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WO2025059641A1 - Inhibiteurs de la pde1 - Google Patents

Inhibiteurs de la pde1 Download PDF

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Publication number
WO2025059641A1
WO2025059641A1 PCT/US2024/046888 US2024046888W WO2025059641A1 WO 2025059641 A1 WO2025059641 A1 WO 2025059641A1 US 2024046888 W US2024046888 W US 2024046888W WO 2025059641 A1 WO2025059641 A1 WO 2025059641A1
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WO
WIPO (PCT)
Prior art keywords
compound
disease
pharmaceutically acceptable
acceptable salt
hypertension
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Pending
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PCT/US2024/046888
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English (en)
Inventor
Richard D JOHNSTON
Kevin Michael Ruley
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Eli Lilly and Co
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Eli Lilly and Co
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Filing date
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Publication of WO2025059641A1 publication Critical patent/WO2025059641A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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 invention relates to certain human PDE1 inhibitors, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.
  • Phosphodiesterases are enzymes that regulate the cellular levels of cAMP and cGMP by controlling the rate at which these cyclic nucleotides are hydrolyzed.
  • PDE1 a calcium and calmodulin-dependent PDE, is one of at least 11 known PDE families.
  • PDE1 is expressed in many tissues, including the brain, heart, lung, kidney, and smooth muscle.
  • PDE1 is comprised of a family of three known isoforms, PDE1A, PDE1B, and PDE1C.
  • diabetic kidney disease or diabetic nephropathy
  • diabetic kidney disease may affect as many as 40 percent of diabetic patients.
  • Treatment options for diabetic kidney disease is limited and includes use of medications that lower blood pressure, management of blood glucose levels, diet, and weight, and implementation of regular physical activity.
  • chronic kidney disease particularly diabetic kidney disease.
  • United States Patent No.8, 299, 080 discloses certain quinoxaline derivatives for treating various disorders such as dysuria and hypertension.
  • European Patent No. 0 040 401 discloses certain substituted triazol oquinoxalin-4-ones possessing antihypertensive activity.
  • Certain other PDE1 inhibitor compounds are disclosed in WO 2018/039051, WO 2017/139186, WO 2019/032383, WO 2019/156861 and WO 2019/027783.
  • the present invention provides certain novel compounds that are inhibitors of human PDE1.
  • the present invention provides certain novel compounds that are selective inhibitors of human PDE1A, PDE1B, and PDE1C relative to other human PDEs, such as PDE3A, PDE4D, and PDE6AB.
  • the present invention provides certain novel compounds that may have antihypertensive effects and may also improve renal blood flow.
  • certain compounds of the present invention may reduce renal fibrosis.
  • R 1 , R 2 , and R 3 are each independently H, halogen, or C1-C3 alkyl optionally substituted with one or more halogen;
  • R 5 is C1-C3 alkyl optionally substituted with one or more halogen or cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention further provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in for the treatment of diabetic kidney disease, chronic kidney disease, acute kidney injury, hypertension, resistant hypertension, Parkinson’s Disease, artherosclerotic cardiovascular disease, angina, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficits associated with schizophrenia, cognitive deficits associated with Alzherimer’s disease, movement disorder, or attention deficit and hyperactivity disorders.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diabetic kidney disease, chronic kidney disease, acute kidney injury, hypertension, resistant hypertension, Parkinson’s Disease, artherosclerotic cardiovascular disease, angina, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficits associated with schizophrenia, cognitive deficits associated with Alzherimer’s disease, movement disorder, or attention deficit and hyperactivity disorders.
  • the invention further provides a pharmaceutical composition, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the invention further provides a process for preparing a pharmaceutical composition, comprising admixing a compound of Formula I or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • This invention also encompasses novel intermediates and processes for the synthesis of compounds of Formula I.
  • treating includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • the term "patient” refers to a mammal, such as a dog or a human, with a human being preferred.
  • the term “effective amount” refers to the amount or dose of compound of the invention, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
  • “C1-C3 alkyl” refers to methyl, ethyl, n-propyl, and isopropyl;
  • C1-C4 alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and isobutyl.
  • halogen refers to F, Cl, Br, and I.
  • alkyl substituted with halogen include trifluoromethyl, chloromethyl, and the like.
  • an effective amount can be readily determined by one skilled in the art using known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount for a patient a number of factors are considered by one skilled in the art, including, but not limited to: the patient’s size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the compounds of the present invention are formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable, including oral and parenteral routes. Most preferably, such compositions are for oral administration.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, L. V. Allen, Editor, 22 nd Edition, Pharmaceutical Press, 2012).
  • the compounds for use according to the methods of disclosed herein may be administered as a single compound or a combination of compounds.
  • the compounds and compositions disclosed herein may be administered in methods of treatment as known in the art. Accordingly, various such compounds and compositions can be administered in conjunction with such a method in any suitable way.
  • administration may comprise oral, intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, parenteral, transdermal, intravaginal, intranasal, mucosal, sublingual, topical, rectal or subcutaneous administration, or any combination thereof.
  • the compounds of Formula I are particularly useful in the treatment methods of the invention, but certain groups, substituents, and compounds are preferred. The following paragraphs describe such preferred groups, substituents, and compounds. It will be understood that these preferences are applicable both to the treatment methods and to the new compounds of the invention.
  • R 1 , R 2 , and R 3 are H.
  • R 4 is C1-C4 alkyl. It is preferred that R 5 is C 1 -C3 alkyl .
  • R 4 is ethyl
  • R 5 is methyl
  • the compounds of Formula I are in the free base form.
  • R 4 is ethyl. It is especially preferred that when R 1 , R 2 , and R 3 are H, R 5 is methyl.
  • R 4 is ethyl
  • R 5 is methyl
  • Examples of the compounds disclosed herein include: pharmaceutically acceptable salts thereof.
  • a pharmaceutically acceptable salt of the compound of the invention may be formed, for example, by reaction of an appropriate free base of the compound of the invention and an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, Gould, P.L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1- 19, (1977).
  • isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions” , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds", Wiley-Interscience, 1994).
  • the designations “isomer 1” and “isomer 2” refer to the compounds that elute from chiral chromatography under specified conditions, first and second, respectively.
  • ACN refers to acetonitrile
  • AcOH refers to glacial acetic acid
  • DBU refers to l,8-diazabicyclo[5.4.0]undec-7- ene
  • DCM dichloromethane or methylene chloride
  • DIPEA refers to N,N- diisopropylethylamine
  • DMF refers to N,N-dimethylformamide
  • DMSO refers to dimethylsulfoxide
  • EDCI refers to l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • ES/MS refers to Electrospray Mass Spectrometry
  • EtOAc refers to ethyl acetate
  • Et2O refers to diethyl ether
  • EtOH refers to ethanol
  • HMDS refers to hezamethyld
  • MTBE refers to methyl -tert-butyl ether
  • NiNTA refers to chromatography with an agarose stationary phase functionalized with nitrilotriacetic acid as chelator
  • POCI3 refers to phosphorus oxychloride
  • RT refers to room temperature
  • SNAr refers to nucleophilic aromatic substitution
  • TEA refers to triethylamine
  • THF tetrahydrofuran
  • Tris refers to 2-Amino-2-hydroxymethyl-propane- 1,3 -diol
  • U/ml refers to units per milliliter
  • wt refers to weight
  • Pd(OAc)2 refers to Palladium(II) acetate.
  • the compounds of the present invention may be prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the schemes, preparations, and examples below.
  • One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention.
  • the products of each step below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • all substituents unless otherwise indicated, are as previously defined.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following representative schemes, preparations, and examples are provided to further illustrate the invention.
  • NP 061818.1 and PDE9A are inserted into pFastBacl (Invitrogen) vector with an N-terminal HIS tag.
  • NP 000912.3 are inserted into pFastBacl (Invitrogen) vector with a C-terminal HIS tag.
  • the nucleotide sequences encoding full-length human PDE8A (NP 002596.1) and PDE11A (AAI12394.1) are inserted into pFastBacl (Invitrogen) vector with an N- terminal Flag tag.
  • the nucleotide sequences encoding full-length human PDE10A (AAD32595.1) are inserted into pFastBacl (Invitrogen) vector with a C-terminal Flag- His tag.
  • nucleotide sequences encoding full-length human PDE6A (NP 000431.2) and PDE6B (AAH00249.1) are inserted into pFastBacDual (Invitrogen) vector with an N- terminal HIS tag and N-terminal Flag tag, respectively, for production of PDE6A/6B dimer.
  • Baculovirus generation and protein expression in Sf9 cells are carried out according to the protocol of Bac-to-Bac Baculovirus Expression system (Invitrogen).
  • the nucleotide sequences encoding full-length human PDE1B (NP 000915.1) and PDE2A (NP_002590.1) are inserted into p!EX4 (Novagen) with a C-terminal HIS tag, and both protein productions in Sf9 cells are carried out according to the vendor’s protocol (Novagen).
  • the His tagged PDE proteins are purified using Ni-NTA agarose (Qiagen) followed by size exclusion chromatography on a SUPERDEX® 200 column (GE Healthcare) in storage buffer (20 mM Tris-HCl, pH7.5, 150 mM NaCl, 10% Glycerol).
  • the Flag tagged PDE proteins including PDE6A/6B are purified using anti-Flag M2- agarose (Sigma), after purification through NiNTA column chromatography and eluted in storage buffer (50 mM Tris-HCl, pH7.5, 150 mM NaCl, 10% Glycerol, 0.1 mg/ml Flag peptide). All purified proteins are stored at -80°C in small aliquots.
  • cyclic nucleotide phosphodiesterase (PDE) enzyme activities are measured with a radiometric enzyme assay based on SPA detection system (scintillation proximity assay).
  • Compounds to be tested are diluted in pure dimethyl sulfoxide (DMSO) using ten point concentration response curves. Maximal compound concentration in the reaction mixture is either 10 or 100 pM. Compounds at the appropriate concentration are preincubated with either of the PDE enzymes for 30 minutes before the reaction is started by the addition of substrate. Reactions are allowed to proceed for 60 minutes at room temperature. Next, reactions are stopped by addition of SPA beads. Samples are read 12 hours later in a MICROBETATM TRILUX® Counter. “IC50” refers to the concentration of the compound that produces 50% of the maximal inhibitory response possible for that compound. IC50 values are calculated by plotting the normalized data vs. log [compound] and fitting the data using a four parameter logistic equation.
  • PDE1B, PDE1 A, and PDE1C are cloned and purified following standard protein generation procedures.
  • the assay buffer is prepared to give a final concentration in the assay of 50 mM Tris-HCl, 50 mM MgCh, 4 mM CaCh, 0.1% Bovine serum albumin and 6 U/ml Calmodulin in water, at pH 7.5.
  • the final enzyme concentration is 0.25, 0.074 and 0.0012 nM, for PDE1 A, PDE1B and PDE1C respectively.
  • the reactions are started by addition of the substrate, [ 3 H]cAMP, to give a final concentration of 47 nM.
  • Table 1 In vitro potency of Example 1 against human PDE1A, PDE1B, and PDE1C.
  • the following phosphodiesterase activities are measured using [ 3 H]cAMP as reaction substrate: human PDE3 A (catalytic domain), human PDE4D, human PDE7B and human PDE8A. All these enzymes are cloned and purified following standard procedures.
  • the assay buffer is prepared to give a final concentration in the assay of 50 mM Tris-HCl, 8.3 mM MgCh, 1.7 mM ethylenediaminetetraacetic acid (EDTA) and 0.1% Bovine serum albumin at pH 7.5. Final enzyme concentrations are 0.008, 0.021, 0.5 and 0.06 nM for PDE3A, PDE4D, PDE7B and PDE8A respectively. Reactions are started by addition of the substrate, [ 3 H]cAMP, to give a final concentration of 47 nM.
  • Example 2 In vitro potency of Example 1 against human PDE3A (catalytic domain), PDE4D, PDE7B and PDE8A,
  • the following phosphodiesterase activities are measured using [ 3 H]cGMP as reaction substrate: human PDE2A, human PDE5A, human PDE6A/6B, human PDE9A, human PDE10A and human PDE11 A.
  • the catalytic active form of human PDE6 is a dimer composed of a a (human PDE6A) and 0 subunits (human PDE6B).
  • the dimer of human PDE6A/6B is produced by the expression and purification strategy, using two purification steps, z.e., NiNTA and anti -FLAG Sepharose chromatography. The rest of the enzymes are cloned and purified in house following standard procedures.
  • the assay buffer is prepared to give a final concentration in the assay of 50 mM Tris-HCl, 8.3 mM MgCh, 1.7 mM EDTA and 0.1% Bovine serum albumin at pH 7.5.
  • Final enzyme concentrations are 0.2, 0.002, 5, 1, 0.03 and 0.03 nM for human PDE2A, human PDE5A, human PDE6AB, human PDE9A, human PDE10A and human PDE11 A, respectively.
  • the reactions are started by addition of the substrate, [ 3 H]cGMP, to give a final concentration of 80 nM in the case of human PDE2A, human PDE10A, human PDE5A, human PDE6AB and human PDE11 A assays, whereas for human PDE9A 20 nM of [ 3 H]cGMP is used.
  • Example 1 is a selective inhibitor of human PDE1A, PDE1B, and PDE1C relative to human PDE2A, PDE3A, PDE4D, PDE5A, PDE6AB, PDE7B, PDE8A, PDE9A, PDE10A, and PDE11 A in vitro.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (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)

Abstract

La présente invention concerne un composé de formule (I), dans laquelle R1, R2, R3, R4 et R5 sont chacun tels que définis dans la description, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé comme inhibiteur de la PDE1 humaine.
PCT/US2024/046888 2023-09-14 2024-09-16 Inhibiteurs de la pde1 Pending WO2025059641A1 (fr)

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US63/582,662 2023-09-14

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0040401A1 (fr) 1980-05-19 1981-11-25 Usv Pharmaceutical Corporation Triazoloquinoxaline-4-ones et -4-thiones
US8299080B2 (en) 2006-12-13 2012-10-30 Aska Pharmaceutical Co., Ltd. Substituted imidazo[1,5-A] quinoxalines as a PDE9 inhibitor
WO2017139186A1 (fr) 2016-02-12 2017-08-17 Eli Lilly And Company Inhibiteur de pde1
WO2018039051A1 (fr) 2016-08-25 2018-03-01 Eli Lilly And Company Dérivé de triazolopyrazinone utile en tant qu'inhibiteur de pde1 humain
WO2019027783A1 (fr) 2017-08-02 2019-02-07 Eli Lilly And Company Dérivés de [1,2,4]triazolo[4,3-a]pyrazin-6(5h)-one
WO2019032383A1 (fr) 2017-08-10 2019-02-14 Eli Lilly And Company Dérivés de [1,2,4] triazolo utilisés en tant qu'inhibiteurs de pde1 pour le traitement du diabète
WO2019156861A1 (fr) 2018-02-06 2019-08-15 Eli Lilly And Company Dérivés de [1,2,4]triazolo[4,3-a]pyrazin-8-one

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0040401A1 (fr) 1980-05-19 1981-11-25 Usv Pharmaceutical Corporation Triazoloquinoxaline-4-ones et -4-thiones
US4354027A (en) * 1980-05-19 1982-10-12 Usv Pharmaceutical Corporation Triazoloquinoxalin-4-ones
US8299080B2 (en) 2006-12-13 2012-10-30 Aska Pharmaceutical Co., Ltd. Substituted imidazo[1,5-A] quinoxalines as a PDE9 inhibitor
WO2017139186A1 (fr) 2016-02-12 2017-08-17 Eli Lilly And Company Inhibiteur de pde1
WO2018039051A1 (fr) 2016-08-25 2018-03-01 Eli Lilly And Company Dérivé de triazolopyrazinone utile en tant qu'inhibiteur de pde1 humain
WO2019027783A1 (fr) 2017-08-02 2019-02-07 Eli Lilly And Company Dérivés de [1,2,4]triazolo[4,3-a]pyrazin-6(5h)-one
WO2019032383A1 (fr) 2017-08-10 2019-02-14 Eli Lilly And Company Dérivés de [1,2,4] triazolo utilisés en tant qu'inhibiteurs de pde1 pour le traitement du diabète
WO2019156861A1 (fr) 2018-02-06 2019-08-15 Eli Lilly And Company Dérivés de [1,2,4]triazolo[4,3-a]pyrazin-8-one

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BASTIN, R.J. ET AL.: "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 4, 2000, pages 427 - 435
BERGE, S.M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
E.L. ELIELS.H. WILEN: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
GOULD, P.L.: "Salt selection for basic drugs", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 33, 1986, pages 201 - 217, XP025813036, DOI: 10.1016/0378-5173(86)90055-4
J. JACQUES ET AL.: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY AND SONS, INC.
L.V.ALLEN: "Remington: The Science and Practice of Pharmacy", 2012, PHARMACEUTICAL PRESS
SAMIDURAI A ET AL., PHARMACOL THER., vol. 226, October 2021 (2021-10-01), pages 107858

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