EP0671914A1 - Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds - Google Patents

Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds

Info

Publication number
EP0671914A1
EP0671914A1 EP94903351A EP94903351A EP0671914A1 EP 0671914 A1 EP0671914 A1 EP 0671914A1 EP 94903351 A EP94903351 A EP 94903351A EP 94903351 A EP94903351 A EP 94903351A EP 0671914 A1 EP0671914 A1 EP 0671914A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
formula
hydrogen
compound
lower alkyl
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
EP94903351A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0671914A4 (enrdf_load_stackoverflow
Inventor
Frank C. Barone
Giora Feuerstein
Tian-Li Yue
Paul G. Lysko
Hung-Yuan Cheng
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0671914A1 publication Critical patent/EP0671914A1/en
Publication of EP0671914A4 publication Critical patent/EP0671914A4/xx
Ceased 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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 relates to a new medical use of, and method of treatment using, the hydroxycarbazole compounds of Formula I, as oxygen radical scavengers, or antioxidants, for protection of vital organs, particularly the central nervous system including the brain, from oxidative damage.
  • the present invention provides a new use for such hydroxycarbazole compounds for making pharmaceutical compositions useful in prevention of organ reperfusion injury including related acute inflammation, particularly neuroprotection, that is, protection of the central nervous system from traumatic and post-traumatic injury associated with stroke, e. g., prevention of stroke and neurotrauma, and reduction of morbidity resulting from the sequelae of stroke.
  • R7-R13 are independently -H or-OH.
  • A is independently H, -OH, or a moiety of Formula II:
  • Rj is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
  • R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
  • R3 is hydrogen or lower alkyl of up to 6 carbon atoms;
  • R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
  • X is a valency bond, -CH2, oxygen or sulfur
  • Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
  • R5 and R ⁇ are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a - CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
  • R5 and R6 together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
  • LPO and oxygen radicals in tissue damage associated with ischemia is further supported by the protective effect of natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M.A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).
  • natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M.A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).
  • the present invention provides a new medical use for the hydroxycarbazole compounds of Formula I as oxygen radical scavengers or antioxidants for protection of vital organs from oxidative damage.
  • the present invention provides a new use for compounds preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula II wherein Rl is - H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is - H, and R7 is -OH, or a pharmaceutically
  • the present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma, particularly neuroprotection, that is, prevention of stroke and reduction of morbidity resulting from the sequelae of stroke, in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of a compound selected from the group consisting essentially of the compounds of Formula I, preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R1 Q is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H
  • R ⁇ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
  • R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
  • R3 is hydrogen or lower alkyl of up to 6 carbon atoms
  • R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
  • X is a valency bond, -CH2, oxygen or sulfur
  • Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
  • R5 and R ⁇ are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a - CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or R5 and R6 together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
  • This patent further discloses a compound of Formula HI, better known as carvedilol ( 1 -(carbazol-4-yloxy-3- [[2- (o-methoxyphenoxy )ethyl] amino] -2- propanol), having the structure shown in Formula IV:
  • Carvedilol is known to be both a competitive ⁇ - adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations .
  • the vasodilatory actions of carvedilol result primarily from ocj -adrenoceptor blockade, whereas the ⁇ -adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension.
  • These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans, as well as for utility in the treatment of angina and CHF.
  • ischemic organ trauma as in stroke, a high proportion of ischemic organ cells become irreversibly damaged and necrotic, the extent of injury being dependent upon the length of time that the trauma, e.g. the arterial occlusion, persists.
  • the protection of central nervous system neurons from such damage and necrosis during occlusion occurring in stroke and post-traumatic reperfusion is essential to achieving the therapeutic goal of restoration of neurological function; here and throughout this application this property is referred to by the term "neuroprotection" and its synonyms.
  • ⁇ -adrenoceptor antagonists for instance propranolol
  • carbazolyl-(4)-oxypropanolamine compounds of Formula I are effective cardioprotective agents at antihypertensive doses which unexpectedly minimize these consequences.
  • ⁇ -adrenoceptor blocking and vasodilatory properties of carvedilol provides cardioprotection during and after acute myocardial infarction.
  • Some of the compounds of Formula I are known to be metabolites of carvedilol in human and other mammalian (e.g. gerbil) systems.
  • the preferred compounds of the present invention that is, the compounds of Formula I wherein A is the moiety of Formula ⁇ wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R1 Q is -OH are known to be metabolites of carvedilol.
  • the hydroxycarbazole compounds of Formula I are oxygen radical scavengers.
  • oxygen scavengers the above- described compounds act to inhibit LPO, and further that the hydroxycarbazole compounds of Formula I are surprisingly effective protective agents in generally preventing a wide variety of disease states associated with oxidative tissue damage to the organs due to LPO following ischemic traumas.
  • the compounds of the present invention are especially useful in neuroprotection, that is, prevention of stroke, and reduction of morbidity resulting from the sequelae of stroke.
  • the compounds of Formula I preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is - H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and R7 is -OH, exhibit neuroprotection, and are especially useful for protecting cerebral tissue from stroke and neurotrauma as well as for preventing oxidative tissue damage of ischemic human cerebral tissue following occurence of an ischemic event such as stroke or cerebral trauma.
  • chronic administration of these compounds can both reduce the risk of cerebral ischemia or stroke in individuals at risk thereof as well as provide adjunctive therapy by reducing the magnitude of oxidative tissue damage following an ischemic cerebral event. Because hypertensive individuals are at increased risk of stroke, the neuroprotective use of the present compounds at appropriate dosing regimens in combination with antihypertensive therapy significantly reduces the risk of stroke, and the sequelae of stroke in such patients.
  • the compounds of Formula I preferably those selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R ⁇ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and R7 is -OH, are useful for neuroprotection in humans according to the present invention at dosages ranging from about 1-3 mg kg i.v. b.i.d. and 3-30 .mg/kg p.o. b.i.d.
  • the present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of a compound selected from the group consisting essentially of the compounds of Formula I, preferably those selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ s -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is
  • compositions of the compounds of Formula I for neuroprotective use according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinyl- pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP94903351A 1992-12-01 1993-12-01 Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds Ceased EP0671914A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US98392092A 1992-12-01 1992-12-01
US983920 1992-12-01
PCT/US1993/011598 WO1994012178A1 (en) 1992-12-01 1993-12-01 Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds

Publications (2)

Publication Number Publication Date
EP0671914A1 true EP0671914A1 (en) 1995-09-20
EP0671914A4 EP0671914A4 (enrdf_load_stackoverflow) 1995-10-25

Family

ID=25530181

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94903351A Ceased EP0671914A1 (en) 1992-12-01 1993-12-01 Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds

Country Status (8)

Country Link
EP (1) EP0671914A1 (enrdf_load_stackoverflow)
JP (1) JPH08503711A (enrdf_load_stackoverflow)
KR (1) KR950703950A (enrdf_load_stackoverflow)
CN (1) CN1042795C (enrdf_load_stackoverflow)
AU (1) AU673882B2 (enrdf_load_stackoverflow)
CA (1) CA2150695A1 (enrdf_load_stackoverflow)
WO (1) WO1994012178A1 (enrdf_load_stackoverflow)
ZA (1) ZA938897B (enrdf_load_stackoverflow)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040680A1 (en) * 1996-04-29 1997-11-06 Smithkline Beecham Corporation Antioxidant compound
EP0910374A1 (de) * 1996-07-13 1999-04-28 Roche Diagnostics GmbH Topisch einsetzbare pharmazeutische formulierungen enthaltend als wirkstoff ein carbazolyl-(4)-oxy-propanolamin-derivat
US6369106B1 (en) * 1996-12-26 2002-04-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Treatment of ischemic brain injuries with brain targeted anti oxidant compounds
JPH10251147A (ja) * 1997-03-06 1998-09-22 Akira Matsumori 炎症性疾患の予防・治療剤
AR035455A1 (es) * 2001-04-23 2004-05-26 Hoffmann La Roche Derivados triciclicos de alquilhidroxamato , procesos para su elaboracion, composiciones farmaceuticas que los contienen, y el uso de dichos compuestos en la preparacion de medicamentos

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2815926A1 (de) * 1978-04-13 1979-10-18 Boehringer Mannheim Gmbh Neue carbazolyl-(4)-oxy-propanolamin-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9412178A1 *

Also Published As

Publication number Publication date
CN1098908A (zh) 1995-02-22
JPH08503711A (ja) 1996-04-23
AU673882B2 (en) 1996-11-28
CA2150695A1 (en) 1994-06-09
KR950703950A (ko) 1995-11-17
ZA938897B (en) 1994-08-01
WO1994012178A1 (en) 1994-06-09
AU5732394A (en) 1994-06-22
EP0671914A4 (enrdf_load_stackoverflow) 1995-10-25
CN1042795C (zh) 1999-04-07

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