WO2016083816A1 - Dérivés de n-((hétéroarylméthyl)-hétéroaryl-carboxamide utilisés en tant qu'inhibiteurs de la kallikréine plasmatique - Google Patents

Dérivés de n-((hétéroarylméthyl)-hétéroaryl-carboxamide utilisés en tant qu'inhibiteurs de la kallikréine plasmatique Download PDF

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Publication number
WO2016083816A1
WO2016083816A1 PCT/GB2015/053610 GB2015053610W WO2016083816A1 WO 2016083816 A1 WO2016083816 A1 WO 2016083816A1 GB 2015053610 W GB2015053610 W GB 2015053610W WO 2016083816 A1 WO2016083816 A1 WO 2016083816A1
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Prior art keywords
methyl
carboxamide
amino
phenyl
pyrazole
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PCT/GB2015/053610
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English (en)
Inventor
Alun John SMITH
Andrew Richard NOVAK
David Michael Evans
Hannah Joy EDWARDS
Michael John Stocks
Rebecca Louise DAVIE
Sally Louise MARSH
Simon Teanby Hodgson
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Kalvista Pharmaceuticals Limited
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Priority to SG11201809276QA priority Critical patent/SG11201809276QA/en
Publication of WO2016083816A1 publication Critical patent/WO2016083816A1/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
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical compositions containing and the uses of, such inhibitors.
  • the heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have a number of therapeutic applications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
  • Plasma kallikrein is a trypsin -like serine protease that can liberate kinins from kininogens (see K. D.
  • Bhoola et a/. "Kaliikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et ⁇ ,, "Human plasma kallikrein-kinin system: physiological and biochemical parameters” Cardiovascular and haematologicai agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et ai,
  • Plasma prekaliikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekaliikrein that circulates in plasma as a heterodimer complex bound to high molecular weight kininogen which is activated to give the active plasma kallikrein.
  • Kinins are potent mediators of inflammation that act through G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
  • Plasma kallikrein is thought to play a role in a number of inflammatory disorders.
  • the major inhibitor of plasma kallikrein is the serpin CI esterase inhibitor.
  • Patients who present with a genetic deficiency in CI esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gasfro-intesfinal tract and genitals.
  • HAE hereditary angioedema
  • Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin leading to increased vascular permeability.
  • Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased vascular permeability (A.
  • a plasma kaiiikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
  • Plasma kaiiikrein inhibitors have been described previously, for example by Garrett et ai. ("Peptide aldehyde." J. Peptide Res. 52, p62-71 (1998)), T. Griesbacher et a!.
  • the molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLKl, thrombin and other serine proteases, and poor oral availability.
  • the large protein plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been reported for Ecailantide.
  • the vast majority of molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J.
  • ASP-634 An Oral Drug Candidate for Diabetic MacularEdema
  • ARVO 2012 May 6* - May 9* 2012, Fort Lauderdale, Florida, Presentation 2240 that ASP-440, a benzamidine
  • absorption may be improved by creating a prodrug such as ASP-634.
  • prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites.
  • indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADM E-tox and
  • BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 ("BCX4161, An Oral Kallikrein inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study in Healthy Volunteers", Journal of Allergy and Clinical immunology.
  • Preferred compounds will possess a good pharmacokinetic profile and in particular will be suitable as drugs for oral delivery.
  • the present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
  • the invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
  • the present invention provides compounds closely related to or failing within the scope of, but not specifically disclosed in, our co-pending application PCT/ GB2014/051592.
  • the present invention provides compound selected from the group consisting of:
  • l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
  • l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carb ⁇ acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
  • the present invention provides a prodrug of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of the invention, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are potent and selective inhibitors of plasma kailikrein. They are therefore useful in the treatment of disease conditions for which overactivity of plasma kailikrein is a causative factor.
  • the present invention provides a compound of the invention for use in medicine.
  • the present invention also provides for the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kailikrein activity is implicated.
  • the present invention also provides a compound of the invention for use in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
  • the present invention also provides a method of treatment of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the disease or condition in which plasma kallikrein activity is implicated is selected from impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
  • the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
  • the compounds of the present invention may be administered in combination with other therapeutic agents.
  • Suitable combination therapies include a compound of the invention combined with one or more agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), integrin alpha5betal, steroids, other agents that inhibit plasma kallikrein and other inhibitors of inflammation.
  • PDGF platelet-derived growth factor
  • VEGF endothelial growth factor
  • integrin alpha5betal steroids
  • therapeutic agents include those disclosed in EP2281885A and by S. Patei in Retina, 2009 Jun;29(6 Suppl):S45-8.
  • the compounds of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially or simultaneously.
  • the compounds of the present invention may be administered in combination with laser treatment of the retina.
  • the combination of laser therapy with intravitreal injection of an inhibitor of VEGF for the treatment of diabetic macular edema is known (Elman M, Aielio L, Beck R, et al.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologicaily tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, /V-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
  • Hemisaits of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming prodrugs are described in 'The Practice of Medicinal Chemistry, 2 nd Ed. pp561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379,
  • the compounds of the invention can exist in both unsolvated and solvafed forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is water.
  • compounds of the invention exist in one or more geometrical, optical, enantiomeric, diasfereomeric and tautomeric forms, including but not limited to cis- and irons-forms, f- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of formula (I) should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a nonfunctional (i.e., processing aid or diluent) characteristic to the formulations.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
  • the present invention provides a pharmaceuticai composition
  • a pharmaceuticai composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form suitable for intra- vitreai injection. It is envisaged that formulations suitable for such use will take the form of sterile solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be administered to the patient under the supervision of the attending physician.
  • the compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for parenteral
  • parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternai, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-iactone, poiyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
  • degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-iactone, poiyhydroxybutyrate), polyorthoesters and polyanhydrides.
  • parenteral formulations under sterile conditions for example, by iyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyciodextrins.
  • the compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulafes, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
  • Means to deliver compounds in a rate- sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
  • rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
  • rate-sustaining polymers include hydroxypropyl methylceliulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
  • Liquid (including multiple phases and dispersed systems) formulations include emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcei!ulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifylng agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2.001, 11 (6), 981-986.
  • the formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L Lachman (Marcel Dekker, Mew York, 1980).
  • the total daily dose of the compounds of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
  • the total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician wiii readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • 'silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution.
  • Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary gradient pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.
  • Automated FC refers to a Biotage purification system with UV directed sample collection using either SNAP ultra or ZIP Sphere cartridges.
  • AH solvents and commercial reagents were used as received.
  • Chemical names were generated using automated software such as the Autonom software provided as part of the ISIS Draw package from M DL information Systems or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E-WorkBook.
  • Method 8 The carboxylic acid component (1 eq), the amine component (1 eq) and HATU (1.1 eq) were suspended in anhydrous DCM (and DMF if required) and Et 3 N (6 eq) added. The reaction mixture was stirred at rt. The solvent was removed under vacuum. The residue was purified by automated FC.
  • Methylterephthalonitrile (1.42g, 9.99mmol) and Bredereck's reagent (3.48g, 19.98mmol) were dissolved in DMF (15mL). The reaction mixture was heated at 75 * C under nitrogen for 72hrs after which time the solvent was removed in vacuo. Trituration with Pet. Ether gave a bright yellow solid identified as 2-((E)- 2-dimethylamino-vinyl)-terephthalonitrile ester (1.88g, 0.95mmol, 95% yield).
  • l-Amino-isoquinoline-6-carbonitriie 200mg, l.lSmmo! was dissolved in methanol (20mL). This solution was cooled to D C. Nickel (II) chloride hexahydrate (28mg, 0.12mmoi) and di- tertbutyl dicarbonate (516g, 2,36mmoi) were added followed by sodium borohydride (313g, 8.22mmol) portionwise. The reaction mixture was stirred at 0 "C to room temp for 3 days. The MeOH was removed by evaporation.
  • 6-bromo-7-fluoro-2H-isoquinolin-1-one (0.560 g, 2.129 mmol) was converted to 6-bromo-1-chloro-7-fluoro-isoquinoline (460 mg, 82 % yleld).
  • 6-Bromo-1-chloro-7-fluoroisoquinoline (460 mg, 1.78 mmol) was converted using the typical amination procedure to 6-bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 5.5% yleld).
  • 6-Bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 0.099 mmol) was converted using the typical cyanation procedure to 1-amino-7-fluoroisoquinoline-6-carbonitrile (13.3 mg, 64.8 % yleld).
  • 6-Aminomethyl-5-fluoro-isoquinolin-1-ylamine was prepared in 6 steps from 4-bromo-N-(2,2-dimethyl- propionyloxy)-3-fluoro-benzamide using procedures described above.
  • 3-Aminomethyl-[l,7]naphthyridin-8-ylamine dihydrochloride was prepared in 8 steps from 5-bromo-3- methylpicolinic acid using procedures described above.
  • 6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 8 steps from 4- bromo-3-methoxy-2-methyl-benzoic acid using procedures described above.
  • This diazonium solution was diluted with toluene (60 mL) and added to a cooled 0 °C solution of copper cyanide (3.482 g, 38.91 mmoi) and sodium cyanide (4.76 g, 97.2 mmol) in water (30 mL) with vigorous stirring. The reaction was held at 0 °C and allowed to warm to rt after 1 hour. The reaction mixture was diluted with toluene (100 mL). The organic layer was extracted and washed with brine (200 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to afford 4-bromo-2-methoxy-6- methylbenzonitrile (7.02 g, 77 % yleld).
  • 6-Aminomethyl-8-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 6 steps from 4- bromo-2-methoxy-6-methylbenzamide using procedures described above.
  • 6-Chloro-3-methyl-isoquinoline 750 mg, 4.22 mmol was dissolved in 1,2-dichloroethane (70 mL). To this solution was added N-bromosuccinimide (901 mg, 5.07 mmol) and azobisisobutyronitrile (69 mg, 0.42 mmol). The reaction was heated at reflux for 5 hrs. The reaction was diluted with DCM, brine was added and the layers were separated. The organic layer was dried over MgSO 4 , filtered and
  • 3-Azidomethyl-6-chloro-isoquinoline 300 mg, 1.37 mmoi was dissolved in ethanol (50 mL) and acetic acid (1 mL). Zinc powder (180 mg, 2.74 mmoi) was added portionwise. The reaction mixture was stirred at rt for 18 hrs. The mixture was through Celite and the residue washed with ethanol (50 mL).
  • CDl (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropanoic acid (1.81 mi, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at rt for 1.5 hrs. A powdered mixture of magnesium chloride (1.57 g, 16.5 mmol) and methyl potassium maionate (4.5 g, 28.8 mmol) was added portionwise (note CO2 gas evolved). The mixture was allowed to stir at rt. Volatiies were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at rt for 1 hr and extracted with DCM (3 x 100 mL).
  • Acetic anhydride 13.50 mi, 143 mmol was added to a suspension of ethyl 3-oxo-2,3-dihydro-1H- pyrazole-4-carboxylate (22.30 g, 143 mmol) in acetic acid (185 mL). The mixture was stirred at rt overnight. Solvents were removed in vacuo. The remaining solid was triturated from water (200 mL) and filtered, washing with water.
  • the aqueous layer was purified by SCX (10 g), washing with MeOH, eluting with 1% NHs/MeOH to afford 3-(methoxymethyi)-1-((6-(pyrroiidin-1-yi)pyridin-3-yl)methyl)-1H- pyrazole-4-carboxylic acid (336 mg, 0.882 mmol, 77% yield).
  • the crude material was purified by flash chromatography loading in dichloromethane, eluting with a gradient of 0 to 100% EtOAc/iso-Hexanes holding at 70% to elute methyl l-(4-((1H-pyrazol-1- yt)methyt)benzyl)-5-(methoxymethyl)-1H-pyrazoie-4-carboxylate (232 mg, 21.0 % yield) then 85% to elute methyl l-(4-((1H-pyrazol-1-yf)methyf)benzyl)-3-(methoxymethyi)-1H-pyrazole-4-carboxylate (494 mg, 52.0 % yield).
  • Ethyl-2-chloropyrimidine-5-carboxylate (300 g, 1.6 mol) was stirred in 1,4-dioxane (3000 mL) in an ice/water bath. Pyrrolidine (375 mL, 4.5 mol) was added and the mixture stirred for 3 hrs at rt. The reaction mixture was concentrated and separated between ethyl acetate (4000 mL) and water (4000 mL). The organics were washed with water (2000 mL) and saturated brine (3000 mL), dried over sodium sulfate, filtered and concentrated.
  • Acetic acid 2-pyrrolidin-1-yi-pyrimidin-5-ylmethyl ester (112.3 g, 0.51 mol) and methyl-3- (methoxymethyl)-1H-pyrazole-4-carboxylate (CAS no. 318496-66-1, synthesised according to the method described in WO 2012/009009) (86.3 g, 0.51 mol) were combined in acetonitriie (1500 mL). Trimethylsilyl trifluoromethanesulfonate (110.3 mL, 0.61 mol) was added. The mixture was heated to 65-70 °C for 3 hrs and then allowed to cool.
  • the reaction mixture was concentrated and separated between EtOAc (1500 mL) and saturated aqueous sodium hydrogen carbonate (1000 mL). The organics were washed with saturated aqueous sodium hydrogen carbonate (750 mL), washed with saturated brine (1000 mL), dried over sodium sulfate, filtered and concentrated to give a brown solid. The solid was dissolved in hot methanol. The solution was cooled to approximately 10 °C and stirred for 1 hour. The solid produced was filtered.
  • the remaining mixture was diluted with water (250 mL) and stirred and cooled in an ice/water bath. Glacial acetic acid (18 mL, 0.31 mol) was added and the mixture stirred for 1 hour. The solid produced was collected by filtration. The filtrates were cooled in an ice/water bath and glacial acetic acid (23 mL, 0.40 mol) was added. After 1 hour the solid produced was collected on top of the previous filter cake. The combined solids were washed with cold ethanol and dried in vacuo. The solid was dissolved in hot ethanol and cooled to rt. The solid produced was filtered and washed with cold ethanol (2 ⁇ 150 mL). The solid was dissolved in hot ethanol and cooled to rt.
  • ⁇ ,1'-Carbonytdiimidazole (26. Ig, 0.161 mole) was added to a suspension of 3-(methoxymethyl)-1-((2- (pyrrolidin-1-yl)pyrimidin-5-yi)methyi)-1H-pyrazole-4-carboxyiic acid (51. lg, 0.161 mole) in N- methylpyrrolidinone (200 mL) and stirred for 3 hrs to give the acylimidazol eintermediate.
  • acylimidazolide intermediate formed above was added in one portion and stirred for 18hrs.
  • the reaction mixture was poured into water (5000 mL) and stirred for 1.5 hrs.
  • the solid was collected by filtration, washed with water (2 x 250 mL), cold acetonitrile (250 mL) and tert-butyl methyl ether (250 mL) and dried in vacuo to give a white solid identified as 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5- ylmethyl)-1H-pyrazole-4-carboxylic acid (l-amino-isoquinolin-6-ylmethyl)-amide (70.8 g, 93% yield).
  • MH + 473.0
  • the ability of the compounds to inhibit piasma kallikrein may be determined using the following biological assays:
  • Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et a/., Int. J, Tiss. Reac. 1986, 8, 185; Shod et a/., Biochem. Pharmacol., 1992, 43, 1209;
  • KLKl inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et ai., int. J. Tiss. Reac. 1986, 8, 185; Shori et a/., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecher et of., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025).
  • Human KLKl (Ca!lbiochem) was incubated at 25°C with the fluorogenic substrate H-DVal-Leu-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the ICso value for the test compound was determined, Data acquired from this assay are shown in Table 12
  • Selected compounds were further screened for inhibitory activity against other trypsin-like serine proteases using the appropriate enzyme and chromogenic substrate (Chromogenix AB).
  • the activity against the following human enzymes was tested (substrate in brackets):- thrombin (5 -2238), plasmin (S- 2390) and trypsin (S-2222).
  • the enzyme was incubated at 25 °C with the chromogenic substrate.
  • Residual enzyme activity was determined by measuring the change in optical absorbance at 405nm.

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Abstract

La présente invention concerne des composés de formule (I) ; des compositions comprenant de tels composés ; l'utilisation de tels composés en thérapie (par exemple dans le traitement ou la prévention d'une maladie ou d'un état dans laquelle/lequel l'activité de la kallikréine plasmatique est impliquée) ; et des méthodes de traitement de patients au moyen de tels composés.
PCT/GB2015/053610 2014-11-27 2015-11-26 Dérivés de n-((hétéroarylméthyl)-hétéroaryl-carboxamide utilisés en tant qu'inhibiteurs de la kallikréine plasmatique WO2016083816A1 (fr)

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US10266515B2 (en) 2013-12-30 2019-04-23 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
US10364238B2 (en) 2014-11-27 2019-07-30 Kalvista Pharmaceuticals Limited N-((het) arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors
WO2020012424A1 (fr) 2018-07-13 2020-01-16 Richter Gedeon Nyrt. Dérivés d'(aza)indole substitués
CN111432803A (zh) * 2017-11-29 2020-07-17 卡尔维斯塔制药有限公司 包含血浆激肽释放酶抑制剂的剂型
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
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US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11584735B2 (en) 2017-11-29 2023-02-21 Kalvista Pharmaceuticals Limited Solid forms of a plasma kallikrein inhibitor and salts thereof
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WO2021055621A1 (fr) * 2019-09-18 2021-03-25 Shire Human Genetic Therapies, Inc. Inhibiteurs de la kallicréine plasmatique et leurs utilisations
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof
WO2024059186A1 (fr) * 2022-09-15 2024-03-21 Takeda Pharmaceutical Company Limited Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire

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GB201421088D0 (en) 2015-01-14
AR102852A1 (es) 2017-03-29

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