WO2017101777A1 - Sel d'un composé pyrrolopyrimidine - Google Patents

Sel d'un composé pyrrolopyrimidine Download PDF

Info

Publication number
WO2017101777A1
WO2017101777A1 PCT/CN2016/109835 CN2016109835W WO2017101777A1 WO 2017101777 A1 WO2017101777 A1 WO 2017101777A1 CN 2016109835 W CN2016109835 W CN 2016109835W WO 2017101777 A1 WO2017101777 A1 WO 2017101777A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
hydrochloride salt
hydrochloride
pharmaceutical composition
Prior art date
Application number
PCT/CN2016/109835
Other languages
English (en)
Chinese (zh)
Inventor
祝力
戴丽光
韩永信
Original Assignee
北京赛林泰医药技术有限公司
正大天晴药业集团股份有限公司
连云港润众制药有限公司
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 北京赛林泰医药技术有限公司, 正大天晴药业集团股份有限公司, 连云港润众制药有限公司 filed Critical 北京赛林泰医药技术有限公司
Priority to CN201680072397.2A priority Critical patent/CN108368115B/zh
Publication of WO2017101777A1 publication Critical patent/WO2017101777A1/fr

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application belongs to the field of medicinal chemistry, in particular, the present application relates to (3R)-3-[3-amino-4-(7H-pyrrole[2,3-d]pyrimidin-4-yl)-1H-pyrazole- A hydrochloride salt of 1-yl]-3-cyclopentylpropionitrile, a process for preparing the hydrochloride salt, a pharmaceutical composition comprising the hydrochloride salt, and a pharmaceutical use of the hydrochloride salt.
  • Protein kinases also known as protein phosphakinase, are a class of enzymes that catalyze the phosphorylation of proteins.
  • a subgroup of oncoprotein kinases of protein kinases can cause tumor formation and growth when dysregulated, and further lead to tumor metastasis and progression.
  • oncogenic protein kinases are one of the most important targets for the treatment of cancer diseases.
  • Protein kinases can be divided into receptor type and non-receptor type.
  • Janus kinase is a type of non-receptor tyrosine kinase (PTK) that is present in cells and transmits cytokine stimulation signals through the JAK-STAT pathway.
  • the JAK-STAT pathway transmits extracellular chemical signals through the cell membrane into the gene promoter located on the DNA in the nucleus, ultimately affecting the changes in DNA transcription and activity levels in the cell.
  • the JAK family plays a role in cell proliferation and functional cytokine-dependent regulation involving immune responses.
  • the present application provides the hydrochloride salt of a compound of Formula I.
  • the application provides a hydrochloride salt of a compound of formula I:
  • the application provides a pharmaceutical composition comprising the hydrochloride salt of a compound of formula I.
  • the application provides the use of a hydrochloride salt of a compound of formula I for the manufacture of a medicament for the treatment of a dihedral kinase mediated disease.
  • the application provides a method for treating a disease mediated by diphtheria kinase, the method comprising administering to a patient a therapeutically effective amount of a hydrochloride salt of a compound of formula I.
  • the application provides a hydrochloride salt of a compound of formula I for use in the treatment of a dihedral kinase mediated disease, and the above pharmaceutical composition.
  • the application provides a hydrochloride salt of a compound of formula I:
  • the ratio of the amount of the compound of formula I to the amount of HCl in the hydrochloride salt of the compound of formula I is from 1:0.5 to 3, preferably 1:1.
  • the hydrochloride salt of the compound of formula I described herein may exist in a variety of solid forms, may exist as an amorphous form, or may exist as a crystalline form, the amorphous or crystalline form being not limited to one, A variety of forms of amorphous and crystalline forms can be included.
  • the amorphous or crystalline form can be characterized by powder X-ray diffraction (XRD), Raman spectroscopy, differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA).
  • hydrochloride salt of the compound of formula I described herein may exist in unsolvated as well as solvated forms, including hydrated forms.
  • the present application also provides a process for the preparation of the hydrochloride salt of the compound of formula I which comprises precipitating the hydrochloride salt of the compound of formula I from a solvent such as acetonitrile.
  • the preparation of the hydrochloride salt of the compound of formula I described herein can be prepared by known techniques. For example, by contacting the free base compound with an acid containing an anion of the desired salt form in solution, the salt product is then separated from the reaction solution. Salts described herein can also be obtained using other salt preparation techniques.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrochloride salt of a compound of formula I, which comprises a therapeutically effective amount of the hydrochloride salt of a compound of formula I.
  • the pharmaceutical compositions may or may not contain pharmaceutically acceptable carriers, excipients and/or vehicles.
  • compositions of the present invention comprising the hydrochloride salt of the compound of formula I may be administered by typical routes including, but not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • compositions comprising a hydrochloride salt of a compound of formula I as described herein can be carried out by any acceptable mode of administration that provides a similarly useful agent.
  • the pharmaceutical composition of the present application can be obtained by administering the hydrochloride of the compound of formula I of the present application.
  • the salts are prepared in combination with a suitable pharmaceutically acceptable carrier, diluent or excipient and can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, Ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.
  • the application provides the use of a hydrochloride salt of a compound of formula I for the manufacture of a medicament for the treatment of a dihedral kinase mediated disease.
  • the application provides a method for treating a disease mediated by diphtheria kinase, the method comprising administering to a patient a therapeutically effective amount of a hydrochloride salt of a compound of formula I.
  • the application provides a hydrochloride salt of the compound of formula I or a pharmaceutical composition as described above for use in the treatment of a dihedral kinase mediated disease.
  • the two-faced kinases mediated by the present application include, but are not limited to, tumors (eg, lymphoma, leukemia).
  • Lymphomas as described herein may include, but are not limited to, Hodgkins disease or Non-Hodgkins leukemia, including but not limited to B-cell lymphocytes B-celllymphoma or T-cell lymphoma.
  • Leukemias as described herein include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and chronic myelocytic leukemia.
  • the therapeutic dose of the hydrochloride salt of the compound of formula I described herein can be determined, for example, according to the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the pharmaceutical compositions of the present invention comprising the hydrochloride salt of the compound of Formula I may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration.
  • the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound.
  • Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof.
  • An effective dose can be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.
  • patient refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate. Most preferred is a person.
  • Treatment as described herein may be the effect of modulating activity upon contact with JAK based on the hydrochloride salt of a compound of formula I as described herein.
  • modulate is meant the ability to increase or decrease the activity of one or more members of the JAK family.
  • the treatment includes, but is not limited to, one or more of the following:
  • Prevention of disease for example, prevention of a disease, disorder or condition in an individual who is susceptible to a disease, disorder or condition but has not experienced or developed a pathology or symptom of the disease;
  • inhibiting a disease for example, inhibiting a disease, disorder or condition (ie preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder or condition;
  • Relieving a disease for example, alleviating a disease, disorder, or condition (ie, reversing pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder, or condition.
  • an effective amount or “therapeutically effective amount” refers to an active compound that causes a biological or medical response to be sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. The amount of the drug.
  • hydrochloride salt of the compound of the formula I described herein exhibits excellent stability, pharmacokinetic properties and pharmacodynamic properties, and is easy to prepare, and can be used for the preparation of a medicament for treating a disease mediated by diphtheria kinase.
  • the stability of the hydrochloride salt of the compound of formula I described herein can be determined according to the "Guidelines for the Stability Test of APIs and Pharmaceutical Preparations", and the hydrochloride salt of the compound of formula I of the present application is examined under accelerated test conditions. Stability.
  • the hydrochloride salt of the compound of Formula I prepared herein is placed in a light environment (eg, 5000 Lx ⁇ 500 Lx), a high temperature environment (eg, 60 ° C ⁇ 2 ° C), and a high humidity environment (eg, 75%). Stability tests were carried out under RH ⁇ 5% RH), and samples were taken on days 5, 10, and 30, respectively. The appearance traits, moisture content, and total impurities of the samples were compared with the initial data.
  • the pharmacokinetic properties of the hydrochloride salt of the compound of formula I described herein can be determined by animal experiments (e.g., rats, dogs). By administering, for example, by oral or injection, blood is collected at the time of design after administration, and blood samples are analyzed for blood samples and pharmacokinetic parameters are calculated to obtain property results.
  • the pharmacodynamic properties of the hydrochloride salt of the compound of formula I described herein can be determined by in vitro enzymatic activity assays, cell viability assays or animal experiments.
  • the tumor volume was randomly divided into small groups, and adjusted appropriately so that the average body weight of each group of animals was also at the same level.
  • the 5 groups were negative control group, positive control group, low, medium and high dose groups, 5 mice in each group, and started to be administered on the day of grouping, 2 times a day for 14 days, and the tumor was measured every week. Volume and weight 2 times.
  • the mice were sacrificed, the spleens were isolated and weighed.
  • TGI(%) 100% ⁇ (1-(T t -T 0 )/(V t -V 0 )), T t is the average tumor volume measured per treatment group, T 0 treatment group The mean tumor volume at the time, V t is the average tumor volume measured per control group, and V 0 is the average tumor volume at the time of grouping of the control group.
  • the tumor inhibitory effect of the hydrochloride salt of the compound of Example 1 in the animal was determined in the Ba/F3-JAK2 V617F tumor-bearing mouse model, and it was found that the dose of Ba/F3-JAK2 V617F tumor growth was dosed.
  • the inhibitory effect of dependence and the antitumor effect are very significant.
  • the inhibition rate (TGI) against tumor growth reached 85.8%, while the positive control of the same standard, Ruxolitinib (100 mg/kg).
  • the tumor growth inhibition rate (TGI) was only 64.5%.
  • the tumor suppressing effect of the hydrochloride salt of the compound of Example 1 at 50 mg/kg was also remarkable, and the TGI reached 68.4%, which was comparable to the tumor suppressing effect of the 100 mg/kg positive control product Ruxolitinib, indicating that the hydrochloride salt of the compound of Example 1 has a very remarkable Tumor inhibition and significantly better than Ruxolitinib.
  • Healthy adult female SD rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into two groups, three in each group, and the suspension of the test sample (30 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.4 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4200 rpm for 5 min at 4 ° C, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.
  • PK pharmacokinetics

Landscapes

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

Abstract

La présente invention concerne un sel d'un composé pyrrolopyrimidine. En particulier, la présente invention concerne un chlorhydrate d'un composé représenté par la formule I, un procédé de préparation de celui-ci, une composition pharmaceutique le contenant et une utilisation médicale de celui-ci. Le chlorhydrate du composé représenté par la formule I de la présente invention est avantageux pour la mise au point de médicaments efficaces et peut être utilisé pour préparer un médicament destiné à la prévention et au traitement de maladies induites par la kinase Janus.
PCT/CN2016/109835 2015-12-15 2016-12-14 Sel d'un composé pyrrolopyrimidine WO2017101777A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680072397.2A CN108368115B (zh) 2015-12-15 2016-12-14 吡咯并嘧啶化合物的盐

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510932786 2015-12-15
CN201510932786.5 2015-12-15

Publications (1)

Publication Number Publication Date
WO2017101777A1 true WO2017101777A1 (fr) 2017-06-22

Family

ID=59055858

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/109835 WO2017101777A1 (fr) 2015-12-15 2016-12-14 Sel d'un composé pyrrolopyrimidine

Country Status (2)

Country Link
CN (1) CN108368115B (fr)
WO (1) WO2017101777A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020135401A1 (fr) 2018-12-24 2020-07-02 正大天晴药业集团股份有限公司 Utilisation thérapeutique de composé de pyrrolopyrimidine, et composition pharmaceutique solide de composé de pyrrolopyrimidine
WO2021180093A1 (fr) * 2020-03-09 2021-09-16 正大天晴药业集团股份有限公司 Utilisation d'un composé de pyrrolopyrimidine pour le traitement du syndrome hémophagocytaire
WO2022268083A1 (fr) * 2021-06-21 2022-12-29 正大天晴药业集团股份有限公司 Utilisation d'un composé de pyrrolopyrimidine et composition pharmaceutique de celui-ci pour le traitement de la maladie du greffon contre l'hôte chronique
WO2023179547A1 (fr) * 2022-03-21 2023-09-28 正大天晴药业集团股份有限公司 Utilisation d'un composé pyrrolopyrimidique dans le traitement d'une myélofibrose de risque intermédiaire ou élevé
RU2810112C2 (ru) * 2018-12-24 2023-12-21 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Лечебное применение пирролопиримидинового соединения и твердая фармацевтическая композиция пирролопиримидинового соединения

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070514A1 (fr) * 2005-12-13 2007-06-21 Incyte Corporation Pyrrolo[2,3-b]pyrimidines et pyrrolo[2,3-b]pyridines substituees par des groupements heteroaryle en tant qu’inhibiteurs de kinase janus
WO2016095805A1 (fr) * 2014-12-16 2016-06-23 北京赛林泰医药技术有限公司 Composé de pyrrolopyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070514A1 (fr) * 2005-12-13 2007-06-21 Incyte Corporation Pyrrolo[2,3-b]pyrimidines et pyrrolo[2,3-b]pyridines substituees par des groupements heteroaryle en tant qu’inhibiteurs de kinase janus
WO2016095805A1 (fr) * 2014-12-16 2016-06-23 北京赛林泰医药技术有限公司 Composé de pyrrolopyrimidine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020135401A1 (fr) 2018-12-24 2020-07-02 正大天晴药业集团股份有限公司 Utilisation thérapeutique de composé de pyrrolopyrimidine, et composition pharmaceutique solide de composé de pyrrolopyrimidine
CN113242859A (zh) * 2018-12-24 2021-08-10 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗用途及其固体药物组合物
RU2810112C2 (ru) * 2018-12-24 2023-12-21 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Лечебное применение пирролопиримидинового соединения и твердая фармацевтическая композиция пирролопиримидинового соединения
WO2021180093A1 (fr) * 2020-03-09 2021-09-16 正大天晴药业集团股份有限公司 Utilisation d'un composé de pyrrolopyrimidine pour le traitement du syndrome hémophagocytaire
CN114981272A (zh) * 2020-03-09 2022-08-30 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
WO2022268083A1 (fr) * 2021-06-21 2022-12-29 正大天晴药业集团股份有限公司 Utilisation d'un composé de pyrrolopyrimidine et composition pharmaceutique de celui-ci pour le traitement de la maladie du greffon contre l'hôte chronique
WO2023179547A1 (fr) * 2022-03-21 2023-09-28 正大天晴药业集团股份有限公司 Utilisation d'un composé pyrrolopyrimidique dans le traitement d'une myélofibrose de risque intermédiaire ou élevé

Also Published As

Publication number Publication date
CN108368115B (zh) 2020-01-03
CN108368115A (zh) 2018-08-03

Similar Documents

Publication Publication Date Title
US11981684B2 (en) Macrocyclic compounds and uses thereof
US11007197B2 (en) EGFR modulators and uses thereof
US11291667B2 (en) Combination therapy involving diaryl macrocyclic compounds
EP2694072B1 (fr) Combinaison de composé inhibiteur d'akt et d'abiraterone pour utilisation dans des traitements thérapeutiques
CN103889984B (zh) 4-(8-甲氧基-1-(1-甲氧基丙烷-2-基)-2-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-c]喹啉-7-基)-3,5-二甲基异噁唑及其作为溴结构域抑制剂的用途
US10472349B2 (en) Salt of pyridinyl amino pyrimidine derivative, preparation method therefor, and application thereof
TW201625618A (zh) 抑制瞬時受體電位ａ１離子通道
US20170112833A1 (en) Tyrosine Kinase Inhibitor And Uses Thereof
WO2017101777A1 (fr) Sel d'un composé pyrrolopyrimidine
US20110034498A1 (en) Dosing regimens for the treatment of cancer
CN103702991A (zh) 用作jak抑制剂的吡啶-2(1h)-酮衍生物
US20170247339A1 (en) Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
KR102468670B1 (ko) Olig2 활성의 억제
CN113336768B (zh) 一种多靶点酪氨酸激酶抑制剂
TW201620911A (zh) 銜接子關聯激酶１之抑制劑、包含其之組成物、及其使用方法
TW202128687A (zh) ４－胺基－咪唑并喹啉化合物及其用途
WO2019001307A1 (fr) Composé amide, composition le contenant, et utilisation associée
WO2021161983A1 (fr) Nouveau médicament pour le traitement d'une maladie inflammatoire
US11434195B2 (en) Compositions and methods for treatment of central nervous system tumors
WO2023280090A1 (fr) Composition pharmaceutique, son procédé de préparation et son application
WO2024000615A1 (fr) Inhibiteur de protéine tyrosine kinase et son utilisation
TW201829398A (zh) 酪胺酸蛋白激酶調節劑、晶型及其用途
EP4385510A1 (fr) Utilisation d'ensartinib ou d'un sel correspondant dans le traitement d'une maladie portant une mutation de saut d'exon 14 de met
US20230357182A1 (en) Solid forms of (s)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and salts thereof
JP2024520856A (ja) Ｆｇｆｒ４選択的阻害剤の塩及びその製造方法と用途

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: 16874834

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: 16874834

Country of ref document: EP

Kind code of ref document: A1