Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/38—Nitrogen atoms

Definitions

• R is a member selected from the group consisting of H and CH and nontoxic pharmacologically acceptable acid addition salts thereof.
• the compound may be combined with acceptable pharmaceutical vehicles to form compositions for administration.
• This invention relates to a novel process for producing an anti-depressant effect in an organism. More particularly, this invention relates to a process for producing an antidepressant effect in a warm blooded animal by the administration to such animal of an anti-depressant effective amount of a compound of the formula:
• the invention also has reference to a new composition comprising the compound and a pharmaceutical vehicle for use in alleviating depressant states.
• compositions are effective in producing anti-depressant activity, each is subject to certain decided disadvantages.
• hepatic toxicity including jaundice, has been reported in association with the use of monoamine oxidase inhibitors, atropine-like side effects are frequently observed with the tricyclic compounds, and excessive central nervous system stimulation is a main limitation for the amphetamines.
• Depression has been said to vary as much as pain and like pain is one of mans most common ailments. Unfortunately, in spite of many attempts to categorize depressive illness, no satisfactory classification has yet been devised. With such difiiculty in identification of cause, site and mode of action, an anti-depressant drug is similarly difficult to identify.
• Another object of this invention is to provide a process for producing an anti-depressant effect using a new active ingredient that does not display the disadvantages associated with the known anti-depressant compositions.
• a further object of this invention is to provide a novel medication comprising the active ingredient and a pharmaceutical vehicle therefor.
• R is a member selected from the group consisting of H and CH or nontoxic pharmacologically acceptable acid addition salts thereof.
• the invention also embodies a novel composition of a therapeutically effective quantity of said compound or nontoxic pharmacologically acceptable additional salts thereof and a pharmaceutical vehicle therefor.
• the active ingredient of the medication used for the novel process of the invention is selected from the group having the structural formula:
• the active ingredient used in the novel process of this invention may be in the form of the free base and is preferably in the form of a nontoxic pharmacologically acceptable acid addition salt thereof.
• These acid addition salts may be prepared from mineral acids such as halogen acids or sulfuric acid, or organic acids such as citric acid, maleic acid and other similar acids. Additional examples of the preparation of these acids will be presented in the subsequent detailed examples.
• Medications may be prepared for use in the novel process of this invention including, as an active ingredient, at least one of the compounds of Formula I. These medications may be conveniently prepared by combining the active ingredient with a pharmaceutical vehicle having components selected from the fillers, carriers, extenders, excipients and the like, generally used in pharmaceutical formulations. Medications may be prepared in the solid state as tablets or capsules or in the liquid state as suspensions or solutions. Similar dosage forms suitable for oral, parenteral, intramuscular, subcutaneous, intravenous or other convenient routes of administration may also be provided.
• the pharmaceutical vehicle may also include common diluents or tableting adjuncts such as cellulose powder, corn starch, magnesium stearate, calcium sulfate, talc and such, used according to accepted pharmaceutical manufacturing practices.
• Unit dosages (a specific weight, such as mg. or g.) of active ingredient in a medication may be varied so that an adequate amount is present to provide the desired therapeutic dose which produces a particular therapeutic effect Without untoward side effects.
• Unit dosages of between about 1 and mg. per capsule are beneficially used for oral administration of the medication.
• Vials containing a sterile preparation for parenteral administration are beneficially prepared with the unit dosage of about 10 mg. per vial.
• the therapeutic dose administered using the unit dosages described above, will depend upon the depressive state of the patient. Depression tends to be cyclic in nature and varying in severity. Therefore, the therapeutic dose must be individualized according to the need of each patient. Beneficially, initial daily doses ranging between about 3 and 60 mg. per day are considered safe and readily indicative of a required therapeutic dose.
• the mixture was stirred and cooled, during which 300 ml. of water containing 100 ml. of concentrated hydrochloric acid was added. A small amount of insoluble solid material was removed by filtration and washed with ether and water. The aqueous portion of the filtrate and washings was separated and clarified with charcoal. An excess of a saturated aqueous solution of sodium hydroxide was added to the filtrate. The free base was collected, washed with water and dried at 50 C. The crude product (104.5 g. 95%) melted at 111 C.
• the crude free base was dissolved in hot ethanol, and the solution was clarified with charcoal.
• the filtrate and washings were concentrated by evaporation and diluted with hot water to incipient cloudiness.
• the crystals which formed on cooling and scratching were collected, washed with Water and dried at 100 C.
• the cream-colored free base (102 g., 90%) melted at 111112 C.
• EXAMPLE 5 The anti-depressant activity of the active ingredient of the medication used in the novel process of this invention was assessed by its ability to antagonize the ptotic effect of reserpine in mice. The test was performed substantially as described by Chen and Bohner: J. Pharmac. Esp. Ther. 131: 179, 1961. A group of mice were randomly selected from a larger group weighing between about 22 and 35 grams. Each animal received intraperitoneally 4 mg./kg. of reserpine in a 5% ascorbic acid solution. Three hours after the reserpine injection aqueous solutions including TABLE 1 Dose, Anti-resperine Active ingredient ing/kg. activity 3.1 Potent. 1-(2-quin0ly1)piperzine maleate 10. Do.
• EXAMPLE 6 Toxicity of the active ingredients used in this invention was determined by administering each active ingredient in graduated doses orally to separate groups of mice and rats and observing the animals reactions. A control compound, imipramine, was also administered according to the same procedure. The observed results of the toxicity test are presented in the following Table 2 in which active ingredient 1-(2-quino1yl)piperazine maleate is designated A and active ingredient 2-(4-methyl-1-piperazinyl)quinoline maleate is designated B.
• the motor function of the animals was assessed with a rotarod test.
• rats were trained to walk for periods of 100 seconds on a wooden rod (2 inches in diameter) rotating at 13 r.p.m.
• the active ingredients used in this invention were administered as set forth in Example 7 except that larger doses were utilized until motor impairment was observed.
• Imipramine was also administered in the same manner as a control drug.
• the observed results of the rotarod test are set forth in the following Table 3.
• the specificity of the anti-muricidal effect was measured by calculating the ratio of the rotarod ED to the anti-muricide ED A ratio significantly greater than 1 indicates a specific anti-muricidal effect at nondebilitating doses.
• the active ingredients were observed as highly specific anti-muricidal agents as the ratio of rotarod ED to anti-muricidal ED was substantially in excess of 1, i.e., 6.2 and 13.5.
• the control drug imipramine, a ratio of about 1.5 was determined.
• EXAMPLE 7 The potential anti-depressant activity of the active ingredients used in the invention was also assessed by ob- 50 serving its effect upon the muricide tendency of killer rats. The procedure followed was substantially the same as that set forth by Horovitz et al., Int. J. Neuropharmacol. 5:405, 1966. According to this procedure the mouse killing blocking ability of the active ingredients was evaluated in a group of killer rats. Twenty five killing rats of both sexes were used to evaluate each of the active ingredients. At weekly intervals, the active ingredient was administered intraperitoneally in varying doses and muricide responses observed at 15 minute intervals after the injection. Imipramine was administered and observed in the same manner as a standard. The observed results of this example are set forth in Table 3.
• EXAMPLE 8 To determine if the action of the active ingredients of the invention was anti-depressant in nature or if there was in which R is H or CH or nontoxic pharmacologically acceptable acid addition salts thereof.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

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Family Applications (1)

Country Status (5)

Families Citing this family (3)

• 1969
  • 1969-02-14 US US799508A patent/US3629418A/en not_active Expired - Lifetime
• 1970
  • 1970-02-11 CH CH197870A patent/CH530408A/de not_active IP Right Cessation
  • 1970-02-12 ES ES376507A patent/ES376507A1/es not_active Expired
  • 1970-02-13 BR BR216716/70A patent/BR7016716D0/pt unknown
  • 1970-02-13 DE DE19702006638 patent/DE2006638A1/de active Pending

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