）-피리미딘-2-일］-벤질｝-6-옥소-1,6-디히드로-피리다진-3-일）-벤조니트릴 히드로클로라이드 염의 신규한 다형체 및 이의 제조 방법
CN116496205B (zh) 一种卡瑞斯汀的盐及其用途
CN102807575B (zh) 3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其应用
KR20240154068A (ko) P2x3 억제제 화합물 및 이의 염, 다형체 및 용도
WO2016034137A1 (fr) Dérivés de pyrazolo[3,4-c]pyridine
WO2017101881A1 (fr) Dérivé de ginkgolide b, son procédé de préparation et son utilisation
AU2014214324B2 (en) Substituted acetylene derivatives and their use as positive allosteric modulators of mGluR4
CN104334528A (zh) (2-杂芳基氨基)琥珀酸衍生物
WO2016034103A1 (fr) Dérivés de tétrahydrothiéno pyridine substitués et leur utilisation
WO2020143779A1 (fr) Sel de promédicament de pomalidomide
JP5872105B2 (ja) ピロリジン−３−イル酢酸誘導体の塩およびその結晶
US20250213581A1 (en) Combination therapy of a pi3k inhibitor and kras inhibitor and methods of use thereof
WO2023197914A1 (fr) Nouvelle utilisation d'un composé pyrazolopyrimidine
MX2014001756A (es) Compuesto de sal y polimorfo de pirazolopirimidinona, y composición farmacéutica que lo contiene, método de preparación y uso del mismo.
EP3825315B1 (fr) Forme cristalline utilisée en tant qu'inhibiteur d'ask1, son procédé de préparation et son utilisation
EP4091670A1 (fr) Cristal d'un composé d'imidazopyridinone ou d'un sel de celui-ci
CN102532114A (zh) 烟酸衍生物,其制备方法及其药物组合物
CN115960080B (zh) 一种多环化合物及其作为胃饥饿素受体激动剂的用途
CN111349085A (zh) 嘧啶酮类化合物或其可药用的盐、制备方法及用途
CN114478360B (zh) 一种苯甲酰胺类衍生物及其制备方法和应用
EA017630B1 (ru) ЗАМЕЩЕННЫЕ 3-АРИЛСУЛЬФОНИЛПИРАЗОЛО[1,5-a]ПИРИМИДИНЫ, АНТАГОНИСТЫ СЕРОТОНИНОВЫХ 5-HT-РЕЦЕПТОРОВ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
CN111978317A (zh) 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20738038

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20738038

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 20738038

Country of ref document: EP

Kind code of ref document: A1