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EP0375726A1 - Composes analogues de la melatonine - Google Patents

Composes analogues de la melatonine

Info

Publication number
EP0375726A1
EP0375726A1 EP88907911A EP88907911A EP0375726A1 EP 0375726 A1 EP0375726 A1 EP 0375726A1 EP 88907911 A EP88907911 A EP 88907911A EP 88907911 A EP88907911 A EP 88907911A EP 0375726 A1 EP0375726 A1 EP 0375726A1
Authority
EP
European Patent Office
Prior art keywords
compound
hydrogen
radicals
group
melatonin
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
EP88907911A
Other languages
German (de)
English (en)
Other versions
EP0375726A4 (en
Inventor
Margarita L. Dubocovich
James V. Peck
Atef A. Helmy
Vithal J. Rajadhyaksha
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.)
Whitby Research Inc
Original Assignee
Whitby Research 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 Whitby Research Inc filed Critical Whitby Research Inc
Publication of EP0375726A1 publication Critical patent/EP0375726A1/fr
Publication of EP0375726A4 publication Critical patent/EP0375726A4/en
Ceased legal-status Critical Current

Links

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
    • 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

  • This invention relates to novel 2-aryl substituted N-acetyltryptamines having pharmacological activity, e.g., melatonin antagonist activity and methods for the synthesis thereof.
  • Melatonin 5-methoxy-N-acetyltryptamine
  • the synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senesence. The rhythm appears to be the result of both endogenous mechanisms and environmental cues, most notably, the exposure of mammals to light which inhibits melatonin synthesis and secretion.
  • Melatonin is thought to be the hormonal mediator of photo- periodic changes.
  • Evidence suggests that melatonin is involved in the regulation of circadian rhythms and a variety of neural and endocrine functions. Melatonin has been implicated in a number of human disorders, particularly those relating to chronobiologic abnormalities.
  • Figure 1 shows the spatial orientation of the compounds of the instant invention wherein the longi-tudinal axis of the indole moiety and the 2-aryl substituent is polyplanar as described herein and have melatonin antagonist activity; and Figure 2 shows a closely related analogue wherein such longitudinal axis is uniplanar as described herein and is hypothesized as not showing melatonin antagonist activity.
  • Figure 3a is a concentration-response plot and 3b is a Schild Plot showing the melatonin antagonist activity of one of the preferred compounds of the present invention.
  • each R is independently selected from the group consisting of hydrogen, halogen, e.g. fluoro and chloro, and lower alkyl radicals, i.e., C to C4 alkyl radicals, e.g., methyl, ethyl, n-propyl and isopropyl;
  • R 1 is an aryl radical (including heteroaryl radicals) having from 4 to 14 carbon atoms, e.g., a phenyl, thienyl, furanyl, pyridyl or a naphthyl radical;
  • R 2 is selected from the group of hydrogen, lower alkyl, i.e., C ] _ to C alkyl radicals and phenyl radicals;
  • R 3 is selected from the group consisting of hydrogen, halogen, e.g.
  • R 4 is selected from the group consisting of hydrogen, halogen, e.g., fluoro and chloro, hydroxy, lower alkyl, i.e., C ] _ to C alkyl radicals, lower alkoxy, i.e., C ⁇ and C 4 alkoxy and phenoxy radicals
  • R 5 is selected from the group consisting of hydrogen, halogen, e.g., fluoro and chloro, hydroxy, lower alkyl, i.e., Ci to C 4 alkyl, lower alkoxy, i.e., C;L to C 4 alkoxy and phenoxy
  • R 6 is selected from the group consisting of hydrogen, halogen, e.g., fluoro and chloro, hydroxy, lower alkyl,
  • each R is a hydrogen radical
  • R2 is a lower alkyl radical
  • n is 2
  • x is 0.
  • Rl is selected from the group consisting of hydrocarbyl radicals such as phenyl and naphthyl, e.g. phenyl.
  • These compounds have melatonin agonist or antagonist activity and are useful in the treatment of jet lag, depression and other abnormalities which may be associated with circadian or seasonal rhythms and/or the amount of melatonin in the body and/or functions regulated by the hormone melatonin.
  • the longitu-dinal axis of the indole ring and the 2-aryl substituent are preferably polyplanar. That is, the longitudinal axis of the indole moiety (See A of Figure 1) is preferably oriented to lie in a different plane than Rl (See B of Figure 1) . To achieve this orientation Rl must be connected to the indole moiety by a methylene or poly- methylene bridge, i.e., m is an integer of 1 to 3 but not 0. It is also noted that since Rl is a "bulky" group such polyplanar orientation of the compounds of the present invention is energy-favored.
  • R 1 may be selected from the group consisting of phenyl, thienyl, furanyl, pyridyl, pyrrolyl and other aromatic and heteroaromatic radicals comprising single rings of five or six members.
  • radicals may also be substituted with various functional groups.
  • substituents may be selected from the group consisting of hydroxy, nitro, azido, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms.
  • R 1 may also represent polyphenyl radicals such asbiphenyl and similar polyaromatic and poly heteroaromatic radicals.
  • Rl may also be selected from the group consisting of organic radials having fused aromatic rings, that is, radicals comprising at least two rings that share a pair of carbon atoms or a carbon and nitrogen atom.
  • Rl comprises no more than 3 fused aromatic rings, and more preferably Rl comprises 2 fused aromatic rings.
  • radicals suitable for Rl include naphthyl, anthracyl, phenanthryl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzotriazolyl, triazolopyridinyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, benzopy-ranyl, quinolyl, phthalazinyl, purinyl, naphthothienyl, indolizinyl, quinlizinyl, naphthyridinyl, quinoxalinyl, guinazolinyl, cinnolinyl, etc.
  • radicals may also be substituted with various functional groups.
  • substituents may be selected from the group consisting of hyroxy, nitro, azido, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms.
  • a preferred embodiment of the present invention comprises a method of treating any disorder in which it is therapeutic to mimic or inhibit melatonin function or influence circadian rhythms by administering a thera- Chamberically effective amount of one or more of the compounds of the present invention to a patient suffering from such disorder.
  • Another preferred embodiment of the present invention comprises a method of treating chronobiological disorders, e.g., seasonal affective disorders (SAD), sleep disorders, and symptoms such as drowsiness and fatigue that are associated with disturbances in sleep/wake cycles (e.g., jet lag, workers on night shifts, etc.) by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from one or more of such chrono-biological disorders.
  • SAD seasonal affective disorders
  • sleep disorders e.g., sleep disorders, and symptoms such as drowsiness and fatigue that are associated with disturbances in sleep/wake cycles (e.g., jet lag, workers on night shifts, etc.)
  • Another preferred embodiment of the present invention comprises a method of treating various psychiatric disorders related to altered melatonin function or influenced by melatonin and circadian rhythms, e.g., affective disorders (mania and depression) , alcoholism, and stress by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from one or more of such psychiatric disorders.
  • various psychiatric disorders related to altered melatonin function or influenced by melatonin and circadian rhythms e.g., affective disorders (mania and depression) , alcoholism, and stress
  • administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from one or more of such psychiatric disorders.
  • Another preferred embodiment of the present invention comprises a method of treating or inducing various endocrine- related conditions attributed to altered melatonin function or influenced by melatonin and biological rhythms, particularly relating to regulation of reproductive maturation and function, e.g., idiopathic delayed pubert , premature labor, and antifertility, by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from or desiring to induce one or more of such endocrine related conditions.
  • the melatonin agonist compounds of the invention can be used to treat or prevent glaucoma by lowering the intraoccular pressure and to manipulate body weight by administering an effective amount of one or more of the melatonin agonist compounds herein.
  • a preferred embodiment of the present invention uses the melatonin agonists herein to manipulate the breeding cycles in animals by administering to such animal an effective amount of one or more of the compounds of the present invention.
  • a pharmacologically effective daily dose can be from 0.01 mg/kg to 100 mg/kg per day, and preferably from 0.1 mg/kg to 25 mg/kg per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, metabolism, age and other factors which influence response to the drug.
  • a particularly preferred dose is 1.0 mg/kg per day.
  • compositions in dosage unit form which comprise from about 2 mg. to 500 mg. of a compound of the above formula.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agent, for example starch, gelatine, or acacia; and lubricating agents, for example magnesium stearate, stearic acids, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract. Thereby a sustained action over a longer period can be provided.
  • Formulations for oral use can also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate, or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medkiu, for example arachis oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate, or kaolin
  • an oil medkiu for example arachis oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents can be a naturally- occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example of polyoxethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxy-cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbit
  • the said aqueous suspensions can also contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, can also be present.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • compositions of the present invention also include compositions for transdermal and/or intranasal administration.
  • the compounds of the present invention can be compounded with a penetration- enhancing agent such as l-n-dodecylazacyclopentan-2-one or the other penetration-enhancing agents disclosed in U.S. Patent Nos. 3,991,203 and 4,122,170 which are hereby incorporated by reference to describe penetration- enhancing agents which can be included in the transdermal or intranasal compositions of this invention.
  • compositions can be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient.
  • the dosage unit form will generally contain between about 1 mg. and about 100 mg. of the active ingredient of the formula stated above.
  • compositions of this invention can be administered orally or parenterally.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or fusion techniques.
  • Example 1 had no significant direct effects on either spontaneous or stimulated dopamine release when tested at concentrations of 0.1-10 ⁇ M. (As shown in the figure, the compound by itself did not modify the control ratio S 2 /S ⁇ .) The presence of increasing concentrations of melatonin (IpM-lOOnM) in S 2 did progressively decrease the S /S 1 ratio. The concentration of melatonin which inhibited release by 50% (IC 50 ) was 0.04 riM.
  • ⁇ he affinity constant (KB) for antagonists can be estimated from the Schild plot shown in Figure 3b (Arunlakshana and Shild, 1959, Br. J. Pharmacol. 14:48-58) ; and in the case of this compound, the estimated KB was found to be 20 nM.
  • the melatonin receptor assay described above was used to test compounds 1-5 for activity.
  • the compounds did not inhibit 3 H-dopamine release from rabbit retina when present alone during the S 2 period of electrical stimulation.
  • all of the compounds significantly antagonized the ability of 0.1 nM melatonin to inhibit 3 H-dopamine release as shown in the following Table: Table

Landscapes

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

Abstract

Les composés décrits sont représentés par la formule générale: (I), où R1 représente un radical aryle comportant 4 à 14 atomes de carbone, R2 est choisi dans le groupe composé d'un hydrogène, d'un alkyle inférieur et de radicaux de phényle; A représente O, S ou N; m est égal à un nombre compris entre 1 et 3; n est égal à un nombre compris entre 1 et 3; x est égal à 0 ou à 1 et y est égal à 1 lorsque A représente O ou S, et à 2 lorsque A représente N. L'utilisation de ces composés comme substances antagonistes de la mélatonine et leur préparation sont également décrites.
EP19880907911 1987-08-17 1988-05-20 Melatonin analogues Ceased EP0375726A4 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8606287A 1987-08-17 1987-08-17
US8629087A 1987-08-17 1987-08-17
US86062 1987-08-17
US86290 1993-07-01

Publications (2)

Publication Number Publication Date
EP0375726A1 true EP0375726A1 (fr) 1990-07-04
EP0375726A4 EP0375726A4 (en) 1991-01-30

Family

ID=26774333

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19880907911 Ceased EP0375726A4 (en) 1987-08-17 1988-05-20 Melatonin analogues

Country Status (7)

Country Link
EP (1) EP0375726A4 (fr)
KR (1) KR910006124B1 (fr)
AU (1) AU616907B2 (fr)
DK (1) DK42490A (fr)
FI (1) FI900801A0 (fr)
NO (1) NO173732C (fr)
WO (1) WO1989001472A1 (fr)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK108022C (da) * 1964-10-15 1967-07-31 Svend Anton Hansen Wexel Fremgangsmåde til hel eller delvis udskæring af rygbenet af opskårne slagtekroppe, navnlig grisekroppe, og anlæg til udførelse af denne fremgangsmåde.
BR9007382A (pt) * 1989-05-17 1992-04-28 Michael Cohen Composicoes e metodos de efetuar a contracepcao
US5071875A (en) * 1989-09-25 1991-12-10 Northwestern University Substituted 2-amidotetralins as melatonin agonists and antagonists
IT1251544B (it) * 1991-05-13 1995-05-17 Gabriele Biella Composizioni farmaceutiche attive nella terapia dei disturbi del sonno comprendenti melatonina o un suo derivato in associazione con un derivato benzodiazepinico
FR2680366B1 (fr) * 1991-08-13 1995-01-20 Adir Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent.
EP0608362A1 (fr) * 1991-10-18 1994-08-03 Alza Corporation Dispositif pour l'administration transdermique de melatonine
US5206377A (en) * 1991-12-05 1993-04-27 Whitby Research, Inc. Compounds useful as antiproliferative agents
IT1255199B (it) * 1992-07-01 1995-10-20 Franco Fraschini Farmaco sintetizzato analogo della melatonina particolarmente efficacenelle patologie che interferiscono con i ritmi circadiani
US5300481A (en) * 1993-05-05 1994-04-05 The Regents Of The University Of California Methods for controlling flowering in plants
US5654325A (en) * 1993-11-18 1997-08-05 Eli Lilly And Company Melatonin derivatives for use in treating sleep disorders
US6180657B1 (en) 1993-11-18 2001-01-30 Eli Lilly And Company Melatonin derivatives for use in treating desynchronization disorders
FR2713636B1 (fr) * 1993-12-07 1996-01-05 Adir Nouveaux dérivés naphtaléniques, leur procédé de préparation, et les compositions pharmaceutiques qui les contiennent.
US5403851A (en) * 1994-04-05 1995-04-04 Interneuron Pharmaceuticals, Inc. Substituted tryptamines, phenalkylamines and related compounds
US5763471A (en) * 1994-04-07 1998-06-09 Cemaf Melatoninergic agonist spiro indolepyrrolidine! derivatives, process for their preparation and their use as medicinal products
FR2724170B1 (fr) * 1994-09-02 1997-05-30 Cemaf Nouveaux derives de spiro(indole-pyrrolidine) agonistes de la melatonine, leur procede de preparation et leur utilisation a titre de medicament
FR2718445B1 (fr) * 1994-04-07 1996-06-28 Cemaf Nouveaux dérivés de spiro [indole-pyrrolidine] agonistes de la mélatonine, leur procédé de préparation et leur utilisation à titre de médicament.
ES2172415B2 (es) * 2000-07-28 2003-11-16 Univ Madrid Complutense Tratamiento del glaucoma y la hipertension ocular por medio de un analogo de la melatonina.
EP1307191A2 (fr) * 2000-07-28 2003-05-07 Inspire Pharmaceuticals, Inc. Utilisation des derives d'indole pour la preparation d'un medicament pour reduire la pression intraocculaire
WO2002072145A1 (fr) 2001-03-14 2002-09-19 Ono Pharmaceutical Co., Ltd. Remedes antidepresseurs contenant un antagoniste ep1 en tant que principe actif
FR2874611B1 (fr) * 2004-08-31 2006-11-17 Servier Lab Nouveaux derives d'imidazopyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP2350088A1 (fr) 2008-07-30 2011-08-03 Ferrer Internacional, S.A. Composés de la 1,6-dihydro-2h-3-oxa-6-aza-as-indacene
KR101534523B1 (ko) * 2013-04-30 2015-07-09 경희대학교 산학협력단 1,2,3,4-테트라히드로-6-메톡시-1-옥소-베타-카르볼린을 포함하는 피부 미백용 화장료 조성물
FR3065225B1 (fr) 2017-04-12 2024-04-05 Patrick Choay Sas Adjuvants depourvus de cytokines pour milieux de culture cellulaire, notamment pour fecondation in vitro, ou pour la culture de follicules, cellules germinales males ou embryons

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US3370063A (en) * 1964-10-05 1968-02-20 Mcneilab Inc Substituted dimethoxy indoles and method of making the same
US3915990A (en) * 1973-03-13 1975-10-28 Nelson Res & Dev Tryptamines
US4087444A (en) * 1976-09-08 1978-05-02 Eli Lilly And Company Amides as ovulation inhibitors

Non-Patent Citations (2)

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Title
No further relevant documents have been disclosed. *
See also references of WO8901472A1 *

Also Published As

Publication number Publication date
AU2309788A (en) 1989-03-09
AU616907B2 (en) 1991-11-14
DK42490D0 (da) 1990-02-16
NO900790L (no) 1990-03-26
NO173732B (no) 1993-10-18
FI900801A7 (fi) 1990-02-16
WO1989001472A1 (fr) 1989-02-23
FI900801A0 (fi) 1990-02-16
KR910006124B1 (ko) 1991-08-13
DK42490A (da) 1990-04-17
KR890701558A (ko) 1989-12-20
NO900790D0 (no) 1990-02-19
EP0375726A4 (en) 1991-01-30
NO173732C (no) 1994-01-26

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