EP0564520A1 - Utilisation de certains derives de glutarimide dans le traitement de la depression et des etats maniaques - Google Patents

Utilisation de certains derives de glutarimide dans le traitement de la depression et des etats maniaques

Info

Publication number
EP0564520A1
EP0564520A1 EP92901755A EP92901755A EP0564520A1 EP 0564520 A1 EP0564520 A1 EP 0564520A1 EP 92901755 A EP92901755 A EP 92901755A EP 92901755 A EP92901755 A EP 92901755A EP 0564520 A1 EP0564520 A1 EP 0564520A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
azaspiro
dione
decane
moiety
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.)
Withdrawn
Application number
EP92901755A
Other languages
German (de)
English (en)
Inventor
Marcel 21 Rue Alfred-Kastler Hibert
Maurice W. Gittos
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.)
Aventis Pharmaceuticals Inc
Original Assignee
Merrell Dow Pharmaceuticals 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 Merrell Dow Pharmaceuticals Inc filed Critical Merrell Dow Pharmaceuticals Inc
Publication of EP0564520A1 publication Critical patent/EP0564520A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • This invention relates to the manufacture of certain glutarimide derivatives for their use as medicaments in the treatment of depression and mania.
  • this invention relates to the use in the manufacture of a medicament for treating depression and mania utilizing a compound of the formula
  • R ⁇ is hydrogen, C 1 _ 4 alkyl, C 1 _ 4 alkoxy, halogeno, nitro, hydroxy, S0 3 H, S0 2 NK 2 , or S0 2 NH 2 -CH 2 -,
  • R 2 is hydrogen, C 1 _ 4 -alkyl, C ⁇ _ 4 alkoxy, halogeno, nitro or hydroxy, and
  • R and R 2 taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2- or 3,4-positions,R 3 is H or C 1 _ 4 alkyl,
  • R_ and R 5 are H, C 1-4 alkyl or, when taken together with the carbon atom to which they are attached, form a C 3 _ 6 cycloalkyl moiety, n is an integer of 2 to 5 inclusive, A and B independently are oxygen, sulfur or NR 3 , their geometric, stereo- or optical isomers and the mixtures thereof, and the pharmaceutically acceptable acid addition salts thereof.
  • the term "pharmaceutically acceptable acid addition salts” is intended to apply to any non-toxic organic or inorganic acid addition salts of the base compounds represented by Formula (1).
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium ⁇ tonohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, alonic, succinic, glutaric, fu aric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, p-hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic acids, and sulfonic acids such as methanesulfonic acid or 2-hydroxyethane- sulfonic acid.
  • Either the mono- or the di-acid salts can be formed, and such salts can exist in either a hydrated or a substantially anhydrous form.
  • the acid addition salts of these compounds are crystalline materials which are soluble in water and in various hydrophilic organic solvents. Additionally, in comparison to their free base forms, such salts generally demonstrate higher melting points and an increased chemical stability.
  • C 1 _ / . alkyl includes the straight and branched alkyl radicals having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and the like.
  • C 1 _ 4 alkoxy includes the straight and branched alkoxy radicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy and the like.
  • Halogeno includes chloro, bro o and fluoro.
  • the isomers contemplated include the position isomers, the stereoisomers as well as the enantiomeric isomers, and the mixtures thereof.
  • the individual isomers of the compounds of formula I may best be prepared by processes designed to enrich the production of the desired isomers. However, mixtures may be resolved or isolated according to conventional and standard procedures well known in the art, e.g. chromatographic separation, fractional crystallization, use of optically active acids, enzymatic resolution and the like.
  • the compounds of formula (1) contain a glutarimide moiety joined to the defined X moieties by a
  • n 2 o
  • glutarimide moiety has been depicted as an 8-azaspiro[4,5]decane-7,9-dione but also included are the corresponding 4,4-dimethyl-2,6- piperidinedione derivatives.
  • ⁇ -carbolinyl moiety of formula (1h) can also be named as [4- (l,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indol-2-yl] .
  • a preferred subclass of this invention consists of .those compounds of formula (1h) wherein the X moiety is an
  • R 1 -substituted-l,2,3,4-tetrahydro- ⁇ -carboline ring system.
  • Another preferred subclass of this invention relates to those compounds of formula (1f) wherein the X-moiety is a 2,3 dihydronaphtho[l,2-] [l,4]-dioxin-2-yl or 3-yl ring system.
  • Another preferred class of compounds of this invention relates to those compounds of formula (1a) wherein the X-moiety is terminally substituted by the 2,3-dihydro-l,4- benzodioxin-2-yl ring system.
  • the aromatic glutarimide derivatives of formula (1) can be prepared via a condensation of theappropriate nucleophilic a ine of formula (2) with an appropriate glutarimide substrate of formula (3) using processes and techniques analogously known in the art, such as that shown by the following reaction scheme.
  • Such a nucleophilic condensation is preferably conducted by reacting approximately equimolar amounts of the nucleophile (2) with the substrate (3), for a period of from about 1 hour to 24 hours depending upon the particular reactants employed.
  • the reaction temperature can range from about 25°C to 150°C.
  • the reaction is conducted at a temperature ranging from 60°Cto 150°C.
  • nucleophilic primary amines indicated by formula (2) are compounds which are either commercially available or which have been previouslydescribed in the literature. Generic teachings and the details and exemplifications for the preparation of the nucleophilic primary amines embraced by Formula (2) of this invention may readily be obtained from issued U.S. Patent 4,612,312 and U.S. Patent 4,748,182 issued May 31, 1988.
  • the compounds of formula (3) are essentially N-alkyl derivatives of glutarimide.
  • the leaving groups (L) for compounds of formula (3) can represent any group known to those skilled in the art, such as a tosylate (OTS) or a mesylate (OMS), an iodide, bromide or chloride, or hydroxyl group.
  • U.S. Patent 4,612,312 teaches that certain compounds of this invention have properties which are useful for the treatment of hypertension and for treating anxiety. It recently has been found that the compounds possess properties which also will render them useful in the treatment of affective disorders, i.e., the compounds will be useful in the pharmacological treatment of depression and mania.
  • the compounds of the prior art which have been found to be successful in the treatment of affective disorders have also been characterized as "mood elevators" and in recent years a plethora of the tricyclic-type of compounds have been found to be mood elevators having anti- depressant effects in endogenous and involutional depression.
  • Illustrative of such successful tricyclic compounds are amitriphyline, desipramine, imipramine, nortriptyline, opipranol, depepin and butriptyline.
  • many other tricyclic compounds are known but listing all such compounds is unnecessary here as they may be readily ascertained from standard works well known in the art. It is to the end-use application of these compounds to which the compounds of this invention will be useful.
  • the compounds of this invention are effective 5HT 1A agonists capable of exerting a pharmacological effect useful for the treatment of depression and mania in the general range of 0.005 to 10 mg/kg of patient body weight, but preferably in the range of 0.05 to 5 mg/kg of patient body weight per day.
  • the compounds of this invention can be administered either orally, subcutaneously, intravenously, intramuscularly, intraperitoneally or rectally.
  • the preferred route of administration is oral.
  • the amount of compound to be administered can be any effective amount, and will vary depending upon the patient, the mode of administration and the severity of the anxiety to be treated. Repetitive daily administration of the compounds may be desirable, and will vary depending upon the patient's condition and the mode of administration.
  • an anti-depressant effective amount of a formula (1) compound can range from 0.005 to 10 mg/kg of patient body weight per day, preferably from 0.05 to 5 mg/kg of patient body weight per day.
  • the preferred dose of the compounds of formula (1) is about 0.1 mg/kg of patient body weight per day.
  • Pharmaceutical compositions in unit dose form can contain from 1 to 50 mg of active ingredient and can be taken one or more times per day.
  • an anti-depressant effective amount of a formula (1) compound can range from 0.005 to 10 mg/kg of patient body weight per day, preferably from 0.05 to 5 mg/kg of patient body weight per day.
  • a parenteral composition in unit dose form can contain from 0.1 g to 10 mg of active ingredient and can be taken one or more times daily.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, solutions, suspensions or emulsions.
  • Solid dosage unit forms generally employed include capsules or tablets.
  • Capsules can be of the ordinary gelatin type which contain additional excipients such as surfactants, lubricants and inert fillers such as lactose, sucrose and cornstarch.
  • the compounds of formula (1) can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and lubricants such as stearic acid or magnesium stearate.
  • the compounds may be administered as injectable dosages of a solution or a suspension of the compound in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • Suitable diluents or carriers include sterile liquids such as water or oils, with or without the addition of surfactants or other pharmaceutically acceptable adjuvants.
  • sterile liquids such as water or oils
  • surfactants or other pharmaceutically acceptable adjuvants Illustrative of various oils that can be employed in the practice of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
  • ethanol and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention se rapporte à la fabrication de certains dérivés de glutarimide en vue de leur utilisation comme médicaments dans le traitement de la dépression et des états maniaques.
EP92901755A 1990-12-24 1991-12-02 Utilisation de certains derives de glutarimide dans le traitement de la depression et des etats maniaques Withdrawn EP0564520A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP90403757 1990-12-24
EP90403757 1990-12-24

Publications (1)

Publication Number Publication Date
EP0564520A1 true EP0564520A1 (fr) 1993-10-13

Family

ID=8205790

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92901755A Withdrawn EP0564520A1 (fr) 1990-12-24 1991-12-02 Utilisation de certains derives de glutarimide dans le traitement de la depression et des etats maniaques

Country Status (7)

Country Link
EP (1) EP0564520A1 (fr)
JP (1) JPH06504279A (fr)
KR (1) KR930702976A (fr)
AU (1) AU9134191A (fr)
CA (1) CA2097607A1 (fr)
HU (1) HU9301856D0 (fr)
WO (1) WO1992011011A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2552929C1 (ru) * 2013-11-14 2015-06-10 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Фармацевтическая композиция, содержащая производные глутаримидов, и их применение для лечения эозинофильных заболеваний

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
CA1244418A (fr) * 1984-07-30 1988-11-08 Marcel Hibert Glutarimide employe comme anxiolytique et antihypertenseur
DE3680123D1 (en) * 1985-01-23 1991-08-14 Glaxo Group Ltd Tetrahydrocarbazolonderivate.
US4748182A (en) * 1986-03-05 1988-05-31 Merrell Dow Pharmaceuticals Inc. Aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives and their use as anti-hypertensive and anxiolytic agents
US4788290A (en) * 1987-12-11 1988-11-29 American Home Products Corporation Serotonergic pyrazine derivatives
DE3831888A1 (de) * 1988-09-20 1990-03-29 Troponwerke Gmbh & Co Kg Arzneimittel zur behandlung von apoplexia cerebri
EP0375819A1 (fr) * 1988-12-20 1990-07-04 Merrell Dow Pharmaceuticals Inc. Dérivés de 1,7'-[imidazo-[1,2-a]pyridin]5'-(6'H)ones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9211011A1 *

Also Published As

Publication number Publication date
HU9301856D0 (en) 1993-09-28
WO1992011011A1 (fr) 1992-07-09
CA2097607A1 (fr) 1992-06-24
JPH06504279A (ja) 1994-05-19
AU9134191A (en) 1992-07-22
KR930702976A (ko) 1993-11-29

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