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WO2018196757A1 - Composé de 4-aminopyrimidine, son procédé de préparation et son application - Google Patents

Composé de 4-aminopyrimidine, son procédé de préparation et son application Download PDF

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Publication number
WO2018196757A1
WO2018196757A1 PCT/CN2018/084300 CN2018084300W WO2018196757A1 WO 2018196757 A1 WO2018196757 A1 WO 2018196757A1 CN 2018084300 W CN2018084300 W CN 2018084300W WO 2018196757 A1 WO2018196757 A1 WO 2018196757A1
Authority
WO
WIPO (PCT)
Prior art keywords
aminopyrimidin
amino
preparation
carboxamide
compound
Prior art date
Application number
PCT/CN2018/084300
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English (en)
Chinese (zh)
Inventor
赖宜生
郭毅
章颖溢
肖建虎
李月珍
Original Assignee
中国药科大学
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 中国药科大学 filed Critical 中国药科大学
Publication of WO2018196757A1 publication Critical patent/WO2018196757A1/fr

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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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of medicine, and in particular to a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and their use as Bruton's tyrosine kinase inhibitor.
  • BTK Bruton's tyrosine kinase
  • BTK B-cell lymphoma and inflammation
  • BTK is overexpressed in a variety of B cell lymphomas (Blood, 2011, 117(23): 6287-6296; Leuk Res, 2013, 37(10): 1271-1277; Nature, 2010, 463 (7277) ): 88-92; Clin Pharmacol Ther, 2015, 97(5): 469-477).
  • BTK Tyr223 continues to autophosphorylate, resulting in excessive activation of BTK (Blood, 2013, 122(14): 2412-2424).
  • BTK is closely related to autoimmune diseases.
  • BTK is also involved in the regulation of other signaling pathways in vivo, such as the Fc ⁇ receptor signaling pathway (Nat Chem Biol, 2011, 7(1): 4-5) and the Toll-like (TLR) signaling pathway (J Leukoc Biol , 2014, 95(2): 243-250).
  • BTK inhibitors can reduce autoantibody levels and effectively control the occurrence and development of disease; in mouse MRL/lpr systemic lupus erythematosus model, BTK inhibitors can be reduced The production of antibodies and can reduce the risk of renal damage; the rat basophilic leukemia cell model treated with small interfering RNA (siRNA) and LFM-A13 reduced histamine content by 20-25% (Proc Natl Acad) Sci USA, 2010, 107(29): 13075-13080; Nat Chem Biol, 2011, 7(1): 41-50).
  • siRNA small interfering RNA
  • BTK has become an effective target in the field of treatment of B-cell lymphoma and inflammatory diseases.
  • BTK inhibitors such as BMS-986142, M-2951, CC-292, GDC-0853
  • Clinical trials of diseases such as syndrome, multiple sclerosis, systemic lupus erythematosus.
  • Ibrutinib is the only BTK inhibitor approved by the US FDA for the treatment of relapsed or refractory mantle cell lymphoma, treated chronic lymphocytic leukemia (CLL), CLL, Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) carrying a 17p deletion mutation.
  • CLL chronic lymphocytic leukemia
  • WM Waldenstrom macroglobulinemia
  • SLL small lymphocytic lymphoma
  • MZL marginal zone lymphoma
  • the technical problem to be solved by the present invention is to provide a 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • the compounds of the present invention have good BTK inhibitory activity and can be used for the treatment and/or prevention of related diseases caused by BTK overactivation.
  • the present invention discloses a 4-aminopyrimidine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer from 0 to 5;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, OR 3 , NHR 3 or (C 1 -C 8 )alkyl;
  • n an integer from 0 to 5;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • R 3 represents (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 6 -C 10 )aryl or (C 1 -C 10 ) An aromatic heterocyclic group; wherein said aromatic heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; said aryl and aromatic heterocyclic groups may optionally be used Substituted to one to five groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy or (C 3 -C 6 ) ring alkyl;
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer of 0 to 2;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy or phenoxy;
  • n is an integer from 0 to 2;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • L represents C(O) or C(O)NH(CH 2 ) m ;
  • n an integer of 0 to 2;
  • A represents a benzene ring, a five-membered heterocyclic ring or a six-membered heterocyclic ring, wherein the heterocyclic ring may optionally comprise one or more other heteroatoms selected from O, S or N;
  • Each R 1 independently represents halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or phenoxy;
  • n is an integer from 0 to 2;
  • Y is selected from: NH(C 1 -C 8 )alkylamino
  • R 2 represents a propionyl group, an acryloyl group, a 2-chloroacetyl group or a 2-butynyl group;
  • the 4-aminopyrimidine compound represented by the formula (I) is preferably selected from the following compounds:
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), characterized in that:
  • the compound of the formula (I) is prepared by using 4,6-dihydroxypyrimidine as a raw material, Vilsmeier-Haack reaction and chlorination reaction to obtain 4,6- Dichloro-5-pyrimidinecarboxaldehyde 1,1 is oxidized by sodium chlorite to obtain 4,6-dichloro-5-pyrimidinecarboxylic acid 2,2 and reacted with oxalyl chloride to obtain acid chloride, followed by Friedel-Crafts acylation with aromatic hydrocarbon
  • the intermediates 3, 3 are obtained by reacting with ammonia water to obtain intermediates 4 and 4, which are reacted with an amine compound to obtain 5-1 or 5-2, and 5-1 is deprotected with concentrated hydrochloric acid, and is the same as 5-2.
  • the compound of the formula (I) is obtained by reacting with an acid chloride or 2-butynoic acid:
  • n, A, R 1 and R 2 are as defined above.
  • the compound of the formula (I) is prepared by reacting the intermediate 2 with oxalyl chloride to obtain an acid chloride, and then condensing with an amine compound to form an amide 6, 6 reacting with ammonia to obtain intermediate 7,7 and amine compound (HY-Boc) to obtain 8,8 by concentrated hydrochloric acid to remove Boc to obtain 9, and finally 9 react with acid chloride or 2-butynoic acid to obtain general formula (I) Compound:
  • n, n, A, R 1 and R 2 are as defined above.
  • the pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized by general chemical methods.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent stoichiometric or excess acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a compound of formula (I) and pharmaceutically acceptable thereof One or more of the salts.
  • the adjuvant comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), depending on the purpose of the treatment, Preference is given to tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).
  • any excipient known and widely used in the art can be used.
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • a usual solvent, a buffer, or the like may be added.
  • the content of the composition of the present invention in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 85% by mass.
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient.
  • the invention further provides the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a BTK inhibitor.
  • the BTK inhibitors are useful in the treatment of thromboembolism, Waldenstrom's macroglobulinemia, inflammatory conditions, autoimmune diseases, and B cell lymphomas.
  • the inflammatory or autoimmune diseases include, but are not limited to, xenogeneic immune diseases, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, autoimmune mediated One or more of hemolytic anemia, immune complex-mediated vasculitis, and psoriasis.
  • the B cell lymphoma includes, but is not limited to, chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple bone marrow One or more of tumor, mucosa-associated lymphoid tissue lymphoma, Hodgkin's lymphoma, and B-cell non-Hodgkin's lymphoma.
  • the compound of the present invention and (R)-1-[3-[[5-(4-phenoxybenzoyl)-6-aminopyrimidin-4-yl]amino]piperidin are detected by a radioisotope P 33 -ATP labeling method.
  • the radioisotope detection method is highly sensitive and the test results are very accurate, so it is considered to be the "gold standard" for the detection of protein kinase biochemical activity.
  • the experimental results show that some of the compounds of the present invention have a significant inhibitory effect on the activity of BTK kinase.
  • the inhibitory activities of the compounds A-1, A-2, A-8, A-9, A-10, B-2, and B-9 on BTK are equivalent to those of the compound b, and the compounds A-4 and A-6,
  • the activities of B-1, B-7, B-8, and B-11 were superior to those of compound b, and especially the activities of compounds A-6 and B-1 were significantly stronger than that of compound b.
  • the different stereoisomers of the compounds of the invention exhibit respective different activities.
  • compounds A-1 and A-2 are in the S configuration and the R configuration, respectively.
  • the former (S configuration) has a slightly stronger inhibitory activity against BTK than the latter (R configuration); for compound A-4 (R configuration)
  • the activity of the R configuration is significantly stronger than that of the S configuration; for the compounds A-6 (S configuration) and A-7 (R configuration).
  • the S configuration is 1800 times more active than the R configuration.
  • the activity of the compound B-1 was significantly 150 times stronger than that of the compound b, whereas the activity of the compound B-12 was unexpectedly 2600 times lower than that of the compound A-6.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine de médicaments, et concerne particulièrement un composé de 4-aminopyrimidine ayant une structure représentée par la formule (I), ou des sels pharmaceutiquement acceptables de celui-ci, un procédé de préparation du composé, et une utilisation de ce dernier et des sels en tant qu'inhibiteur de la tyrosine kinase de Bruton (BTK). Un résultat d'expériences montre que le composé de la présente invention a un effet d'inhibition significatif sur la BTK, et peut être utilisé pour traiter une thromboembolie, des troubles inflammatoires, des maladies auto-immunes, une macroglobulinémie de Waldenstrom, des lymphomes à cellules B, et d'autres maladies.
PCT/CN2018/084300 2017-04-25 2018-04-24 Composé de 4-aminopyrimidine, son procédé de préparation et son application WO2018196757A1 (fr)

Applications Claiming Priority (2)

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CN201710277753.0 2017-04-25
CN201710277753.0A CN107043366B (zh) 2017-04-25 2017-04-25 4-氨基嘧啶类化合物、其制备方法及医药用途

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264924B (zh) * 2020-02-14 2022-11-08 山东省联合农药工业有限公司 一种二噁烷嘧啶类衍生物及其制备方法与用途
CN116514782B (zh) * 2022-11-08 2025-05-13 江苏海悦康医药科技有限公司 巴瑞替尼有关物质的合成方法

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WO2009055299A1 (fr) * 2007-10-23 2009-04-30 Janssen Pharmaceutica N.V. Inhibiteurs de kinase de type pyrimidine-5-carboxamides et esters d'acide pyrimidine-5-carboxylique substitués
CN104844573A (zh) * 2015-04-17 2015-08-19 中国药科大学 嘧啶类btk抑制剂、其制备方法及医药用途
CN105837576A (zh) * 2015-01-14 2016-08-10 湖北生物医药产业技术研究院有限公司 Btk抑制剂

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EP2526933B1 (fr) * 2006-09-22 2015-02-25 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de Bruton
CN101674834B (zh) * 2007-03-28 2013-06-12 环状药物公司 布鲁顿氏酪氨酸激酶(Bruton's tyrosine kinase)抑制剂
EA201490265A1 (ru) * 2011-07-13 2014-12-30 Фармасайкликс, Инк. Ингибиторы тирозинкиназы брутона
CN105837579A (zh) * 2016-05-30 2016-08-10 青岛科技大学 一种多取代苯并[4,5]咪唑并[1,2-b]吡唑衍生物的制备方法

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WO2009055299A1 (fr) * 2007-10-23 2009-04-30 Janssen Pharmaceutica N.V. Inhibiteurs de kinase de type pyrimidine-5-carboxamides et esters d'acide pyrimidine-5-carboxylique substitués
CN105837576A (zh) * 2015-01-14 2016-08-10 湖北生物医药产业技术研究院有限公司 Btk抑制剂
CN104844573A (zh) * 2015-04-17 2015-08-19 中国药科大学 嘧啶类btk抑制剂、其制备方法及医药用途

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

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CN107043366B (zh) 2020-05-26

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