WO1989010741A1 - 2,3-dihydro-1h-phenalen-2-amines anxiolytiques/anti-depresseurs - Google Patents

2,3-dihydro-1h-phenalen-2-amines anxiolytiques/anti-depresseurs Download PDF

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Publication number
WO1989010741A1
WO1989010741A1 PCT/US1989/001208 US8901208W WO8910741A1 WO 1989010741 A1 WO1989010741 A1 WO 1989010741A1 US 8901208 W US8901208 W US 8901208W WO 8910741 A1 WO8910741 A1 WO 8910741A1
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WIPO (PCT)
Prior art keywords
dihydro
phenalen
compounds
compound
test
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Application number
PCT/US1989/001208
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English (en)
Inventor
Montford F. Piercey
Andrew H. Tang
Robert A. Lahti
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The Upjohn Company
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Publication date
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Priority to KR1019900700028A priority Critical patent/KR900701260A/ko
Publication of WO1989010741A1 publication Critical patent/WO1989010741A1/fr

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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • This invention relates to a new use of certain 2,3-dihydro-lH- phenalen-2-amine derivative as drugs to treat abnormal or unusual symptoms of anxiety, depression or mixed anxiety-depression in a warm-blooded animal patient, including a human exhibiting those symptoms. More particularly this invention provides a new use, method or process for using any of a small group of defined 3,4- dihydro-2-alkylamino-phenalenes or 4- or 5-ol derivatives thereof, or a pharmacologically and pharmaceutically acceptable salt thereof as a drug to treat the symptoms of such anxiety, depression or mixed anxiety/depression condition in such patient.
  • U.S. Patent No. 4,564,698 discloses a class of hexahydro tricyclic phenalene amine derivative compounds having one aromatic ring which compounds are said to exhibit a stimulating effect on the dopamine receptors and thus be useful as drugs to treat heart infarction for reducing blood pressure for their anti-arrhyth- mic activity for Parkinson's disease and CNS disorders of depression. That '698 patent does not disclose the compounds which are the subject of this invention.
  • J. Szmuszkovicz et al disclose a class of 3,4-dihydro-lH-phenalen-2-amine compounds (having two aromatic rings) and alcohol and other derivatives thereof, as anti-psychotic drugs. That defined class of compounds include the compounds that have been found to have further additional CNS drug uses according to this invention.
  • this invention provides a use, method or process for treating a warm-blooded animal patient exhibiting abnormal or unusual anxiety, depression or mixed anxiety/depression symptoms which comprises administering to such patient a compound of the Formula I
  • R 2 is c l to C3-alkyl; 3 is hydrogen or R3 is hydroxy (-0H) in the 4- or 5-position, or a pharmaceutically acceptable salt thereof.
  • examples of such compounds include: 2,3-dihydro-N-methyl-lH-phenalen-2-amine, 2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine, 2,3-dihydro-N-ethyl-lH-phenalen-2-amine, 2,3-dihydro-N,N-diethyl-lH-phenalen-2-amine,
  • anxiolytic anti- depressant or mixed anxiolytic/anti-depressant drugs when give by any of the known routes of administration, e.g., by intravenous, intramuscular, subcutaneous or oral administration procedures in dose ranges of from about 0.5 mg. to about 300 mg. from one to four times per day, depending upon the patient condition being treated, the patient's body weight, the particular drug compound and route of administration selected, and other factors of concern to the pa- tient's physician.
  • (+) and (-) 2,3-Dihydro-2-(N,N-di-n-propylamino) -lH-phenalen-5- ol as its hydrobro ide salt are described in Examples 11 to 14, 16 and 27, and
  • acid addition salts of these compounds include the hydrohalide salts such as the hydrochloride, hydrobromide, hydro- fluoride and hydroiodide, the sulfate and bisulfate, various phos- phorous acid salts, the methanesulfonate, the p-toluenesulfonate, the benzoate, the acetate, and other alkanoic acid salts, as well as the salts of various dicarboxylic and tricarboxylic acids such as maleic, succinic, fumaric, malic, oxalic, itaconic acids and the like.
  • hydrohalide salts such as the hydrochloride, hydrobromide, hydro- fluoride and hydroiodide
  • the sulfate and bisulfate various phos- phorous acid salts
  • methanesulfonate the p-toluenesulfonate
  • benzoate the acetate
  • the Formula I compound and its acid addition salt in their crystalline state may sometime be isolated as solvates, i.e., with a discrete quantity of water of other solvent such as ethyl acetate, ethanol, and the like, associated physically and thus removable without effective alteration of the active chemical drug entity per se.
  • the Formula I compounds, used according to this invention can be resolved into their respective d- and 1-optical isomers by methods known in the art.
  • the optical resolution can be done by at least two different routes.
  • the resolving agents by either route are any of the known resolving agents such as optically active dibenzoyltartaric acid, camphorsul- fonic acid, bis-o-toluoyltartaric acid, tartaric acid, and diacetyl tartaric acid which are commercially available and which are commonly used for resolution of amines (bases), as for example in Organic Synthesis, Coll. Vol. V, page 932 (1973), resolution of R-(+) and S-
  • the compounds used according to the process of this invention are expected to demonstrate in the clinic, anxiolytic properties similar to those of the now known buspirone (BUSPAR®, Bristol Myers) and gepirone compounds.
  • 2,3-Dihydro-N-methyl-lH-phenalen-2-amine, and 2,3-Dihydro- ,N-dimethyl-lH-phenalen-2-amine, tested as their hydrochloride salts, are both DA antagonists in addition to being 5HT1A agonists, while another compound
  • 2,3-Dihydro-2-(N,N-di-n-propylamino)-lH-phenalen-4-ol, tested as its hydrobomide salt was found to be a weak DA agonist, indicating that these compounds are expected to be useful as anxi- olytic, anti-depressant and/or mixed anxiolytic-anti-depressant drugs.
  • mice are shocked each time the animal jumps from one plate to another.
  • Anti-anxiety drugs such as diazepam but not buspirone increase the amount of punished response (i.e., the number of jumps, because of the drug's anti-conflict effects).
  • This example describes the test procedure and provides compar ⁇ ative test data for the effects of 5HT1A agonist compounds on 8- hydroxy-dpropylaminotetratin (8-OH-PAT) binding to 5HT1A receptors in rat hippocampus-area brain homogenates.
  • rat brain tissues were homogenized using a Poly- tron® laboratory blender at setting number 7 for 30 seconds, followed by a centrifugation for 10 minutes and a Polytron® blender treatment of the resuspension at a dilution of 1-400 in 50 millimoles of TRIS ® brand buffer, pH 7.4.
  • An incubation mixture consisted of 1.0 ml. of the homogenate suspension and 0.1 ml. of - -ligand - -DPAT, specific activity 85 Ci/millin-ole), and 0.1 ml. of the test drug solution or suspension on the vehicle alone. Incubations were for 30 minutes at 30 ⁇ C. Samples were filtered using a cell harvester set up. Samples were run in duplicate and at least four concentrations of test drug compound were used to obtain a dose sufficient to block 50% of DPAT binding (IC50) . The IC5 Q figures were calculated using a standard statistical method.
  • the test result effects of three known 5HT1A agonist compounds on 8-OH-DPAT binding in the above rat hippocampus homogenate test is set forth in Table 1.
  • the femoral artery and vein were cannulated for blood pressure measurement and drug administration, respectively.
  • Body temperature was maintained at 37°C. using an isothermal pad. The animal's head was held in a stereotopic device and a small burr hole was made in the cranium.
  • Extracellular action potentials were recorded with a glass microelectrode (tip size, ⁇ 1 micrometer) filled with pontamine sky blue dye in 2M sodium chloride in water solution.
  • Dopaminergic neurons were identified by their long duration action potential (>2.5 milliseconds) and firing pattern ( ⁇ 12 spikes/- second) according to the method of Bunney and Aghajanian (Bunney, B.S. and Aghajanian, G.K. , "Antipsychotic Drugs and Central dopamin ⁇ ergic Neurons: A Model for Predicting Therapeutic Efficacy and Incidence of Extrapyramidal Side Effects" in Predictability in Psvchopharmacologv: Preclinical and Clinical Correlates. (A. Subil- vosky et al. , Editors) Raven Press, NY (1975), pp. 225-245).
  • the recording electrode was hydraulically lowered into the substantia nigra pars compacta (SNPC) area (P 2.8-3.2 mm, L2.0-2.2) according to the coordinates of Pelligrino et al [Pelligrino, L. J. et al, A Stereotoxic Atlas of the Brain. 2nd Edition (1979) , Plenum Press Publishers, N.Y. , NY].
  • Serotonergic neurons were identified by a biphasic large positive-negative action potential with slow and regular firing rates (approximately 0.8 to 2.5 spikes/second) according to the criteria of Aghajanian et al [Aghajanian, G.K. et al, "Action of Psychotogenic Drugs ... Neurons" in J.
  • Test results data for several compound in this above procedure are set forth in Table 2.
  • the data numbers in the 5HT neuron test estimate the dosage (in microgram/kg. of body weight, i.v.) of the test compound drug required to depress the firing rates of the neurons by 50% from a vehicle control test firing rate.
  • the data numbers in the DA neuron test indicate the dosage (in micro rams/kg. of body weight, i.v.) required to reverse amphetamine depression (DA antagonism) by 50% or to depress DA neuron firing rates (DA agonism) by 50%,
  • test animals male CF-2 or Charles River form mice, 18 to 29 g. each, were divided into eight pairs of mice per dose.
  • mice were housed two per cage with a familiar partner, i.e., a mouse from the same home cage.
  • mice from different home cages were placed together for the first time into a tiny plastic cage (7 inch x 5.5 inch; 17.78 cm x 12.4 cm.) with fresh wood litter on the floor and with a cardboard lid. This condition forces the animals into continuous proximity and presumably heightens the stress of the situation. Face-to-face interaction of the mice was measured by visual observation for three minutes. Very rarely, interaction was excluded if the mice were passively touching (for example, sleeping) or if they were vocalizing (as during fighting).
  • mice This test is believed to be sensitive prediction for anxiolytic activity of classical benzodiazepine anxiolytics and 5HT1A agonists such as buspirone and 8-0HDPAT.
  • Table 3 summarizes the effects of the test drug compounds as 5HT1A agonists on social interactions of the mice, in terms of the dosages of the test drug compound in mg. of drug/kg. of mouse body weight, s.c, which caused significant (active) increases or non ⁇ significant effects in face-to-face interactions between the mice in a novel closed but well lit environment.
  • mice are injected intraperitoneally (i.p.) with test compound 30 minutes before challenge with yohimbine at 20 mg./kg. i.p.
  • Each group of mice is placed in a 1 liter glass beaker with wood shavings on bottom, a wire mesh cover and side wrappings of white paper.
  • a compound is con ⁇ sidered active if at least three of the mice are dead after two hours aggregation.
  • the ED50 of the test compound is the dose required to produce death in two of the four animals using standard quantal statistics (Spearman and Karber, Finney, D.J., Statistical Method in Biological Assay, Hafner Publ. Co., New York, NY, page 524, 1952).
  • mice For antagonism of oxotremorine-hypothermia, a group of mice are intraperitoneally injected with test compound 30 minutes prior to 1 mg./kg. s.c. oxotremorine hydrochloride. Animals are put into a 19°C. temperature environment for 30 minutes. Oxotremorine anta ⁇ gonism is recorded for each animal with an i.p. temperature more than 4°F. above the mean i.p. temperature of a control group injected with oxotremorine alone.
  • the ED50 is the dose required to get oxotre ⁇ morine antagonism in two of four animals using Spearman-Karber statistics (Spearman and Karber, Finney, D.J., Statistical Method in Biological Assay, Hafner Publ. Co., New York, NY, page 524, 1952).
  • Spearman-Karber statistics Spearman and Karber, Finney, D.J., Statistical Method in Biological Assay, Hafner Publ. Co., New York, NY, page 524, 1952.
  • the data for our compounds are as follows:
  • compound (c) was not active on these assays at a dose of 50 mg./kg., it is also expected to have clinically useful anti- depressant activity clinically (Csanalosi, I. et al., J. of Clinical Psychopharmacology, 7, N, 1, pp. 31-33, "Gepirone ... A Pilot Study”) .
  • dosage unit form refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined quantity of the essential active ingredient compound of this inven ⁇ tion calculated to produce the desired effect in combination with the required pharmaceutical means which adapt the said ingredient for systemic administration.
  • the specification for the novel dosage unit forms of this invention are dictated by and directly dependent on the physical characteristics of the essential active ingredient and the particular effect to be achieved in view of the limitations inherent in the art of compounding such an essential active material for beneficial effects in humans and animals as disclosed in detail in this specification under exemplified embodiments, these being features of the present invention.
  • suitable dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in suitable liquid vehicles, sterile preparations in suitable liquid vehicles for intramuscular and intravenous administration, suppositories, and sterile dry prepar ⁇ ations for the extemporaneous preparation of sterile injectable preparations in a suitable liquid vehicle.
  • Suitable solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected from the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like.
  • Capsules both hard and soft, are filled with composi ⁇ tions of the selected Formula I compound or salt thereof ingredients in combination with suitable diluents and excipients, for example, edible oils, talc, calcium carbonate and the like and also calcium stearate.
  • suitable diluents and excipients for example, edible oils, talc, calcium carbonate and the like and also calcium stearate.
  • Liquid preparations for oral administration are prepared in water or aqueous vehicles which advantageously contain suspending agents, for example, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like.
  • the injectable formulation In the case of injectable forms, the injectable formulation must be sterile and must be fluid to the extent that easy syringeability exists.
  • Such preparations must be stable under the conditions of manufacture and storage, and ordi ⁇ narily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like.
  • preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like.
  • osmotically active agents for example, sugars or sodium chloride in isotonic concentrations.
  • Carriers and vehicles include vegetable oils, ethanol, polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like.
  • any solid preparations for subsequent extemporaneous preparation of sterile injectable prepar ⁇ ations are sterilized, preferably by exposure to a sterilizing gas, for example, ethylene oxide.
  • a sterilizing gas for example, ethylene oxide.
  • the aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration.
  • a daily dose of 0.5 to 300 mg. Is indicated, preferentially 20 to 200 mg. ; In units of one to four subdivided doses per day, and the exact amount is adjusted based on the weight, age and condition of the patient.
  • the active ingredients of this invention can also be compounded in combination with other ingredients.
  • the amount of such other active ingredients is to be determined with reference to the usual dosage of each such ingredient.
  • these active compounds can be combined with hypotensive agents such as ⁇ -methyldopa (100-250 mg.); with diuretics such as hydrochlorothiazide (10-50 mg.); tranquilizers such as meprobamate (200-400 g.), diazepam (2-10 mg.), muscle relaxants such as carisoprodol (200-400 mg.).

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Abstract

On a découvert que certains composés dérivés de 2,3-dihydro-1H-phenalen-2-amine et de 4-ol et 5-ol, par exemple, 2,3-dihydro-N-methyl-1H-phenalen-2-amine, 2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine, 2,3-dihydro-2-(N,N-di-propylamino)-1H-phenalen-4-ol et 2,3-dihydro-2-(N,N-dipropylamino)-1H-phenalen-5-ol, ou leurs sels pharmaceutiquement acceptables, sont utiles comme médicaments pour traiter des symptomes anormaux ou inhabituels d'anxiété et/ou de dépression chez un patient animal à sang chaud.
PCT/US1989/001208 1988-05-09 1989-03-28 2,3-dihydro-1h-phenalen-2-amines anxiolytiques/anti-depresseurs WO1989010741A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019900700028A KR900701260A (ko) 1988-05-09 1989-03-28 2,3-디하이드로-1h-페날렌-2-아민 불안해소/우울증 방지제

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US191,316 1980-09-26
US19131688A 1988-05-09 1988-05-09

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WO1989010741A1 true WO1989010741A1 (fr) 1989-11-16

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JP2955358B2 (ja) * 1989-06-09 1999-10-04 ファルマシア・アンド・アップジョン・カンパニー 中枢神経系活性を有する複素環系アミン

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0041293A1 (fr) * 1980-05-30 1981-12-09 Akzo N.V. Amines tricycliques biologiquement actives, procédés pour leur préparation et compositions pharmaceutiques les contenant
WO1987004153A1 (fr) * 1985-12-31 1987-07-16 The Upjohn Company Composes de 2,3-dihydro-1h-phenalene-2-amine utiles comme medicaments anti-psychotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0041293A1 (fr) * 1980-05-30 1981-12-09 Akzo N.V. Amines tricycliques biologiquement actives, procédés pour leur préparation et compositions pharmaceutiques les contenant
WO1987004153A1 (fr) * 1985-12-31 1987-07-16 The Upjohn Company Composes de 2,3-dihydro-1h-phenalene-2-amine utiles comme medicaments anti-psychotiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chimie-Thérapeutique, vol. 6, no. 3, May-June 1971, R. Violland et al.: "VII. Psycho-tropes potentiels. Synthèse et activité pharmacologique d'amino-2 tétralines apparentées à divers psychotomimétiques", pages 196-202 *
Drug Development Research, vol. 17, no. 1, 1989, Alan R. Liss, Inc., P.F. VonVoightlander et al.: "Dopamine receptor agonist activity of U-66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties", pages 71-81 *

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KR900701260A (ko) 1990-12-01

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