WO2005044261A1 - Promedicaments analogues de la melatonine - Google Patents

Promedicaments analogues de la melatonine Download PDF

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Publication number
WO2005044261A1
WO2005044261A1 PCT/US2004/035490 US2004035490W WO2005044261A1 WO 2005044261 A1 WO2005044261 A1 WO 2005044261A1 US 2004035490 W US2004035490 W US 2004035490W WO 2005044261 A1 WO2005044261 A1 WO 2005044261A1
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WO
WIPO (PCT)
Prior art keywords
melatonin
composition
moieties
analogue
melatonin analogue
Prior art date
Application number
PCT/US2004/035490
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English (en)
Inventor
Max T. Baker
Mohamed Naguib Attala
Original Assignee
University Of Iowa Research Foundation
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 University Of Iowa Research Foundation filed Critical University Of Iowa Research Foundation
Publication of WO2005044261A1 publication Critical patent/WO2005044261A1/fr

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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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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

  • Benzodiazepines decrease duration of REM sleep after single administration of a high dose or long-term administration of low dose. Benzodiazepines also reduce slow-wave sleep, thus negatively influencing sleep quality. In contrast, a single low dose of melatonin produced no suppression of REM sleep. Furthermore, unlike benzodiazepines, melatonin does not induce "hangover" effects. In a previous publication of one of the inventors, British Journal of Anesthesia
  • Patent 6,522,064 had as its primary objective the development of pineal hormone melatonin (N-acetyl-5-methoxytryptamine) or its biologically active analogues as a general anesthetic which can be used without any significant anesthetic hangover.
  • melatonin N-acetyl-5-methoxytryptamine
  • analogues N-acetyl-5-methoxytryptamine
  • melatonin and its analogues to derive improved compounds which may be used for anesthetic effect generally and in small doses for hypnotic effect sedation or even sleep inducement.
  • the preferred carrier is comprised of one volume of l-methyl-2-pyrrolidinone, one volume of propylene glycol and two volumes of water. It goes without saying that the volumetric ratios of these carrier solvents may be varied somewhat, depending upon the circumstances. These discoveries resulted in our U.S. Patent 6,638,966. Because melatonin and the melatonin analogues of our previous patents are somewhat difficultly soluble in aqueous vehicles, the Applicants have continued their efforts to find active analogues which could be administered with aqueous vehicles. Disclosed here are prodrugs of melatonin analogues which can be administered preferentially in aqueous vehicles.
  • Melatonin is a water-insoluble compound that cannot be administered to patients by injection using an aqueous vehicle. Furthermore, melatonin can not be formulated into an organic solvent that is free of side effects. For example, organic solvents such as ethanol, N-methyl-pyrrolidione, ethyl acetate, tetrahydrofuran, and propylene glycol, will solublize melatonin; however, these solvents are either toxic to the patient, have undesirable side-effects, or they are not approved for administration to humans by parenteral administration.
  • organic solvents such as ethanol, N-methyl-pyrrolidione, ethyl acetate, tetrahydrofuran, and propylene glycol
  • Melatonin also cannot be administered in an oil-in- water emulsion because it is poorly soluble in oils that can be made into oil-in-water emulsions, such as soybean, safflower, or olive oil. It is therefore desired to have a compound, which exerts the beneficial effects of melatonin including anti-oxidation, sedation, anesthesia, protection of organs to chemical, infectious and cardiovascular damage, and can be administered in a water-based or aqueous vehicle. This invention fulfills this desire or need.
  • these melatonin analogue prodrugs are stable in a vial at acidic pH, but will breakdown upon injection into the body to liberate the melatonin analogue and the tertiary amine, which is nontoxic.
  • the melatonin analogue being not modified on the indole moiety exerts similar pharmacological properties as melatonin: antioxidation, sedation and anesthesia.
  • Melatonin N-acetyl-5-methoxytryptamine
  • the chemical formula for melatonin is N-acetyl-5-methoxytryptamine.
  • biologically active analogues As used herein, this phrase refers to the precise compound itself and other compounds having the same general structure, but only differing in minor moieties, and therefore still having the same biological activity of anesthetic-inducing effectiveness.
  • the biologically active compound melatonin may be derived or extracted from the pineal gland, or it can be synthesized from 5-Methoxyindol as a starting material by known routes, Szmuszkovicz et al., J. Org. Chem. 25, 857 (1960). Biochemical role of melatonin: Chem. & Eng. News 45, 40 (May 1, 1967). Chemically, the word description of the above is illustrated by the following schematic:
  • Ri, R and R 3 can independently be any hydrocarbon moiety which upon hydrolysis provides a non toxic tertiary amine including for example alkyl, cycloalkyl, haloalkyl, phenyl, or aromatic groups, but preferably R ls R 2 and R 3 are short chain, i.e., C ⁇ to C 8 , most preferably C ⁇ to C 4 alkyl.
  • R l5 R 2 and R 3 may also contain multiple substituent groups including in addition, alkoxy, carboxylic acid or ester groups, and may have up to C 20 .
  • the indole structure of the melatonin analogue may be substituted at the 2-position with substituents including bromine, chlorine, chlorine, fluorine, phenyl, 4-fluorophenyl, 4- bromophenyl, 4-trifluorophenyl or other related groups (see our U.S. Patent 6,638,966).
  • the anesthetic active i.e., the prodrug of N-acetyl-5-methoxytryptamine (melatonin), or its biologically active analogues, can be administered with traditionally acceptable pharmaceutical carriers. Examples include Intralipid®, Cyclodextrin, and others, some of which are briefly hereinafter described.
  • composition may be administered by conventional administration methods for anesthetics, i.e., oral administration, nasal respiratory administration, bolus injection, intravenous administration by repeated doses or by continuous infusion, rectal, vaginal, sublingual, cutaneous and slow release routes. It may be, and often is preferred, that it be administered in two or more ways, such as by bolus injection followed by continuous intravenous administration.
  • anesthetics i.e., oral administration, nasal respiratory administration, bolus injection, intravenous administration by repeated doses or by continuous infusion, rectal, vaginal, sublingual, cutaneous and slow release routes. It may be, and often is preferred, that it be administered in two or more ways, such as by bolus injection followed by continuous intravenous administration.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, and aqueous suspensions.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin and these pay be used.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases.
  • Nebulised solutions may be breathed directly from the nebulising device, or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the anesthetic may be used alone or often in combination with other anesthetics simultaneously administered.
  • both the compound of melatonin or its analogue and the other active agent(s) can be administered to a patient, within a reasonable period of time. It may indeed act synergistically with other anesthetic drugs.
  • the compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously.
  • ком ⁇ онент also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active compound may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
  • a fast dissolving oral formulation is meant, an oral delivery form which, when placed on the tongue of a patient, dissolves within about 10 seconds.
  • the dosage will vary depending upon the deepness of the anesthesia desired, but based upon limited studies to date, it is believed that the dosage most effective will be within the range of 0.001 mg/kg of body weight to about 500 mg/kg of body weight, more predictably preferred is the range of 5 mg/kg of body weight to about 350 mg/kg of body weight.
  • the synthesis of the melatonin analogue prodrugs may be summarized by the following reaction scheme. Melatonin analogue prodrug synthesis
  • R 4 can be hydrogen, bromine, chlorine, fluorine, phenyl, bromophenyl, trifluoromethylpheny. or any other lipophilic substituent
  • Melatonin analogue prodrug Prodrug shown above upon hydrolysis will yield the melatonin analogue and a tertiary amine.
  • Another example of a melatonin analogue prodrug is illustrated below.
  • Active melatonin analogue inactive nontoxic degradation product From the above illustrations, it can be seen that active melatonin analogue prodrugs, transformable into the active melatonin analogue within the body are provided. These are aqueous carrier soluble and as such have ease of administration and will break down upon injection into the body to liberate the melatonin analogue and a non toxic tertiary amine.

Abstract

L'invention concerne des composés pouvant servir de promédicaments analogues de la mélatonine et qui sont solubles dans des solvants aqueux. De la mélatonine ou des analogues de la mélatonine comportant des modifications au niveau du groupe indole sont couplés à une amine tertiaire pour former une amine quaternaire de façon à former une double liaison carbone saturée entre le carbonyle de la structure de la mélatonine et l'azote aminé. Cette structure est stable dans des environnements acides, mais instable à un pH basique ou neutre. Par conséquent, ces promédicaments analogues de la mélatonine sont stables dans un flacon à un pH acide, mais se décomposent lorsqu'ils sont injectés dans le corps pour libérer l'analogue de la mélatonine et l'amine tertiaire, qui est non toxique. L'analogue de la mélatonine qui n'est pas modifié sur le groupe indole possède des propriétés pharmacologiques similaires à celles de la mélatonine : antioxydantes, sédatives et anesthésiantes.
PCT/US2004/035490 2003-10-27 2004-10-26 Promedicaments analogues de la melatonine WO2005044261A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51495203P 2003-10-27 2003-10-27
US60/514,952 2003-10-27

Publications (1)

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WO2005044261A1 true WO2005044261A1 (fr) 2005-05-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341493A (zh) * 2020-10-21 2021-02-09 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005721A1 (fr) * 1988-11-14 1990-05-31 The Upjohn Company Acides alpha-amino-indole-3-acetiques utiles en tant qu'agents anti-diabetiques, anti-obesite et anti-athero-sclerotiques
WO1992006955A1 (fr) * 1990-10-17 1992-04-30 Pulitzer Italiana S.R.L. Derive de melatonine presentant une activite therapeutique en dermatologie
WO1998006695A1 (fr) * 1996-08-09 1998-02-19 Sederma S.A. Derives de la melatonine et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques
US6638966B2 (en) * 2000-09-19 2003-10-28 University Of Iowa Research Foundation Use of melatonin analogues for induction of general anesthesia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005721A1 (fr) * 1988-11-14 1990-05-31 The Upjohn Company Acides alpha-amino-indole-3-acetiques utiles en tant qu'agents anti-diabetiques, anti-obesite et anti-athero-sclerotiques
WO1992006955A1 (fr) * 1990-10-17 1992-04-30 Pulitzer Italiana S.R.L. Derive de melatonine presentant une activite therapeutique en dermatologie
WO1998006695A1 (fr) * 1996-08-09 1998-02-19 Sederma S.A. Derives de la melatonine et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques
US6638966B2 (en) * 2000-09-19 2003-10-28 University Of Iowa Research Foundation Use of melatonin analogues for induction of general anesthesia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOZZO A, LESIEUR D, DURIEZ P, FRUCHART J-C: "Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model", FREE RADICAL BIOLOGY AND MEDICINE, vol. 26, no. 11-12, 1999, pages 1538 - 1543, XP002320904 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341493A (zh) * 2020-10-21 2021-02-09 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用
CN112341493B (zh) * 2020-10-21 2023-08-15 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用

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