US3794726A - Inhibiting aggressive behavior with 1,2,3-benzotriazin-(3h)-one - Google Patents

Inhibiting aggressive behavior with 1,2,3-benzotriazin-(3h)-one Download PDF

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Publication number
US3794726A
US3794726A US00282311A US3794726DA US3794726A US 3794726 A US3794726 A US 3794726A US 00282311 A US00282311 A US 00282311A US 3794726D A US3794726D A US 3794726DA US 3794726 A US3794726 A US 3794726A
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compound
benzotriazin
activity
chlorpromazine
administered
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Z Ariyan
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Uniroyal Chemical Co Inc
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Uniroyal Inc
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Assigned to UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY reassignment UNIROYAL CHEMICAL COMPANY, INC., WORLD HEADQUARTERS, MIDDLEBURY, CT. 06749, A CORP. OF NEW JERSEY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NEW YORK CORP.
Assigned to UNIROYAL CHEMICAL COMPANY, INC. reassignment UNIROYAL CHEMICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNIROYAL, INC., A NJ CORP.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine

Definitions

  • This compound has been found to be highly selective for the abolition of aggressive behavior at doses which cause little or no signs or symptoms of central nervous system depression or toxicity.
  • Chlorpromazine is a strong central nervous system (CNS) depressant, both in normal and schizophrenic patients. Its most salient feature, however, is the ability to inhibit aggressive behavior in abusive and destructive schizophrenics. It has been the drug of choice for the treatment of so-called back-ward schizophrenics, and is now used in out-patient therapy in cases of simple schizophrenia. The compounds have many sideeffects, the most serious of which is that it causes depression at the same time that it alleviates the schizophrenic symptoms. Incidentally, it also has a disadvantage in that it is quite toxic and has caused liver damage and blood disorders.
  • the abolition of aggressive behavior in schizophrenics without neurotoxicity, as characterized by depression, would be a most desirable feature for a new drug in the therapy of mental disease.
  • the compound of the present invention has been found to be an agent which selectively blocks aggressive behavior but which does not cause depression.
  • the invention is a method of treating aggressive behavior comprising administering a therapeutically effective dose of l,2,3-benzotriazin-4(3H)-one to an anxious animal.
  • 3,- 316,262 discloses that certain 3-substituted-l,2,3-benzotriazin-4(3H)-ones have antiphlogistic, antipyretic, analgesic, and sedative activity coupled with low toxicity. This patent does not, however, disclose antiaggression activity, i.e., the ability to selectively abolish aggressive behavior at doses which cause little or no signs or symptoms of CNS depression or toxicity.
  • 1,2,3-benzotriazin-4(3H)-one is disclosed as having sedative activity (but not anti-aggression activity), while benz-halogenated and 3-dialkyl-aminoalkyl analogs thereof were found to be devoid of pharmacological activity.
  • British Pat. No. 932,680 mentions a 3- aminobenzotriazinone N-carboxylic acid hydroxy-ethyl ester as a compound which possesses pronounced mus- .cle relaxing and analgesic activity.
  • U.S. Pat. No. 3,075,982 discloses certain derivatives as having valuable pharmaceutical properties as 1 i2$ -vc- 7.
  • U.S. Pat. No. 2,949,465 discloses 1,2,3-benzotriazin-4(3I-l)-one derivatives as plant fungicides.
  • U.S. Pat. No. 2,935,445 discloses trichloromethylthio derivatives as a nematocide.
  • U.S. Pat. No. 3,014,906 discloses 6-sulfamyl-3,7- disubstituted-l,2,3-benzotriazines as diuretics and for relief as pre-menstrual tension and similar periods of stress.
  • U.S. Pat. No. 3,471,489 discloses substituted l,2,3-benzotriazin-4(3H)-ones as useful insecticides, herbicides and central nervous system depressants.
  • British Pat. No. 1,110,265 discloses 3-phenyl 1,2,3-benzotriazin-4-ones as pharmacologically active compounds useful as sedative-hypnotics, anticonvulsants and hypoglycemics.
  • U.S. Pat. No. 3,492,406 discloses 3-(2- fluorophenyl)-1,2,3-benzotriazin-4-ones as an anorexigenic agent in mammals.
  • the present invention provides a method of inhibiting aggressive behavior in an anxious animal subject without causing the central nervous system depression which is a typical side effect of drugs heretofore used to treat aggressive behavior. This is achieved by administering to an anxious animal subject a therapeutically effective amount of l,2,3-benzotriazin-4(3H)-one, either as such, or in the form of a pharmaceutical composition including said compound.
  • the amount administered will be from about 2 to 100, preferably, from about 2 to 25 mg/kg/day of body weight.
  • the amount will be from about 0.03 to 1.4, preferably, from about 0.03 to 0.3 mg/kg/day of body weight.
  • the composition in the case of a tablet, will comprise, in addition to the active ingredient, fillers, binders and diluents such as lactose, methylcellulose, talc, gum tragacanth, gum acacia, agar, polyvinylpyrrolidone, stearic acid and/or corn starch.
  • a filler such as sodium carboxymethylcellulose and/or a syrup, e.g., a glycerine based syrup.
  • the most outstanding property of the compound of the present invention is the highly selective abolition of aggressive behavior in doses which cause little or no signs or symptoms of central nervous system depression or toxicity.
  • the compound can be classified as a psychotherapeutic agent, but it is unique in that no other agent of this class possesses the same spectrum of activity.
  • the compound of the present invention has a Neuropharmacological Profile [Samuel Irwin, Science 136,
  • lii'niice which rs eaisres that of the major tranquilizers such as chlorpromazine. It differs from chlorpromazine, however, in that it is a much weaker depressant of motor activity in the mouse. It was very active in inhibiting aggressive behavior in three models of experimental aggression; namely, isolated fighting behavior in mice, electroshock-induced fighting in mice, and septal rat aggression.
  • a major tranquilizer such as chlordiazepoxide
  • the compound of the present invention was found to be much more selective in inhibiting aggressive behavior than the latter. It does not possess significant anticonvulsant activity and in this respect it differs from chlordiazepoxide.
  • the compound of the present invention is orally active in mice and rats and orally is less toxic than chlorpromazine or chlordiazepoxide.
  • the compound of the present invention was studied in the Neuropharmacological Profile, which is a standardized multidimensional observation technique used on mice to grade symptomatology and acute toxicity relative to dosage.
  • the present compound In a dose range of 3-300 mg/kg, the present compound produced depression, reduced motor activity, hyporeflexia and hypothermia. A loss of righting occurred at the 300 mg/kg dose level and no convulsions were observed at any level. Depending on the dosage used, the onset of action varied between and 30 minutes and the effects lasted for approximately 30 minutes to several hours. The results of the Neuropharmacological Profile indicate that this compound is a central nervous system depressant having sedative properties.
  • mice or rats per dose were placed in individual photocell activity cages 30 minutes (mice) or 60 minutes (rats) after i.p. (intraperitoneal) administration of the drug, for a 30 minute activity count.
  • Table 1 shows the results obtained by comparing drug-treated groups with control activity. The SD being that dose causing a 50 percent reduction from control activity.
  • mice 140.0 mg/kg in mice and greater than 450 mg/kg in rats.
  • NTD is defined as the dose necessary to cause percent of mice or rats trained to walk a rotating wooden rod (5 rpm) to fall at the time of peak effect, and is a measure of drug effects on motor function or central nervous system toxicity.
  • Table II The results set forth in Table II were obtained when l,2,3-benzotriazin-4(3I-I)-one was tested against chlorpromazine and chlordiazepoxide.
  • the time of peak effect for each agent in both species was about 30-60 minutes after drug administration.
  • 1,2,3-benzotriazin-4('3H)-one was considerably less potent than either reference drug.
  • 1,2,3-benzotriazin-4(3I-I)-one appeared to be more centrally toxic in rats than in mice.
  • the compound of the present invention was compared with chlorpromazine and chlordiazepoxide for its anti-aggressive activity.
  • Four models of experimentallyinduced aggression in rodents were studied (RD. Sofia, Life Sciences 8: 705, 1969). The results of these experirnents are summarized in Table III.
  • the present compound is selectively active in blocking electroshock-induced fighting in mice; the ratio being 4.2 upon intraperitoneal injection. In this respect, it closely resembles chlordiazepoxide which gave a ratio of 3.3. Clorpromazine would be considered inactive in this respect since it did block electroshockinduced fighting, but only at neurotoxic doses.
  • Anti-convulsant activity was tested in the following procedures.
  • mice Groups of ten mice each were injected i.p. with a vehicle and the test drug and placed in individual plexiglas squares. Thirty minutes after i.p. injection, each mouse was administered an electric shock transcorneally at SOmA intensity, 0.2 seconds duration (Swinyard, et al., J. Pharmacol. Expzl. Ther. 106: 319, 1952). The criterion for activity is protection against tonic extension of the hind limbs. The dose necessary to protect 50 percent of the mice (MES-, was determined. The following results were obtained.
  • Cats were adminispresent invention shows potentiation of barbiturate antered the present compound at 20, 40 and 80 mg/kg esthesia. orally in capsule form and were observed continuously 2.
  • the (MOA) inhibitors are administered prior to the admin- Scoring System is the Same as that used in the mouse istration of DOPA, which is a noradrenaline precursor, p l A 20 and 40 g/kg h r w no signs or convulsions or excitation occur.
  • chlordiazepoxide has been shown depressant compouhds- Ah EDfifl in this test is defined by Baxter, Life Sciences, 3: 531, 1964, to increase the as that dose of test drug which Wiii cause the LD! (25 threshold of the hypothalamus to electrical stimulation.
  • chiorpmmazihe (10 mg/kg) chioi'di' cally plated in the perifornical region of the hypothalaaZepOXide mg/kg) was active in this test- Since mus, were used in this study.
  • Stimulation was accoml,2,3- n was hot Selectively plished in the unanesthetized, freely moving animal, live in the killer rat aggression test, which appears to and the threshold for the hissing response was deterdetect antidepressant activity it is Possih1e that this mined with the following stimulus parameters: square agent might Possess weak a a ah activity at wave stimulation of 150 Hz with a duration of 0.5 msec doses which cause neurotoxicity. Hence, a thii d test for and voltage ranging from 5.4 to 30. The present comdetection of anti-depressant activity was conducted. pound was administered orally in capsule form. The 4.
  • the stimulation threshold for Groups of mice were given 32 mg/kg of tetrabenazine the hiss response was determined at l, 2, 4, 6 and 24 intraperitoneally 30 minutes after injection of hours. If an effect was observed, the stimulation was 1,2,3-benzotriazin 4(3H)one (20 mg/kg). The degree carried out daily until the thresholds returned to conof ptosis (eyelid drooping or closure) was then deter- 0 trol values. The compound was administered in a dose mined exactly 30 minutes after tetrabenazine adminisrange of 20 to 40 mg/kg. Thecompound was studied in tration.
  • the compound of the present invention did not four implanted cats; two cats administered 20 mg/kg reverse tetrabenazine-induced ptosis as do the antideand two at 40 mg/kg.
  • the compound had no effect on pressants, desipramine or amitriptyline. hypothalamic stimulation at either dose.
  • the rage re- 5.
  • Oxotremorine Antagonism sponse was not changed in intensity of character and the delay from stimulus to response was not changed. A few measurements were made in an effort to establish if this compound decreased the threshold for the Cardiovascular Activity l,2,3-benzotriazin-4(3l-I)-one was also studied in the DOCA hypertensive rat, cardiovascular, and pharmacodynamic dog preparation.
  • the compound was administered to groups of five rats made hypertensive by the administration of desoxycorticosterone acetate and saline. Blood pressures were recorded 4 and 24 hours after oral administration of 25 and 100 mg/kg.
  • l,2,3-benzotriazin-4(3H)-one had no effect on the systolic blood pressure of the hypertensive rat at 25 mg/kg; however, at 100 mg/kg two out of five animals experienced a fall in blood pressure of 24 mm Hg at the four-hour observation period.
  • the apparent antihypertensive effect of the compound at the 100 mm/kg level is probably not significant, since it occurred at a dose twice that of the neurotoxic dose in rats.
  • the pharmacodynamic assay was performed using anesthetized dogs and recording blood pressure, electrocardiogram, and respiration. Responses to the fol- 25 lowing drugs were observed before and after the administration of l,2,3-benzotriazin-4(3H)-one, epinephrine, norepinephrine, dimethylphenylpiperazinium iodide (DMPP), acetylcholine, tyramine, and histamine.
  • DMPP dimethylphenylpiperazinium iodide
  • Table VIII gives the results of five day lethality stud- These data show that l,2,3-benzotriazin-4(3I-I)-one is less toxic than chlorpromazine, but more toxic than chlordiazepoxide when administered to mice; however, when administered to rats, it is less toxic than either of the two standard reference drugs.
  • the compound of the present invention may be administered to an anxious animal subject in any of a number of forms and via any of several routes.
  • the compound or compositions thereof may be orally administered in the form of tablets, pills, capsules, or in the form of a solution or liquid suspension. They may also be administered in the form of a parenteral suspension or solution.
  • the compound or compositions thereof may also be administered rectally, in the form of a suppository.
  • a tablet, pill or capsule consisting entirely of the desired compound, although ordinarily, a composition comprising an effective amount of the compound and varying amounts of one or more physiologically inert materials such as carriers, vehicles, binders and the like will be used. Additionally, the compounds may be orally administered in the form of a suspension thereof in a suitable vehicle such as a syrup.
  • parenterally administering the compound or compositions use may be made of a parenteral solution or suspension of the compound in a suitable solvent or suspension medium.
  • compositions of the present invention may also be administered rectally in the form of a suppository comprising an effective amount of the desired compound and a suitable vehicle such as petroleum jelly.
  • compositions according to the invention are specific formulations of compositions according to the invention:
  • EXAMPLE 1 Tablets may be prepared by the compression of a wet granulation containing the following:
  • a liquid suspension for oral administration may be prepared in the following formulation:
  • DFC Dry filled capsules
  • a parenteral suspension for intra-muscular administration may be prepared in the following formulation:
  • Dosage l suppository every 3 to 4 hours.
  • a method of inhibiting aggressive behavior in an anxious animal subject comprising administering to an anxious animal subject, an amount of l,2,3-benzotriazin-4(3H)-one which is effective to inhibit aggressive behavior in said animal subject without simultaneously causing depression.
  • said orally administrable dosage form is a pill, tablet, capsule, solution or suspension.
  • said effective amount is from about 2 to about mg/kg of body weight of said animal per day.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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US00282311A 1972-08-21 1972-08-21 Inhibiting aggressive behavior with 1,2,3-benzotriazin-(3h)-one Expired - Lifetime US3794726A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5234925A (en) * 1991-08-14 1993-08-10 Dana-Farber Cancer Institute, Inc. 2-aza-2-desamino analogues of 5,8-dideazafolic acid
WO2016081736A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines as modulators of gpr139
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2935445A (en) * 1957-11-21 1960-05-03 American Cyanamid Co Nu-trichloromethylthio-1, 2, 3-benzotriazine-4-one as a novel nematocide
US3471489A (en) * 1968-07-29 1969-10-07 Dow Chemical Co 1,2,3-benzotriazin-4(3h)-ones
US3652560A (en) * 1970-06-18 1972-03-28 Dow Chemical Co 3-((alkylthio)methyl)-1 2 3-benzotriazin-4(3h)-ones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2935445A (en) * 1957-11-21 1960-05-03 American Cyanamid Co Nu-trichloromethylthio-1, 2, 3-benzotriazine-4-one as a novel nematocide
US3471489A (en) * 1968-07-29 1969-10-07 Dow Chemical Co 1,2,3-benzotriazin-4(3h)-ones
US3652560A (en) * 1970-06-18 1972-03-28 Dow Chemical Co 3-((alkylthio)methyl)-1 2 3-benzotriazin-4(3h)-ones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. Org. Chem., Vol. 26, (1961), pp. 613 615. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5234925A (en) * 1991-08-14 1993-08-10 Dana-Farber Cancer Institute, Inc. 2-aza-2-desamino analogues of 5,8-dideazafolic acid
WO2016081736A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines as modulators of gpr139
US9556130B2 (en) 2014-11-20 2017-01-31 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139
KR20170084324A (ko) * 2014-11-20 2017-07-19 다케다 야쿠힌 고교 가부시키가이샤 Gpr139의 모듈레이터로서의 4-옥소-3,4-디히드로-1,2,3-벤조트리아진
CN107108531A (zh) * 2014-11-20 2017-08-29 武田药品工业株式会社 作为gpr139的调节剂的4‑氧代‑3,4‑二氢‑1,2,3‑苯并三嗪类
US9770450B2 (en) 2014-11-20 2017-09-26 Takeda Pharmaceutical Company Limited 4-OXO-3,4-dihydro-1,2,3-benzotriazine as modulators of GPR139
US10159677B2 (en) 2014-11-20 2018-12-25 Takeda Pharmaceutical Company Limited 4-OXO-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139
EP3536324A1 (en) * 2014-11-20 2019-09-11 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines as modulators of gpr139
EA033728B1 (ru) * 2014-11-20 2019-11-20 Takeda Pharmaceuticals Co 4-оксо-3,4-дигидро-1,2,3-бензотриазины в качестве модуляторов gpr139
US10561662B2 (en) 2014-11-20 2020-02-18 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139
CN107108531B (zh) * 2014-11-20 2020-10-20 武田药品工业株式会社 作为gpr139的调节剂的4-氧代-3,4-二氢-1,2,3-苯并三嗪类
CN112062730A (zh) * 2014-11-20 2020-12-11 武田药品工业株式会社 作为gpr139的调节剂的4-氧代-3,4-二氢-1,2,3-苯并三嗪类
US11173161B2 (en) 2014-11-20 2021-11-16 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139
CN112062730B (zh) * 2014-11-20 2023-09-29 武田药品工业株式会社 作为gpr139的调节剂的4-氧代-3,4-二氢-1,2,3-苯并三嗪类
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives

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GB1422745A (en) 1976-01-28
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