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WO2001070686A1 - Derives de 5-hydroxy-indole destines au traitement du glaucome - Google Patents

Derives de 5-hydroxy-indole destines au traitement du glaucome Download PDF

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Publication number
WO2001070686A1
WO2001070686A1 PCT/US2000/031144 US0031144W WO0170686A1 WO 2001070686 A1 WO2001070686 A1 WO 2001070686A1 US 0031144 W US0031144 W US 0031144W WO 0170686 A1 WO0170686 A1 WO 0170686A1
Authority
WO
WIPO (PCT)
Prior art keywords
indol
ester
compounds
compound
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.)
Ceased
Application number
PCT/US2000/031144
Other languages
English (en)
Inventor
Jesse A. May
Paul W. Zinke
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.)
Novartis AG
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
Priority to AU2001216035A priority Critical patent/AU2001216035A1/en
Priority to US10/220,997 priority patent/US6806285B1/en
Publication of WO2001070686A1 publication Critical patent/WO2001070686A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • the present invention is directed to novel substituted 3-(2-aminopropyl)-lH- indol-5-ols. These novel compounds are useful 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. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated.
  • 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.
  • U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT 2A/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 B agonists for the treatment of depression and other CNS conditions.
  • O00/12475 discloses indoline derivatives as 5-HT 2B and 5-HT 2C receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity.
  • WO00/35922 discloses certain pyrazino[l ,2- ⁇ ]quinoxaline derivates as 5-HT 2 c agonists for the treatment of obsessive-compulsive disorder, depression, eating disorders, and other disorders involving the CNS.
  • 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 new derivatives of 3-(2-aminopropyl)-lH- indol-5-ol 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 ⁇ aHcyl
  • R is chosen from C 3 . 6 alkyl, C 3 . 6 alkyl substituted with hydroxyl, CO(OC ] - alkyl),
  • R 1 is chosen from hydrogen, C ⁇ aHcyl; and pharmaceutically acceptable salts and solvates of the compounds.
  • the total number of carbon atoms in a substituent group is indicated by the Ci-j prefix where the numbers i and j define the number of carbon atoms; this definition includes branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups. It is important to recognize that 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 readily prepared from, for example, ⁇ - methyl-5-hydroxy-tryptarnine [J. Med. Chem. 33, 755 (1990), J. Org. Chem. 25, 1548 (I960)] or a desirably substituted derivative of structure 1 wherein G is as defined previously. That is, compounds of Formula I can be prepared by reacting the appropriate indole 1, or preferably a suitable amino-protected intermediate, e.g. 2 (Scheme 1 ) with the desired activated acid derivative, such as an acid halide or active ester, or the like, to provide the esters 3. Removal of the N-protective group from the intermediate 3 provides the desired compounds of Formula I.
  • the indole derivatives of interest for use as starting materials for the preparation of 1 can be either purchased from commercial suppliers or prepared by well known methods [Comp. Heterocycl. Chem. II, Vol. 2: 1 19, 1996; Indoles, Sundberg, 1996].
  • one such approach begins with the desired 5-alkoxy- 2-nitrotoluene 5 and proceeds via a Leimgruber-Batcho indole synthesis [J. Med.Chem. 22, 63 (1979) and U.S. Patent 3,732,245] to give the desired indoles 7 (Scheme 2).
  • Intermediates 7 can be readily transformed into indoles 1 by well known methods [J. Med. Chem. 33, 755 (1990), J. Org. Chem. 25, 1548 (I960)].
  • 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.
  • nipradolol nipradolol
  • ct2 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.
  • Step A [2-(5-Hydroxy-lJ7-indol-3-yI)-l-methylethyl]carbamic acid 9//-fluoren-9- ylmethyl ester
  • Step A Isobutyric acid 3-[2-(9-fl r -fluoren-9-ylmethoxycarbonylamino)-propyl]- li/-indol-5-yl ester
  • Step A 2,2-Dimethyl-propionic acid 3-[2-(9 /-fluoren-9- ylmethoxycarbonylamino)-propyl]-l//-indol-5-yl ester
  • Step B 2,2-Dimethyl-propionic acid 3-(2-aminopropyl)-l-ff-indol-5-yl ester
  • Step A Cyclopropanecarboxylic acid 3-[2-(9 jT-fluoren-9- ylmethoxycarbonylamino)-propyI]-l.H r -indol-5-yl ester
  • the solution stability of the example compounds were assessed using an accelerated stress test.
  • the compound was dissolved in pH 5, 0.025 M sodium citrate buffer (5-15 ⁇ g/mL).
  • 2 mL of each solution in a glass vial was heated at 75°C for 14 days.
  • Samples were analyzed periodically using HPLC and % degradation was calculated for the sample.
  • the predicted shelf life 25°C was based on the loss of 10% compound (T 0 ) and the fact that the rate of degradation for a first order reaction decreased 50% for every 10°C drop in temperature.
  • Example 2 The predicted shelf lives for representative compounds of Formula I are listed in Table 2.
  • the parent compound, ⁇ -methylserotonin, and the corresponding propionic acid ester derivative (Example 1) are included for reference.
  • Example 1 a straight chain alkyl ester, did not provide an increase in the stability of the parent compound.
  • the other Examples in Table 1 more sterically hindered esters, were less susceptible than the parent compound to both oxidative degradation and ester hydrolysis as illustrated by the decreased level of degradation observed under the experimental stress conditions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux 3-(2-aminopropyl)-H-indol-5-ols, utiles pour abaisser et réguler la tension intraoculaire et traiter le glaucome.
PCT/US2000/031144 2000-03-17 2000-11-14 Derives de 5-hydroxy-indole destines au traitement du glaucome Ceased WO2001070686A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001216035A AU2001216035A1 (en) 2000-03-17 2000-11-14 5-hydroxy indole derivatives for treating glaucoma
US10/220,997 US6806285B1 (en) 2000-03-17 2000-11-14 5-Hydroxyl indole derivatives for treating glaucoma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19020500P 2000-03-17 2000-03-17
US60/190,205 2000-03-17

Publications (1)

Publication Number Publication Date
WO2001070686A1 true WO2001070686A1 (fr) 2001-09-27

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PCT/US2000/031144 Ceased WO2001070686A1 (fr) 2000-03-17 2000-11-14 Derives de 5-hydroxy-indole destines au traitement du glaucome

Country Status (2)

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AU (1) AU2001216035A1 (fr)
WO (1) WO2001070686A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1515974A4 (fr) * 2002-06-17 2007-02-28 Merck & Co Inc Nouveaux bloqueurs de canaux maxi k, methodes d'utilisation et procedes de fabrication associes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000333A1 (fr) * 1991-06-21 1993-01-07 Smithkline Beecham Plc Analogues de tryptamine, synthese et utilisation en tant qu'agonistes de recepteurs 5-ht2 ou semblables a 5-ht¿1?
WO1994003162A1 (fr) * 1992-07-31 1994-02-17 Glaxo Group Limited Medicaments de traitement ou de prevention de la pression intraoculaire elevee
WO1998031354A2 (fr) * 1997-01-17 1998-07-23 Smithkline Beecham Plc Nouveau traitement
WO2000016761A2 (fr) * 1998-09-18 2000-03-30 Alcon Laboratories, Inc. Agonistes de 5ht2 serotoninergiques utiles pour traiter le glaucome

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000333A1 (fr) * 1991-06-21 1993-01-07 Smithkline Beecham Plc Analogues de tryptamine, synthese et utilisation en tant qu'agonistes de recepteurs 5-ht2 ou semblables a 5-ht¿1?
WO1994003162A1 (fr) * 1992-07-31 1994-02-17 Glaxo Group Limited Medicaments de traitement ou de prevention de la pression intraoculaire elevee
WO1998031354A2 (fr) * 1997-01-17 1998-07-23 Smithkline Beecham Plc Nouveau traitement
WO2000016761A2 (fr) * 1998-09-18 2000-03-30 Alcon Laboratories, Inc. Agonistes de 5ht2 serotoninergiques utiles pour traiter le glaucome

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LYON, ROBERT A. ET AL: "Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens", XP002161467, retrieved from STN Database accession no. 109:47843 *
EUR. J. PHARMACOL. (1988), 145(3), 291-7 *
GUPTA Y K ET AL: "THERAPEUTIC POTENTIALS OF 5-HT RECEPTOR MODULATORS", INDIAN JOURNAL OF PHARMACOLOGY,XX,XX, vol. 26, no. 2, 1 June 1994 (1994-06-01), pages 94 - 107, XP000571272, ISSN: 0253-7613 *
ISMAIEL, ABD M. ET AL: "5-HT1 and 5-HT2 binding profiles of the serotonergic agents.alpha.-methylserotonin and 2-methylserotonin", J. MED. CHEM. (1990), 33(2), 755-8, XP000876594 *
OSBORNE N N ET AL: "DO BETA-ADRENOCEPTORS AND SEROTONIN 5-HT1A RECEPTORS HAVE SIMILAR FUNCTIONS IN THE CONTROL OF INTRAOCULAR PRESSURE IN THE RABBIT?", OPHTHALMOLOGICA,CH,KARGER, BASEL, vol. 210, 1996, pages 308 - 314, XP002051581, ISSN: 0030-3755 *
OSBORNE N N: "SEROTONIN AND MELATONIN IN THE IRIS/CILIARY PROCESSES AND THEIR INVOLVEMENT IN INTRAOCULAR PRESSURE", ACTA NEUROBIOLOGIAE EXPERIMENTALIS,PL,WARSZAW, vol. 54, no. SUPPL, 1994, pages 57 - 64, XP000878634, ISSN: 0065-1400 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1515974A4 (fr) * 2002-06-17 2007-02-28 Merck & Co Inc Nouveaux bloqueurs de canaux maxi k, methodes d'utilisation et procedes de fabrication associes
US7294646B2 (en) 2002-06-17 2007-11-13 Merck & Co. Inc. Maxi-k channel blockers, methods of use and process for making the same

Also Published As

Publication number Publication date
AU2001216035A1 (en) 2001-10-03

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