WO2003051291A2 - Composes de 5-hydroxy-indole substitues destines au traitement du glaucome - Google Patents

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

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Publication number
WO2003051291A2
WO2003051291A2 PCT/US2002/038625 US0238625W WO03051291A2 WO 2003051291 A2 WO2003051291 A2 WO 2003051291A2 US 0238625 W US0238625 W US 0238625W WO 03051291 A2 WO03051291 A2 WO 03051291A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
composition
compound
halogen
Prior art date
Application number
PCT/US2002/038625
Other languages
English (en)
Other versions
WO2003051291A3 (fr
Inventor
Jesse A. May
Anura P. Dantanarayana
Abdelmoula Namil
Najam A. Sharif
Paul W. Zinke
Thomas R. Dean
Original Assignee
Alcon, Inc.
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. filed Critical Alcon, Inc.
Priority to AU2002364711A priority Critical patent/AU2002364711A1/en
Publication of WO2003051291A2 publication Critical patent/WO2003051291A2/fr
Publication of WO2003051291A3 publication Critical patent/WO2003051291A3/fr

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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 relates to treatment for lowering intraocular pressure and to
  • the present invention relates to
  • IOP intracranial pressure
  • glaucoma or functionally distinct types of glaucoma are typically characterized by elevated IOP,
  • hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of
  • normotension or low tension glaucoma patients can also benefit from agents that lower and
  • Such therapies are in general administered by one of two possible routes, topically (direct
  • Serotonin (5-hydroxy tryptamine; 5-HT) is an endogenous biogenic amine with a
  • 5-HT is known to interact with at least seven major 5-HT receptors (5-HT, - 5-
  • tissue contraction eventually leading to the final biological response, for example, tissue contraction or
  • 5-HT 5-HT
  • AC adenylyl cyclase
  • PLC phospholipase C
  • the 5-HT 3 receptor is unique in that it couples to an ion channel
  • CNS central nervous system
  • the present invention provides compounds having the following
  • R 1 and R 2 are C,. 6 alkyl or R 1 and R 2 can together complete a four to seven-
  • heterocyclic ring which may contain a second heteroatom selected from O, S,
  • R 3 is hydrogen, C alkyl;
  • R 4 , R 5 , and R 7 are independently selected from
  • R 6 is hydrogen, or
  • R 1 and R 2 are methyl
  • R 3 and R 6 are hydrogen and R 4 , R 5 and R 7
  • R 6 is hydrogen or valproic acid.
  • the present invention provides compositions containing the
  • compositions of the invention may also include bufotenine in a pharmaceutically acceptable excipient.
  • compositions are most preferably in the form of topical ophthalmic formulations for
  • compositions of the invention are preferably formulated as topical ophthalmic
  • the present invention further provides a method of lowering intraocular pressure in
  • composition comprising a compound having the structure as described above.
  • compositions containing bufotenine may include the use of compositions containing bufotenine.
  • the composition can be administered systemically or locally to the
  • eye e.g., topically, intracamerally, or via an implant.
  • the compounds provide neuroprotective activity and are useful for
  • U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT 2A ⁇ C agonists.
  • U.S. Patent 5,902,815 discloses the use of 5-HT 2A agonists to prevent adverse effects of
  • WO 98/31354A2 discloses 5-HT 2B agonists for the
  • therapeutic agent that is, the desired hydroxytryptamine compound in the present case.
  • Serotonin is a very polar
  • N.N-dimethyl-serotonin N,N-dimethyl-5-HT or
  • O-acetyl bufotenine does readily cross the blood-brain barrier and is rapidly
  • bufotenine has a low propensity to cross the blood-brain barrier, if it does
  • a prodrug modification such as O-acetyl bufotenine
  • Bufotenine has not been reported to have IOP lowering activity, or any other
  • IOP insulin pressure
  • R 1 and R 2 are C, .6 alkyl or R 1 and
  • R 2 can together complete a four to seven-membered heterocyclic ring which may contain a
  • R 3 is hydrogen, C alkyl; R 4 , R 5 ,
  • R 7 are independently selected from hydrogen, C M alkyl, halogen, nitrile, C, .6 alkylthiol,
  • the most preferred compounds are those wherein
  • R 1 and R 2 are methyl; R 3 , R 4 , R 6 are hydrogen, R 5 , R 7 are hydrogen, halogen, or
  • Valproic acid is a clinically proven
  • compounds of Formula I can contain one or more chiral
  • This invention contemplates all enantiomers, diastereomers and, mixtures thereof.
  • Ci-j 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
  • halogen which means fluorine, chlorine, bromine, or iodine, would indicate that the unit
  • halogen atoms which may be
  • the compounds of the invention can be made using known synthetic techniques.
  • the compounds of the invention can be administered systemically or locally to the
  • the compounds are preferably
  • ophthalmologically acceptable preservatives may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous,
  • Ophthalmic solution formulations may be
  • the ophthalmic solution may include an ophthalmologically acceptable
  • hydroxymethylcellulose may contain an agent to increase viscosity, such as, hydroxymethylcellulose,
  • Gelling agents can also be used, including, but not limited to, gellan and
  • 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
  • the compounds of the invention are preferably formulated as topical ophthalmic
  • formulations would be delivered to the surface of the eye 1 to 4 times per day according to
  • the compounds can also be used in combination with other IOP lowering agents,
  • ⁇ -blockers such as, but not limited to, ⁇ -blockers, prostaglandins, carbonic anhydrase inhibitors, ⁇ - 2
  • the compounds can also be used in combination with other agents
  • glaucoma useful for treating glaucoma, such as, but not limited to, calcium channel blockers and
  • NMDA antagonists These agents may be administered topically, but usually systemically.
  • Bufotenine was purchased as the oxylate salt from BioSynth International and
  • Oxalic acid or oxalate salts are typically not well tolerated by rabbits when evaluated in such studies, and hence it is
  • DOI that produced a mean of five twitches was determined to be 0.1 mg/kg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des nouveaux composés présentant une activité agoniste de 5-HT2, des compositions contenant ces composés ainsi que des méthodes d'utilisation correspondantes permettant d'abaisser la pression intraoculaire et/ou d'assurer une neuroprotection.
PCT/US2002/038625 2001-12-14 2002-12-05 Composes de 5-hydroxy-indole substitues destines au traitement du glaucome WO2003051291A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002364711A AU2002364711A1 (en) 2001-12-14 2002-12-05 Substituted 5-hydroxy-indole compounds for the treatment of glaucoma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34044501P 2001-12-14 2001-12-14
US60/340,445 2001-12-14

Publications (2)

Publication Number Publication Date
WO2003051291A2 true WO2003051291A2 (fr) 2003-06-26
WO2003051291A3 WO2003051291A3 (fr) 2003-10-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/038625 WO2003051291A2 (fr) 2001-12-14 2002-12-05 Composes de 5-hydroxy-indole substitues destines au traitement du glaucome

Country Status (2)

Country Link
AU (1) AU2002364711A1 (fr)
WO (1) WO2003051291A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989445B2 (en) 2003-12-15 2006-01-24 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7208512B2 (en) 2001-12-20 2007-04-24 Alcon, Inc. Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use 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
US7396856B2 (en) 2002-12-13 2008-07-08 Alcon, Inc. Benzopyran analogs and their use for the treatment of glaucoma
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
US7476687B2 (en) 2003-11-26 2009-01-13 Alcon, Inc. Substituted furo[2,3-g]indazoles for the treatment of glaucoma
CN109172580A (zh) * 2018-09-06 2019-01-11 中山万汉制药有限公司 包含前列腺素衍生物的组合物以及包含该组合物的眼用液体制剂

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571833A (en) * 1991-06-21 1996-11-05 Smithkline Beecham Plc Tryptamine analogues, their synthesis and their use as 5-HT1 -like or 5-HT2 receptor agonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571833A (en) * 1991-06-21 1996-11-05 Smithkline Beecham Plc Tryptamine analogues, their synthesis and their use as 5-HT1 -like or 5-HT2 receptor agonists

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7285553B2 (en) 1998-05-19 2007-10-23 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7208512B2 (en) 2001-12-20 2007-04-24 Alcon, Inc. Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
US7396856B2 (en) 2002-12-13 2008-07-08 Alcon, Inc. Benzopyran analogs and their use for the treatment of glaucoma
US7476687B2 (en) 2003-11-26 2009-01-13 Alcon, Inc. Substituted furo[2,3-g]indazoles 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
US6989445B2 (en) 2003-12-15 2006-01-24 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7268131B2 (en) 2003-12-15 2007-09-11 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7439262B1 (en) 2003-12-15 2008-10-21 Alcon, Inc. Substituted 1-alkylamino-1-H-indazoles for the treatment of glaucoma
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
CN109172580A (zh) * 2018-09-06 2019-01-11 中山万汉制药有限公司 包含前列腺素衍生物的组合物以及包含该组合物的眼用液体制剂
CN109172580B (zh) * 2018-09-06 2021-04-27 中山万汉制药有限公司 包含前列腺素衍生物的组合物以及包含该组合物的眼用液体制剂

Also Published As

Publication number Publication date
AU2002364711A1 (en) 2003-06-30
WO2003051291A3 (fr) 2003-10-23
AU2002364711A8 (en) 2003-06-30

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