EP1268439A1 - 5-hydroxy indazole derivatives for treating glaucoma - Google Patents

5-hydroxy indazole derivatives for treating glaucoma

Info

Publication number
EP1268439A1
EP1268439A1 EP00982109A EP00982109A EP1268439A1 EP 1268439 A1 EP1268439 A1 EP 1268439A1 EP 00982109 A EP00982109 A EP 00982109A EP 00982109 A EP00982109 A EP 00982109A EP 1268439 A1 EP1268439 A1 EP 1268439A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
indazol
halogen
aminopropyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00982109A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jesse A. May
Zixia Feng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Inc
Original Assignee
Alcon Inc
Alcon Universal 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 Alcon Inc, Alcon Universal Ltd filed Critical Alcon Inc
Publication of EP1268439A1 publication Critical patent/EP1268439A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to substituted 3-(2-aminoethyl)-lH-indazol- 5-ols, some of which are novel, for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
  • IOP intraocular pressure
  • glaucoma The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
  • the several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease.
  • Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma.
  • Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP.
  • Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
  • Patent 5,571,833 discloses tryptamine derivatives that are 5-HT 2 agonists for the treatment of portal hypertension and migraine.
  • U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT A /2C agonists.
  • U.S. Patent 5,902,815 discloses the use of 5-HT 2A agonists to prevent adverse effects of NMDA receptor hypo- function.
  • WO98/31354A2 discloses 5-HT 2 B agonists for the treatment of depression and other CNS conditions. Agonist response at the 5-HT A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT 2 receptor possible [Psychopharmacology, Vol. 121 :357, 1995].
  • the present invention is directed to substituted 3-(2-aminoethyl)-lH-indazol- 5-ols, some of which are novel. It is believed that these compounds will have a high affinity for and function as agonists at the serotonergic 5- ⁇ T 2 receptor, and will thereby be useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
  • IOP intraocular pressure
  • a phenolic moiety e.g. a hydroxyl group at indazole ring position five, such compounds can be particularly sensitive to oxidation reactions well known to occur with phenolic compounds in general, including the related hydroxytryptamines [J. Phys. Chem. 103, 8606 (1999), Chem. Res.
  • Such cleavage would deliver the desired therapeutic agent, that is, the desired novel 5- hydroxy-indazole compounds of the present invention.
  • the concept of utilizing such derivatized phenolic compounds as chemical delivery agents is well known in the art [Drugs Pharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)].
  • the present invention is directed to derivatives of 3-(2-aminoethyl)-lH- indazol-5-ol, some of which are novel, which can be used to lower and control IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma in warm blooded animals, including man.
  • the compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
  • G is chosen from hydrogen, halogen, or C ⁇ a-kyl
  • R and R 4 are independently chosen from hydrogen, or R 3 , R 4 and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R 2 and
  • R together can be (C ⁇ 2 ) m to form a saturated heterocycle; when R 2 and R 3 are part of a heterocycle, R 1 can be hydrogen or R 5 can be hydrogen or when R, R 1 , R 2 , R 5 , and G all are hydrogen R 3 and R 4 cannot both be hydrogen; W is C,.
  • X and Y are independently chosen from hydrogen, -io alkyl or X and Y can together form a lower alkyl chain of (CH 2 ) m ; m is 2 - 4; n is 1 or 2; and pharmaceutically acceptable salts and solvates of the compounds of Formula I.
  • G is chosen from hydrogen, halogen, or C ⁇ - 4 alkyl
  • R and R are hydrogen
  • R 3 , R 4 and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R 2 and R 3 together can be (CH ) m to form a saturated heterocycle; when R 2 and R 3 are part of a heterocycle, R 1 can be hydrogen or
  • R 5 can be hydrogen or C ⁇ - alkyl
  • R 6 , R 7 , R 8 are independently chosen from hydrogen or
  • X and Y are independently chosen from hydrogen, -io alkyl or X and Y can together form a lower alkyl chain of (CH 2 ) m ; m is 2 - 4; n is 1 or 2.
  • Preferred compounds are:
  • G is chosen from hydrogen, halogen, or C ⁇ - 4 alkyl;
  • R 3 and R 4 are independently chosen from hydrogen, Ci ⁇ alkyl or R 3 , R 4 and the carbon atom to which they are attached can form a cyclopropyl ring;
  • R 6 , R 7 , R 8 are independently chosen from hydrogen or Ci ⁇ alkyl
  • X and Y are independently chosen from hydrogen, Ci-io alkyl or X and Y can together form a lower alkyl chain of (CH 2 ) m ; m is 2 or 3; n is 1 or 2.
  • the total number of carbon atoms in a substituent group is indicated by the C,-, prefix where the numbers i and j define the number of carbon atoms; this definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups.
  • a substituent may be present either singly or multiply when incorporated into the indicated structural unit.
  • the substituent halogen which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
  • the compounds of Formula I can be prepared by using one of several synthetic procedures. For example, condensation of the suitably substituted indazol-3- carboxaldehyde (1), which can be prepared from the corresponding indazole by known methods [J. Med. Chem. 38, 2331 (1995)], with the appropriate nitroalkane gives the corresponding nitroalkene (2), which can be reduced with, e.g. LiAlH 4 , and if desired dealkylated with, e.g. boron tribromide, to provide the desired compounds 3 of Formula I.
  • condensation of the suitably substituted indazol-3- carboxaldehyde (1) which can be prepared from the corresponding indazole by known methods [J. Med. Chem. 38, 2331 (1995)]
  • the appropriate nitroalkane gives the corresponding nitroalkene (2), which can be reduced with, e.g. LiAlH 4 , and if desired dealkylated with, e.g. boron tribro
  • Conversion of the secondary alcohol moiety of 6 to the desired primary amine can be accomplished using the well known sequence involving initial activation by formation of a sulfonate ester followed by displacement of this ester by reaction with sodium azide, and finally reduction of the azide with concomitant removal of any phenol protective groups, e.g. benzyl, to provide the desired amine (3).
  • compound 4 can be reacted with an aldehyde, e.g. acetaldehyde, under acidic conditions to provide the chalcone intermediate, e.g. 7 [J. Chem. Soc, 2403 (1953)] (Scheme 3). Addition of a suitably protected amine, e.g.
  • a suitable amino-protected intermediate e.g. 14 (Scheme 5)
  • the desired activated acid derivative such as an acid halide or active ester, or the like
  • the compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
  • the compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8.
  • the compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.25% to 2% by weight.
  • 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
  • the compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, ⁇ -blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), ⁇ l antagonists (e.g.
  • ⁇ 2 agonists e.g., iopidine and brimonidine
  • miotics e.g., pilocarpine and epinephrine
  • prostaglandin analogs e.g., latanoprost, travaprost, unoprostone, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151 ,444, "hypotensive lipids” (e.g., lumigan and compounds set forth in 5,352,708)
  • neuroprotectants e.g., compounds from U.S. Patent No. 4,690,931 , particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, and appropriate compounds from WO94/13275, including memantine.
  • Example 1 The preferred compounds of Formula I are described in Examples 1 and 2. The most preferred compound is in Example 1. Examples of formulations anticipated to be suitable for delivery of this compound to the eye are provided.
  • Step A l-[5-BenzyIoxy-3-(2-oxo-propyl)-indazol-l-yl]-ethanone
  • Step B l-[5-Benzyloxy-3-(2-hydroxypropyl)-indazoI-l-yl]-ethanone
  • Step C l-[3-(2-Azido-propyl)-5-benzyloxy-indazol-l-yl]-ethanone
  • Step A l-(5-Benzyloxy-l/7-indazol-3-yl)-propan-2-one
  • Step B l-(5-Benzyloxy-l-methyl-l 7-indazol-3-yl)-propan-2-one
  • iodomethane (0.53 ml, 8.6 mmol
  • potassium carbonate 1.2 g, 8.6 mmol
  • Step C 3-(2-Aminopropyl)-l-methyl-lH-indazol-5-ol fumarate
  • the product of Step B (0.3 g, 0.1 mmol) was treated in the manner similar to that described in Example 1 Steps B through D to give an oil which was converted to the fumarate salt (0.071 g): mp 136-139°C; LCMS m/z 206 (M+H) + .
  • Step A 3-(2-(9-Fluorenylmethoxycarbonylamino)propyl)-l/7-indazol-5-ol To a mixture of dioxane and water (4:1, 10 mL) was added 3-(2-aminopropyl)-
  • Step B 2-Methyl-propionic acid 3-(2-(9 fluorenylmethoxycarbonylamino)propyl)-lH-indazol-5-yl ester
  • Receptor and binding agonist activity according to this invention can be determined using the following methods.
  • 5HT 2 receptors is determined as described below with minor modification of the literature procedure [Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat or human cerebral cortex homogenates (400 ⁇ l) dispersed in 50 mM TrisHCl buffer (pH 7.4) are incubated with [ 125 I]DOI (80 pM final) in the absence or presence of methiothepin (10 ⁇ M final) to define total and non-specific binding, respectively, in a total volume of 0.5 ml. The assay mixture is incubated for 1 hour at 23°C in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer.
  • Test compounds (at different concentrations) are substituted for methiothepin. Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter. The data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter. The concentration of the compound needed to inhibit the [ 125 I]DOI binding by 50% of the maximum is termed the IC 50 or K * value.
  • the relative agonist activity of serotonergic compounds at the 5HT receptor can be determined in vitro using the ability of the compounds to stimulate the production of [ 3 H]inositol phosphates in [ 3 H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by their ability to activate the enzyme phospholipase C.
  • These cells are grown in culture plates, maintained in a humidified atmosphere of 5% CO and 95% air and fed semi -weekly with Dulbecco's modified Eagle medium (DMEM) containing 4.5 g/1 glucose and supplemented with 2mM glutamine, 10 ⁇ g/ml gentamicin, and 10% fetal bovine serum.
  • DMEM Dulbecco's modified Eagle medium
  • the A7r5 cells are cultured in 24-well plates as previously [J. Pharmacol. Expt. Ther., 286, 41 1 (1998)]. Confluent cells are exposed for 24-30 hrs to 1.5 ⁇ Ci [ 3 H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of serum-free medium. Cells are then rinsed once with DMEM/F-12 containing 10 mM
  • Concentration-response data are analyzed by the sigmoidal fit function of the Origin Scientific Graphics software (Microcal Software, Northampton, MA) to determine agonist potency (EC 50 value) and efficacy (Emax).
  • Serotonin (5HT) is used as a positive control (standard) agonist compound and the efficacy of test compounds is compared to that of 5HT (set at 100%).
  • the concentration of the compound needed to stimulate the production of [ 3 H]-IPs by 50%) of the maximum response is termed the EC 50 value.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP00982109A 2000-03-17 2000-11-14 5-hydroxy indazole derivatives for treating glaucoma Withdrawn EP1268439A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19028300P 2000-03-17 2000-03-17
US190283P 2000-03-17
PCT/US2000/031143 WO2001070701A1 (en) 2000-03-17 2000-11-14 5-hydroxy indazole derivatives for treating glaucoma

Publications (1)

Publication Number Publication Date
EP1268439A1 true EP1268439A1 (en) 2003-01-02

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ID=22700701

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EP00982109A Withdrawn EP1268439A1 (en) 2000-03-17 2000-11-14 5-hydroxy indazole derivatives for treating glaucoma

Country Status (12)

Country Link
EP (1) EP1268439A1 (enExample)
JP (1) JP2003535821A (enExample)
KR (1) KR20030095183A (enExample)
CN (1) CN1450995A (enExample)
AR (1) AR026708A1 (enExample)
AU (2) AU2001219180B2 (enExample)
BR (1) BR0017163A (enExample)
CA (1) CA2401959A1 (enExample)
MX (1) MXPA02008825A (enExample)
PL (1) PL365422A1 (enExample)
WO (1) WO2001070701A1 (enExample)
ZA (1) ZA200206853B (enExample)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
WO2002098350A2 (en) 2001-06-01 2002-12-12 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
US7196082B2 (en) 2002-11-08 2007-03-27 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
CN100384827C (zh) * 2002-11-08 2008-04-30 默克公司 用于治疗高眼压症的眼用组合物
CA2505127A1 (en) * 2002-11-08 2004-05-27 James B. Doherty Ophthalmic compositions for treating ocular hypertension
EP1581209A4 (en) 2002-12-13 2009-03-11 Alcon Inc NEW BENZOPYRAN ANALOGUE AND ITS USE FOR THE TREATMENT OF GLAUKOM
JP2004262812A (ja) * 2003-02-28 2004-09-24 Rohto Pharmaceut Co Ltd 眼圧低下剤
AU2004271978B2 (en) * 2003-09-04 2009-02-05 Merck & Co., Inc. Ophthalmic compositions for treating ocular hypertension
AR046890A1 (es) 2003-12-15 2005-12-28 Alcon Inc [1,4] oxazino [2,3-g] indazoles sustituidos para el tratamiento del glaucoma.
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
AU2005308523B2 (en) 2004-11-29 2010-01-07 Warner-Lambert Company Llc Therapeutic pyrazolo[3,4-b] pyridines and indazoles
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
KR100972921B1 (ko) * 2009-12-02 2010-07-28 제이케이이앤씨 주식회사 회전 격판식 선회류 세정 및 탈취장치
WO2025000053A1 (en) * 2023-06-28 2025-01-02 Psylo Pty Ltd Compounds

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FR2680366B1 (fr) * 1991-08-13 1995-01-20 Adir Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent.
WO1999059499A2 (en) * 1998-05-19 1999-11-25 Alcon Laboratories, Inc. Serotonergic 5ht7 receptor compounds for treating ocular and cns disorders
GB9819020D0 (en) * 1998-09-01 1998-10-28 Cerebrus Ltd Chemical compounds III
AU755119B2 (en) * 1998-09-18 2002-12-05 Alcon Laboratories, Inc. Serotonergic 5HT2 agonists for treating glaucoma

Non-Patent Citations (1)

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Title
See references of WO0170701A1 *

Also Published As

Publication number Publication date
MXPA02008825A (es) 2004-10-15
PL365422A1 (en) 2005-01-10
WO2001070701A1 (en) 2001-09-27
AU2001219180B2 (en) 2005-04-07
JP2003535821A (ja) 2003-12-02
AR026708A1 (es) 2003-02-26
AU1918001A (en) 2001-10-03
KR20030095183A (ko) 2003-12-18
BR0017163A (pt) 2003-01-14
ZA200206853B (en) 2004-11-02
CA2401959A1 (en) 2001-09-27
CN1450995A (zh) 2003-10-22

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