WO2019107943A1 - Composé inhibiteur de jak son procédé de préparation - Google Patents

Composé inhibiteur de jak son procédé de préparation Download PDF

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Publication number
WO2019107943A1
WO2019107943A1 PCT/KR2018/014884 KR2018014884W WO2019107943A1 WO 2019107943 A1 WO2019107943 A1 WO 2019107943A1 KR 2018014884 W KR2018014884 W KR 2018014884W WO 2019107943 A1 WO2019107943 A1 WO 2019107943A1
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WO
WIPO (PCT)
Prior art keywords
group
cancer
nmr
mhz
disease
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PCT/KR2018/014884
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English (en)
Korean (ko)
Inventor
강수성
김신애
박은희
박재돈
이광석
전현호
한승희
홍기범
Original Assignee
주식회사한국파마
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Publication of WO2019107943A1 publication Critical patent/WO2019107943A1/fr

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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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to JAK inhibitor compounds, and methods for their preparation.
  • Protein kinases are a class of enzymes that regulate a variety of important biological processes, including cell growth, survival and differentiation, organogenesis and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of the protein (or substrate), thereby modulating the cellular activity of the substrate in a variety of biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in the host of human disease, including cancer. A subpopulation of protein kinases (also referred to as tumor protein kinase), when not regulated, induces tumor formation and growth, and also contributes to tumor progression and progression. Thus, tumor protein kinases are one of the largest and most interested groups of protein targets for cancer regulation and drug development.
  • JAK Janus Kinase
  • JAK1 Janus kinase-1
  • JAK-2 Janus kinase-2
  • JAK3 Janus kinase-3)
  • TYK2 Protein-Tyrosine Kinase 2
  • JAK protein ranges from 120 kDa to 140 kDa and includes seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other is potentially regulatory and / or STAT Is a pseudokinase domain capable of functioning as a docking site for < Desc / Clms Page number 2 >
  • JH JAK homology
  • Blocking signal transduction at the level of JAK kinase has the potential for the development of therapies for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer of the human body, Will have a therapeutically beneficial effect on the patient suffering from.
  • Patent Document 1 As a result, all of the contents disclosed in Patent Document 1 are cited by the prior art in this specification.
  • Patent Document 1 US 2007/0135461 A1 (Jun. 14, 2007)
  • R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
  • R 2 is a hydrogen group, or a C 1 -C 3 alkyl group
  • R 3 represents a hydrogen group, , or ego
  • R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
  • R 1 is not a hydrogen group.
  • R 1 is a methyl group, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen group or a methyl group, or a pharmaceutically acceptable salt thereof.
  • R 4 and R 5 each independently represent a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group, or a pharmaceutically acceptable salt thereof.
  • compositions for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising a compound of any one of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention can modulate signal transduction at the level of JAK kinase, for example, to show therapeutic effects on inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer of the human body.
  • An aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
  • R 2 is a hydrogen group, or a C 1 -C 3 alkyl group
  • R 3 represents a hydrogen group, , or ego
  • R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
  • R 1 is not a hydrogen group.
  • the compounds represented by the above formula (I) can control the activity of Janus kinase (JAK).
  • the term "modulate" refers to the ability to increase or decrease the activity of one or more of the JAK kinases.
  • the compounds of the present invention can be used in a method of modulating JAK by contacting JAK with at least one compound or composition of the invention.
  • a compound of the invention may act as an inhibitor of one or more JAKs.
  • JAKs that the compounds of the invention bind and / or modulate include any member of the JAK family.
  • the JAK is JAK1, JAK2, JAK3, or TYK2.
  • the JAK is JAK1 or JAK2.
  • the JAK is JAK2.
  • JAK is JAK3.
  • Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising the compound represented by the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof.
  • JAK-related diseases include diseases or diseases or conditions that are directly or indirectly related to the expression or activity of JAK, such as hyperplasia and / or abnormal activity.
  • JAK-related diseases include diseases, diseases or conditions that can be prevented, alleviated or cured by controlling JAK activity.
  • JAK-related diseases include, but are not limited to, immune system related diseases such as organ transplant rejection (e.g., transplant rejection and graft versus host response), multiple sclerosis, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis Inflammatory bowel disease, ulcerative colitis, Crohn's disease, severe myasthenia gravis, immunoglobulin nephritis, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune, (PV) or water-repellent oil pumice window (BP).
  • organ transplant rejection e.g., transplant rejection and graft versus host response
  • multiple sclerosis rheumatoid arthritis
  • inflammatory arthritis e.g., psoriatic arthritis
  • type I diabetes lupus
  • psoriasis Inflammatory bowel disease ulcerative colitis
  • JAK-related diseases include inflammatory and inflammatory diseases.
  • inflammatory diseases include inflammatory diseases of the eye such as blinking, uveitis, scleritis, conjunctivitis or related diseases, inflammatory diseases of the respiratory tract such as upper respiratory tract including nose and sinus such as rhinitis or sinusitis, Obstructive pulmonary disease, and the like), inflammatory myopathies such as myocarditis and other inflammatory diseases.
  • Other inflammatory diseases include, for example, systemic inflammatory response syndrome (SIRS) and sepsis shock, and may also be used to treat them.
  • SIRS systemic inflammatory response syndrome
  • sepsis shock and may also be used to treat them.
  • JAK-related diseases include cancer characterized by solid tumors such as prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, (AML) or multiple myeloma), and skin cancers such as skin T-cell lymphoma (CTCL) and skin B-cell lymphoma are administered to a mammal in need of such treatment, .
  • skin T-cell lymphomas include Sezary syndrome and bacterial sarcoma.
  • it can be used to treat diseases or conditions related to ischemic reperfusion injury or inflammatory ischemic cases such as stroke or cardiac arrest, and can also be used to treat stenosis, percutaneous dermatitis or fibrosis.
  • the JAK inhibitors of the present invention may also be used to treat conditions associated with hypoxia or astrocytosis, such as diabetic retinopathy, cancer or neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390 (Pt 2): 427-36) and [Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Epub 2004 Mar 2].
  • the JAK inhibitors of the present invention can also be used to treat Alzheimer's disease.
  • JAK inhibitors of the present invention can also be used to treat gout and prostatic enlargement due to, for example, benign prostatic hyperplasia or benign prostatic hyperplasia.
  • compositions of the present invention may be administered orally in dosage forms such as tablets, capsules (each of which includes a sustained release or time release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions . They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • composition of the present invention can be administered intranasally via topical use of suitable intranasal vehicles, or via the transdermal route using a transdermal patch.
  • administration of the dose will, of course, be continuous rather than intermittent throughout the course of the administration.
  • the compounds may specifically illustrate the compounds of Tables 1 and 2.
  • the values of JAK1, JAK2, and JAK3 are shown by testing the IC50 concentration of each compound.
  • the compounds of the present invention represented by formula (I) including the exemplified compounds of Tables 1 and 2 above can be prepared by the methods specifically described in the general synthesis procedures described below. As a person skilled in the art, it will be understood from the description of this general synthesis procedure that the synthesis method for the specific exemplified compounds or the example compounds will also be understood from the description of the individual synthesis methods for each compound.
  • tert-butyl (1-aryl piperidin-4-yl) carbamate (2 mmol) was added to a 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. The yield ( ⁇ 100% yield) was used without further purification.
  • Reagents and conditions (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ° C
  • CDI (1.07 g, 6.61 mmol) was added dropwise to a solution of 4-chloro- 1H- pyrrolo [2,3- b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF , And the reaction mixture was stirred at room temperature for about 1 hour. To this mixture was slowly added dropwise 2.0 mmol of various amines (30 mmol, solvent THF), followed by stirring at room temperature for about 1 hour. The resulting mixture was poured into ethyl acetate and a white solid was obtained as a precipitate.

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  • 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 composé inhibiteur de JAK et son procédé de préparation et, plus spécifiquement, un composé de formule chimique I ci-Dessous et un sel pharmaceutiquement acceptable de celui-ci. La présente invention régule la transduction de Signal au niveau de la kinase JAK, ce qui permet d'obtenir des effets de traitement sur des maladies inflammatoires, des maladies auto-immunes, des troubles myéloprolifératifs, un cancer du corps humain et similaires.
PCT/KR2018/014884 2017-11-28 2018-11-28 Composé inhibiteur de jak son procédé de préparation WO2019107943A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0161102 2017-11-28
KR1020170161102A KR102034538B1 (ko) 2017-11-28 2017-11-28 Jak 저해제 화합물, 및 이의 제조방법

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023112056A1 (fr) * 2021-12-17 2023-06-22 Pi Industries Ltd. Nouveaux composés de pyridine carboxamide bicycliques fusionnés substitués pour lutter contre des champignons phytopathogènes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102551758B1 (ko) * 2020-11-30 2023-07-05 주식회사한국파마 신규한 jak 특이 저해제 화합물, 및 이의 제조방법

Citations (3)

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KR20080026654A (ko) * 2005-07-14 2008-03-25 아스텔라스세이야쿠 가부시키가이샤 헤테로시클릭 야누스 키나제 3 억제제
KR20090106604A (ko) * 2007-01-12 2009-10-09 아스텔라스세이야쿠 가부시키가이샤 축합 피리딘 화합물
KR20140059195A (ko) * 2011-08-12 2014-05-15 닛산 가가쿠 고교 가부시키 가이샤 트리시클릭 헤테로시클릭 화합물 및 jak 저해제

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KR20090106604A (ko) * 2007-01-12 2009-10-09 아스텔라스세이야쿠 가부시키가이샤 축합 피리딘 화합물
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023112056A1 (fr) * 2021-12-17 2023-06-22 Pi Industries Ltd. Nouveaux composés de pyridine carboxamide bicycliques fusionnés substitués pour lutter contre des champignons phytopathogènes

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KR20190062081A (ko) 2019-06-05

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