WO2022212638A1 - Promédicaments d'inhibiteurs d'adamts, leurs procédés de préparation et leurs utilisations médicales - Google Patents

Promédicaments d'inhibiteurs d'adamts, leurs procédés de préparation et leurs utilisations médicales Download PDF

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Publication number
WO2022212638A1
WO2022212638A1 PCT/US2022/022736 US2022022736W WO2022212638A1 WO 2022212638 A1 WO2022212638 A1 WO 2022212638A1 US 2022022736 W US2022022736 W US 2022022736W WO 2022212638 A1 WO2022212638 A1 WO 2022212638A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
pharmaceutically acceptable
heterocyclyl
cycloalkyl
Prior art date
Application number
PCT/US2022/022736
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English (en)
Inventor
Peng Zhao
Jian Liu
Fengqi Zhang
Chunying Song
Original Assignee
Jiangsu Hengrui 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 Jiangsu Hengrui Pharmaceuticals Co., Ltd. filed Critical Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Priority to CN202280026358.4A priority Critical patent/CN117136051A/zh
Publication of WO2022212638A1 publication Critical patent/WO2022212638A1/fr

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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • osteoarthritis Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011, 23: 471-478). The pathogenesis of osteoarthritis is not very clear, with mechanical damage, inflammation, aging, and metabolism factors being involved. Osteoarthritis is not a passive degenerative disease, but an active dynamic alteration arising from an imbalance between the repair and destruction of joint tissues ⁇ Hunter et al, Lancet. 2019, 393: 1745 1759). Currently, the pharmacological treatments available for osteoarthritis are limited to symptomatic relief of pain and inflammation. Disease-modifying drugs that arrest or slow down disease progression are not available.
  • the extensive region between the G2 and G3 domains is heavily modified by GAG keratan sulfate (KS) and chondroitin sulfate (CS). Based on the difference in the amino acid sequence, the CS domain is further divided into two subdomains, CS1 and CS2.
  • the GAG chains provide aggrecan with its high anionic charge. Multiple aggrecan monomers bind to hyaluronan (HA) through G1 domains, which is stabilized by a link protein, forming large supramolecular aggregates.
  • the large aggrecan aggregates absorb water and provide the resilient properties for the cartilage ( Roughley et al., The Journal of Experimental Orthopaedics. 2014, 1: 8).
  • a high concentration of aggrecan, a high degree of sulfation and the ability to form large aggregation is required for the normal function of cartilage.
  • R 2a , R 2b , R 3a and R 3b are each identical or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, and sometimes more preferably one to three, groups independently selected from halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; or two of R 2a , R 2b , R 3a and R 3b together with the carbon atom(s) to which they are attached form cycloalkyl or heterocyclyl;
  • the disease or condition includes arthritis, preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis, which are further preferably related to the activity of ADAMTS-5 and/or ADAMTS-4.
  • arthritis preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis, which are further preferably related to the activity of ADAMTS-5 and/or ADAMTS-4.
  • Q 6 and Q 7 are identical or different and each is independently selected from hydrogen, alkyl, haloalkyl, deuterium alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof is a compound of formula (III), or a pharmaceutically acceptable salt thereof:
  • X 1 is -L-R°
  • X 1 is -L-R°
  • R°, L, R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each as defined in formula (IP-1).
  • the present disclosure also provides a method of inhibiting ADAMTS-5 and/or ADAMTS- 4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II- 1), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound.
  • the present disclosure also relates to use of a compound of formula (I), (II), (II- 1 ), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for the inhibition of ADAMTS-5 and/or ADAMTS-4.
  • the present disclosure also relates to the compound of formula (I), (II), (II- 1 ), (III) or (III- 1), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for use in inhibiting ADAMTS-5 and/or ADAMTS-4.
  • rheumatoid arthritis particularly refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g, asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly refers to rheumatoid arthritis, and osteoarthritis (OA). Most particularly refers to osteoarthritis (OA).
  • the pharmaceutical composition can be in the form of a sterile injectable aqueous solution.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can also be a sterile injectable oil-inwater microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injectable solution or microemulsion can be introduced into an individual’s bloodstream by local bolus injection. Alternatively, it can be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compound.
  • a continuous intravenous delivery device can be utilized. An example of such a device is Deltec CADD-PLUS. TM. 5400 intravenous injection pump.
  • the substituent group(s) is (are) preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from selected from alkenyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.
  • bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl.
  • Representative examples of bridged cycloalkyls include, but are not limited to, the following groups:
  • a spiro heterocyclyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably
  • spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6- membered mono-spiro heterocyclyl.
  • Representative examples of spiro heterocyclyl include, but are not limited to the following groups:
  • Cycloalkoxyl refers to a cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • Heterocyclyloxy refers to a heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • Niro refers to a -NO2 group.
  • “Substituted” refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents.
  • the person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory.
  • the combination of amino or hydroxy group having free hydrogen and carbon atoms having unsaturated bonds may be unstable.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • a preparation process of a compound of formula (II) or a pharmaceutically acceptable salt thereof comprising a step of: under an acidic condition, removing R 1 of the compound of formula (IIA) or a salt thereof to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:
  • R l is alkyl; preferably, R l is Ci- 6 alkyl;
  • reaction temperature in the following reactions was room temperature.
  • HPLC Preparative High Performance Liquid Chromatography
  • NMR proton nuclear magnetic resonance
  • Step 2 ( ⁇ )-Tert-butyl 3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoate Int-1-3
  • Int-1-2 (8.2 g, 41.36 mmol), ammonium carbonate (33.78 g, 351.56 mmol), sodium cyanide (5.07 g, 103.40 mmol), EtOH (50 mL) and water (50 mL) was sealed and heated to 80 ⁇ C for 18h.
  • the reaction mixture was cooled and poured into a mixture of EtOAc (100 mL) and water (100 mL), the layers were separated, and the aq. layer was extracted with EtOAc (100 mL ⁇ 3).
  • prodrug molecules 3, 4, 5 and 6 have improved Fassif solubility separately.
  • HPMC K100LV hydroxypropyl methylcellulose (HPMC) K100LV

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés de formule (I) utiles en tant qu'inhibiteurs d'ADAMTS-5 et/ou d'ADAMTS-4, des compositions pharmaceutiques associées, ainsi que leur utilisation en tant qu'agents thérapeutiques pour le traitement de maladies impliquant la dégradation du cartilage ou la rupture de l'homéostasie du cartilage, en particulier l'ostéoarthrose et/ou la polyarthrite rhumatoïde.
PCT/US2022/022736 2021-04-02 2022-03-31 Promédicaments d'inhibiteurs d'adamts, leurs procédés de préparation et leurs utilisations médicales WO2022212638A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280026358.4A CN117136051A (zh) 2021-04-02 2022-03-31 Adamts抑制剂的前药、其制备方法和医药用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163170371P 2021-04-02 2021-04-02
US63/170,371 2021-04-02

Publications (1)

Publication Number Publication Date
WO2022212638A1 true WO2022212638A1 (fr) 2022-10-06

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PCT/US2022/022736 WO2022212638A1 (fr) 2021-04-02 2022-03-31 Promédicaments d'inhibiteurs d'adamts, leurs procédés de préparation et leurs utilisations médicales

Country Status (3)

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CN (1) CN117136051A (fr)
TW (1) TW202304886A (fr)
WO (1) WO2022212638A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060019994A1 (en) * 2002-09-13 2006-01-26 Burrows Jeremy N I-sulphonlyl piperidine derivatives
US20180002293A1 (en) * 2014-12-22 2018-01-04 Galapagos Nv 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as adamts inhibitors for the treatment of osteoarthritis
US20190300503A1 (en) * 2016-06-09 2019-10-03 Galapagos Nv 5-[3-[piperazin-1-yl]-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as adamts 4 and 5 inhibitors for treating e.g. osteoarthritis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060019994A1 (en) * 2002-09-13 2006-01-26 Burrows Jeremy N I-sulphonlyl piperidine derivatives
US20180002293A1 (en) * 2014-12-22 2018-01-04 Galapagos Nv 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as adamts inhibitors for the treatment of osteoarthritis
US20190300503A1 (en) * 2016-06-09 2019-10-03 Galapagos Nv 5-[3-[piperazin-1-yl]-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as adamts 4 and 5 inhibitors for treating e.g. osteoarthritis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem ANONYMOUS : "5-[3-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]-3- (furan-2-ylmethyl)-2-hydroxy-3,5-dihydro-4H-imidazol-4- one ", XP055976011 *
DATABASE PubChem PUBCHEM : "SUBSTANCE RECORD for SID 346771727", XP055976012 *

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Publication number Publication date
CN117136051A (zh) 2023-11-28
TW202304886A (zh) 2023-02-01

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