TREATMENT OF POST-TRAUMATIC SYNDROME DISORDER

Abstract

This invention is related to 3-(2-(4-(2-methoxyphenyl)piperazine-1-yl) ethyl) quinazoline-4(3H)-one, pharmaceutically acceptable salts, enantiomers, diasteroisomers, stereoisomers, crystals, hydrates, solvates, prodrugs, and metabolites thereof for the treatment of Post-Traumatic Syndrome Disorder (PTSD), and pharmaceutical compositions containing the compounds for the treatment of Post-Traumatic Syndrome Disorder (PTSD).

Claims

1. A quinazoline compound having the formula 3-(2-(4-(2-methoxyphenyl)piperazine-1-yl) ethyl) quinazoline-4(3H).

2. A pharmaceutical composition for treating Post-Traumatic Syndrome Disorder (PTSD) comprising the quinazoline compound according to claim 1 and pharmaceutically acceptable salts, enantiomers, diasteroisomers, stereoisomers, crystals, hydrates, solvates, prodrugs, or metabolites thereof.

3. The pharmaceutical composition according to claim 2 that does not contain any ingredients that would modify the phannacophore for the treatment of Post-Traumatic Syndrome Disorder.

4. The pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable salts are selected from the group consisting of inorganic addition salts selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; organic addition salts selected from the group consisting of acetate, propionate, hexanoate, heptanoate, glycolate, piruvate, lactate, malonate, malate, maleate, lumarate, tartrate, citrate, succinate, mesylate, acistrate, besylate, tosylate, xinafoatc, benzoate, p-toluenesulfonate, cinnamate, p-chlorobenzenesulfonate, 2-naplitalenesulfonate, p-toluenesulphonate, camphorsulfonate, trimethylacetate, t-butylacetate, laurylsulphate, gluconate, glutarate, hydroxynaphthoate, salicylate, stearate, muconate, mandelate, and 2-hydroxyethanesulfonate; alkaline addition salts of metals selected from the group consisting of sodium, potassium, lithium, calcium, magnesium, bismuth, and bromide; salts with the organic bases primary, secondary or tertiary amines; and salts with an amino acid selected from the group consisting of arginine, lysine, histidine, caffeine, procaine, hydrobamine, choline, betaine, ethylenediamine, glycosamine, teobromine, purine, morpholine.

5. A method of treating Post-Traumatic Syndrome Disorder (PTSD) comprising administering a therapeutically effective amount of the quinazolinone compound according to claim 1 to a person in need thereof.

6. A pharmaceutical composition for treating Post-Traumatic Syndrome Disorder (PTSD) comprising the quinazolinone compound according to claim 1 and one or more excipients.

7. The pharmaceutical composition according to claim 6 further comprising at least one additional active principle, selected from the group consisting of anti-depressant, anxiolytic, anti-retroviral, anti-cancer, antibiotic, antidiabetic, anti-hypertensive, analgesic, and anti-inflammatory active principles.

8. A dosage form comprising the quinazolinone compound according to claim 1 in an amount of 0.01 to 5000 mg.

9. A method of using the quinazolinone compound according to claim 1 comprising using said compound in the treatment of Post-Traumatic Syndrome Disorder (PTSD).

10. A method of treating Post-Traumatic Syndrome Disorder (PTSD) comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 2 to a person in need thereof.

11. A method of treating Post-Traumatic Syndrome Disorder (PTSD) comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 6 to a person in need thereof.

12. A dosage form comprising the pharmaceutical compound according to claim 2 wherein the quinazoline compound is present in an amount of 0.01 to 5000 mg.

13. A dosage form comprising the pharmaceutical compound according to claim 3 wherein the quinazoline compound is present in an amount of 0.01 to 5000 mg.

14. A dosage form comprising the pharmaceutical compound according to claim 4 wherein the quinazoline compound is present in an amount of 0.01 to 5000 mg.

15. A pharmaceutical composition according to claim 2 further comprising at least one additional active principle selected from the group consisting of anti-depressant, anxiolytic, anti-retroviral, anti-cancer, antibiotic, antidiabetic, anti-hypertensive, analgesic, and anti-inflammatory active principles.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0031] Count of c-fos positive neurons in brain regions. The brain regions exemplified in FIG. 1 are locus ceruleus (FIG. 1A), amygdala (FIG. 1B), hypothalamus (FIG. 1C) and bed nuclei stria terminalis (FIG. 1D). The experiment comprised three different groups (n=10 per group): mice not subjected to the Single-Prolonged Stress protocol (Sham), mice subjected to the Single-Prolonged Stress protocol (SPS) and mice subjected to the Single-Prolonged Stress protocol but pre-treated with 3-(2-(4-(2-methoxyphenyl)piperazine-1-yl) ethyl) quinazoline-4(3H)-one, named IA1-29, at 30 mg/kg (IA1-29+SPS).

EXAMPLE

[0032] The quinazolinone of the invention was named IA1-29 and was tested in an in vivo model that mimics the activation that occurs in the brain after a prolonged stress stimulus.

[0033] The effects of the administration of IA1-29 at 30 mg/kg p.o. in brain activation were assessed in mice subjected to the Single Prolonged Stress (SPS) model. The SPS protocol is a well established model of PTSD that combines multiple stressors (physical restraint, forced swim, predator scent and ether anesthesia (Borghans & Homberg, 2015; Yamamoto et al., 2009)). The activation of specific brain regions was determined by counting the number of neurons expressing the c-fos protein, an immediate early gene product that can be used as a marker of cell activation in individual neurons. Interestingly, the SPS-Induced c-fos expression in key brain regions involved in stress response was suppressed by the prior administration of IA1-29. The count of c-fos positive neurons in some of these regions can be visualized in FIG. 1. The experiment comprised three different groups (n=10 per group): mice not subjected to the SPS protocol (Sham), mice subjected to the SPS model (SPS) and animals submitted to the SPS protocol but pre-treated with IA1-29 at 30 mg/kg (IA1-29+SPS). The brain regions exemplified in FIG. 1 are locus ceruleus (FIG. 1A), amygdala (FIG. 1B), hypothalamus (FIG. 1C) and bed nuclei stria terminalis (FIG. 1D). The statistical analysis between the groups was performed by ANOVA followed by bonferroni post-hoc test. * p<0.05 between SPS and Sham groups. # p<0.05 between IA1-29+SPS and SPS groups.

[0034] A person having skills in the concerned art, by way of the explanations and examples comprised herein will promptly appreciate the advantages of the invention, and will be able to propose equivalent embodiments of the invention without departing from the scope of the attached inventions.