DESC:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceutical compositions, and in specific relates to a pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression that is safer and more effective.
Background of the invention:
[0002] Mental health illnesses are associated with human suffering, social alienation, disability and poor quality of life. One of the most prevalent and burdening public health problems is major depressive disorder. According to the World Health Organization (WHO), depression is the second most debilitating illness next to heart disease.

[0003] Depression is a mental state of low mood and aversion to activity. Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. Also called major depressive disorder or clinical depression, it affects how you feel, think and behave and can lead to a variety of emotional and physical problems. Major depressive disorder is one of the most investigated diseases by disciplines including neuropharmacology and genetics, and is believed to be a combination of hereditary, environmental and developmental factors.

[0004] Major depressive disorder causes Angry outbursts, irritability or frustration, even over small matters. Sleep disturbances, including insomnia or sleeping too much. Major depressive disorder is one of the most researched diseases in fields such as neuropharmacology and genetics.

[0005] Major depressive disorder is characterized by periods of depressed mood lasting for more than two weeks, accompanied by some or all of the following symptoms: hopelessness, worthlessness, disturbed appetite, weight gain or loss, disturbed sleep rhythm (insomnia or hypersomnia), reduced concentration, psychomotor agitation or retardation and recurrent suicidal thoughts. However, the molecular mechanisms underlying depression are not fully understood. New treatment options are crucial not only to reduce the number of people living with such conditions, but to treat the substantial population that is either resistant to existing pharmacotherapies or cannot tolerate their adverse effects.

[0006] Pyrrole is a heterocyclic aromatic organic compound. Diarylpyrrole mannich bases explored for their efficacy against mycobacterium tuberculosis with many changes in the structure in accordance with the results of screening. Various diarylpyrrole mannich bases are considered for in vivo screening against mycobacterium. Diarylpyrrole derivatives come under the class of antidepressants. The commercially available types of anti-depressants include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and typical antidepressants. However, these types of anti-depressants do not show comparative potency to that of standard antidepressants.

[0007] Therefore, there is a need for a drug composition that is equipotential with standard antidepressant drugs for their serotonin reuptake inhibition. The composition must possess more potent, less toxic and thus more selective than the compositions described above. There is a need of novel composition that is safer and more effective . Moreover, the composition should decrease the time of onset of anti-depressive action.
Objectives of the invention:
[0008] The primary objective of the invention is to provide a pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression.

[0009] Another objective of the invention is to provide a composition comprising diarylpyrrole methylamines with comparative potency to that of standard antidepressants.

[0010] The other objective of the invention is to provide a composition that is safer and more effective against depression.

[0011] Yet another objective of the invention is to provide a composition that decreases the time of onset of anti-depressive action.
Summary of the invention:
[0012] The present disclosure proposes a pyrrole derivative-based antidepressant composition. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0013] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provides a pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression that is safer and more effective

[0014] According to an aspect, the invention provides a composition of diarylpyrrole methylamines composition comprising a plurality of aryl groups, a pyrrole ring, and a methyl amine. The plurality of aryl groups are configured to bond with the pyrrole ring. The plurality of aryl groups comprise at least two aryl groups (diaryl). The pyrrole ring is a heterocyclic moiety that presents the amino acids proline and hydroxyproline in a hydrogenated form and characteristic residue for Histidine, and analog derivatives.

[0015] Further, the diaryl comprises phenyl, substituted phenyl or heteroaryl substituents. The methylamine is configured to bond with the pyrrole ring to form diarylpyrrole methylamines. The methylamine comprises at least one amino group and at least one methyl group. Methylamines is a primary aliphatic amine, a one-carbon compound and a member of methylamines. It is a conjugate base of a methylammonium. The structure of the diarylpyrrole methylamines is represented by formula 1,

[0016] In another aspect, the pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression that is safer and more effective. The composition comprising diarylpyrrole methylamines with comparative potency to that of standard antidepressants. The composition that is safer and more effective against depression. The composition that decreases the time of onset of anti-depressive action.

[0017] According to an aspect, the invention provides a method to synthesize pyrrole derivative-based antidepressant composition. The method for synthesize Diarylpyrrolemethylamines is undergoes by a series of four steps. In the first step, a Stetter reaction which involves the synthesis of arylpentan-1, 4- diones from aromatic aldehydes. In the next step, synthesis of diarylpyrroles via Paal – Knorr synthesis from the above intermediates. Later in next step, Diarylpyrrole carboxaldehydes (PA1-PA12) is synthesized from diaryl pyrroles (P1-P12) via Vilsmeier Haack formylation. In the final step, Diarylpyrrole methylamines (SA-1-SA-12) are synthesized from diarylpyrrole carboxaldehydes (PA1-PA12) by reductive amination.

[0018] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed invention disclosure:
[0019] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.

[0020] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression that is safer and more effective

[0021] According to an exemplary embodiment of the invention, the pyrrole derivative-based antidepressant composition comprising a plurality of aryl groups, a pyrrole ring, and a methyl amine. The plurality of aryl groups configured to bond with the pyrrole ring. The plurality of aryl groups comprises at least two aryl groups, i.e., diaryl. The pyrrole ring is a heterocyclic moiety that presents the amino acids proline and hydroxyproline in a hydrogenated form and characteristic residue for Histidine, and analog derivatives.

[0022] Further, the diaryl comprises phenyl, substituted phenyl or heteroaryl substituents. The methylamine is configured to bond with the pyrrole ring to form diarylpyrrole methylamines. The methylamine comprises at least one amino group and at least methyl group. It is a primary aliphatic amine, a one-carbon compound and a member of methylamines. It is a conjugate base of a methylammonium. The structure of the diarylpyrrole methylamines is represented by formula 1,

[0023] A series of twelve diarylpyrrole methylamines (SA1-SA12) are synthesized in order to investigate their serotonin reuptake inhibition potential and antidepressant effectiveness. The chemicals are created and refined. IR, NMR, and mass spectrum data are used to describe the compounds. For serotonin reuptake inhibition, the compounds SA1-SA12 are compared to the standard medicine Sertraline, and the molecule SA-5 demonstrated potency equal to the reference drug. In mice, the composition also had antidepressant efficacy comparable to standard antidepressants.

[0024] For instance, table 1 represents twelve diarylpyrrole methylamines (SA1-SA12) synthesized in order to investigate their serotonin reuptake inhibition potential and antidepressant effectiveness.

[0025] Table 1:
Sample Absorbance 1 Absorbance 2
Blank (no platelets or added 5-HT) 0.010 0.011
Blank (5-HT in platelets) 0.219 0.221
5-HT (200ng/ml) incubated with platelets 1.240 1.268
5-HT (50ng/ml) incubated with platelets 0.584 0.562
5-HT (200ng/ml) incubated with platelets and Sertraline (100 ng/ml) 0.221 0.219
5-HT (200ng/ml) incubated with platelets and SA1 (100 ng/ml) 0.237 0.228
5-HT (200ng/ml) incubated with platelets and SA2 (100 ng/ml) 0.243 0.238
5-HT (200ng/ml) incubated with platelets and SA3 (100 ng/ml) 0.255 0.246
5-HT (200ng/ml) incubated with platelets and SA4 (100 ng/ml) 0.252 0.248
5-HT (200ng/ml) incubated with platelets and SA5 (100 ng/ml) 0.219 0.220
5-HT (200ng/ml) incubated with platelets and SA6 (100 ng/ml) 0.264 0.254
5-HT (200ng/ml) incubated with platelets and SA7 (100 ng/ml) 0.277 0.267
5-HT (200ng/ml) incubated with platelets and SA8 (100 ng/ml) 0.287 0.268
5-HT (200ng/ml) incubated with platelets and SA9 (100 ng/ml) 0.284 0.268
5-HT (200ng/ml) incubated with platelets and SA10 (100 ng/ml) 0.314 0.321
5-HT (200ng/ml) incubated with platelets and SA11 (100 ng/ml) 0.278 0.291
5-HT (200ng/ml) incubated with platelets and SA12 (100 ng/ml) 0.316 0.322

[0026] The compound SA-5 (absorbance 0.220) showed 5-HT reuptake inhibition equipotent to the standard drug Sertraline (absorbance 0.220).

[0027] A series of diarylpyrrole methylamines composition is to provide potency equal compounds in SA1-SA12 were compared against the standard drug Sertraline for their serotonin reuptake inhibition. The composition also showed antidepressant activity comparable to that of Sertraline. The composition that shows more safer and more effective antidepressants. It provides a 5-HT reuptake inhibition to decrease the time of onset of anti-depressive action.

[0028] For instance, table 2 represents the results of the tail suspension test as immobility time in seconds during the course of the 6-minute test.

[0029] Table 2:
Group 1
(Sertraline 10 mg/kg b.w) Group 2
(Control) Group 3
(SA5 – 10 mg/kg b.w) Group 4
(SA5 – 20 mg/kg b.w)
75 211 85.2 10
12 218 91.8 12
80 223.8 89.4 20
12 247.8 106.8 35.2
12 310.2 87 43.8
53.4 210 120.6 78

[0030] For instance, table 3 represents the tail suspension test results are expressed as a forced swim test in seconds of test time, which is approximately 6 minutes.

[0031] Table 3:
Group 1
(Sertraline 10 mg/kg b.w) Group 2
(Control) Group 3
(SA5 – 10 mg/kg b.w) Group 4
(SA5 – 20 mg/kg b.w)
12 138 72.6 12
16.8 150 78.6 16.8
10.2 133.8 67.2 11.4
10.2 133.8 84.6 10.2
48 142.8 60 13.8
13.8 127.2 58.8 0

[0032] For instance, table 4 represents the results of the elevated plus maze test expressed as a ratio of open arm to closed arm entries during the test, which lasted roughly 5 minutes.

[0033] Table 4:
Group 1
(Sertraline 10 mg/kg b.w) Group 2
(Control) Group 3
(SA5 – 10 mg/kg b.w) Group 4
(SA5 – 20 mg/kg b.w)
0.625 0.09 0.43 1.25
0.75 0.0409 0.38 1
0.82 0.4 0.56 0.57
2 0.18 0.71 1.4
0.47 0.5 0.6 0.78
0.55 0.33 0.36 1.5

[0034] For instance, table 5 represents findings of the elevated plus maze test as a ratio of time spent in the open arm to time spent in the closed arm during the test, which lasted around 5 minutes.

[0035] Table 5:
Group 1
(Sertraline 10 mg/kg b.w) Group 2
(Vehicle) Group 3
(SA5 – 10 mg/kg b.w) Group 4
(SA5 – 20 mg/kg b.w)
0.89 0.08 0.28 0.804
0.57 0 0.29 1.24
0.74 0.16 0.3 0.74
1.31 0.11 0.35 0.63
0.4 0.05 0.34 0.78
0.61 0.11 0.25 0.82

[0036] The diarylpyrrole methylamines are configured to be utilized as antidepressant activity in mice along with in vitro serotonin reuptake activity.

[0037] According to another exemplary embodiment of the invention, a method to synthesize pyrrole derivative-based antidepressant composition. The method to synthesize Diarylpyrrolemethylamines is undergoes by a series of four steps. The first step is Stetter reaction which involves the synthesis of arylpentan-1, 4- diones from aromatic aldehydes. The second step involves synthesis of diarylpyrroles via Paal – Knorr synthesis from the above intermediates. Diarylpyrrole carboxaldehydes (PA1-PA12) is synthesized from diaryl pyrroles (P1-P12) via Vilsmeier Haack formylation. Diarylpyrrole methylamines (SA-1-SA-12) are synthesized from diarylpyrrole carboxaldehydes (PA1-PA12) by reductive amination.

[0038] The desired 1, 4-diones are synthesized by Stetter reaction. Appropriate aromatic aldehydes (1 m. mole) are treated with methylvinylketone (3 m. moles) with the use of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazoliumchloride (0.12 m. moles) as a catalyst in the presence of triethylamine (1.5 m. moles) and sodium acetate (0.12 m. moles) using dimethylformamide as a solvent. The aromatic aldehydes are selected from group comprising benzaldehyde, phenylethanone, 2,4-Dichlorobenzaldehyde, 4-Chlorobenzaldehyde, 2-Chlorobenzaldehyde and 2-Flourobenzaldehyde or any other appropriate aromatic aldehydes thereof. The catalyst comprises either 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride or Imidazolium or thiazolium salts or cyanides or alkylthiazolium based ionic liquids or any other catalyst thereof.

[0039] The reaction mixture is refluxed under nitrogen for a period of 8- 12 hours. The reaction is monitored by TLC and quenched by adding cold water. The mixture is extracted with three successive quantities of ethyl acetate. The combined ethyl acetate fractions are dried over anhydrous sodium sulfate and concentrated. The concentrate is subjected to column chromatography to obtain the desired compounds in a pure form.

[0040] Primary aromatic amine (2 m. mole) are added to arylpentan-1, 4-dione (1m. mole) taken in a round bottom flask. The aromatic amine such as aniline, phenylenediamine, toluidine, 4-Chloroaniline and para toluidine or any other primary aromatic amine or combinations thereof. Glacial acetic acid is added to this mixture and refluxed on a sand bath for 6 – 8 hours. Progress of the reaction is observed by TLC. The reaction mixture is neutralized by adding dilute sodium bicarbonate solution and extracted with successive volumes of ethyl acetate. The ethyl acetate layers are combined and concentrated. Pure diaryl pyrrole is obtained by purification using column chromatography.

[0041] Diarylpyrrole (1 m. mole) is dissolved in chloroform. Vilsmeier reagent is prepared by adding dimethyl formamide to phosphorus pentachloride (1 m. mole) taken in a beaker. The reagent was stirred on an ice bath for a few minutes. The solution of diarylpyrrole is added slowly to the Vilsmeier reagent while stirring on a water bath. After completion of addition, the reaction mixture is stirred at room temperature for about two to three hours. Completion of the reaction is monitored through TLC. After completion, the reaction is quenched by the addition of chilled water. The aqueous layer are extracted with three quantities of ethyl acetate. The ethyl acetate fractions are combined, dried by the addition of anhydrous sodium sulfate and concentrated. The resulting 1, 5- diarylpyrrole-3-carbaldehyde is purified by column chromatography.

[0042] The diarylpyrrole aldehyde (1 m.mol.) is dissolved in 5 ml of ethanol and 2 m. mol. of methylamine is added to this solution. The reaction mixture is stirred at room temperature for three to four hours. One m.mol of sodiumborohydride is added to this reaction mixture and stirring is continued for a period of about six to twelve hours. The progress of the reaction is monitored by TLC. Once the reaction is complete, the reaction mixture is poured into cold water and extracted with ethylacetate. The ethylacetate layer are separated, dried over anhydrous sodium sulphate and concentrated. The compounds are washed with diethylether to remove any traces of impurities.

[0043] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, the pyrrole derivative-based antidepressant composition with diarylpyrrole methylamines for treatment of depression that is safer and more effective. The composition comprising diarylpyrrole methylamines with comparative potency to that of standard antidepressants. The composition that is safer and more effective against depression. The composition that decreases the time of onset of anti-depressive action.

[0044] According to another exemplary embodiment of the invention, the pyrrole derivative-based antidepressant composition may comprises the aromatic aldehydes are selected from group comprising benzaldehyde, phenylethanone, 2,4-Dichlorobenzaldehyde, 4-Chlorobenzaldehyde, 2-Chlorobenzaldehyde and 2-Flourobenzaldehyde or any other appropriate aromatic aldehydes thereof. The Para toluenesulfonic acid maybe used for preparation of diarylpyrroles instead of acetic acid.

[0045] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
,CLAIMS:CLAIMS:
We Claim:
1. A pyrrole derivative-based antidepressant composition, comprising:
5 to 15 weight percentage of plurality of aromatic aldehydes;
10 to 20 weight percentage of methyl vinyl ketone;
5 to 15 weight percentage of triethylamine;
0.1 to 1 weight percentage of sodium acetate;
53 to 63 weight percentage of at least one aromatic amine;
1 to 10 weight percentage of methylamine; and
1 to 5 weight percentage of sodium borohydride,
whereby said pyrrole derivative-based antidepressant composition exhibits serotonin reuptake inhibitory activity with high binding energy and thereby aids in safe and effective treatment of depression.
2. The pyrrole derivative-based antidepressant composition as claimed in claim 1, wherein said plurality of aromatic aldehydes are selected from group comprising benzaldehyde, phenylethanone, 2,4-Dichlorobenzaldehyde, 4-Chlorobenzaldehyde, 2-Chlorobenzaldehyde and 2-Flourobenzaldehyde or any other appropriate aromatic aldehydes thereof.
3. The pyrrole derivative-based antidepressant composition as claimed in claim 1, wherein said at least one aromatic amine such as aniline, phenylenediamine, toluidine, 4-Chloroaniline and para toluidine or any other primary aromatic amine or combinations thereof.
4. The pyrrole derivative-based antidepressant composition as claimed in claim 1, wherein structure of said pyrrole derivative-based antidepressant composition is represented by formula 1,

5. A method to synthesize pyrrole derivative-based antidepressant composition, comprising:
treating plurality of aromatic aldehydes with methylvinylketone by utilizing a catalyst and dimethylformamide as a solvent to obtain a first reaction mixture wherein said first reaction mixture refluxed under nitrogen about a period of 8 to 12 hours and monitored using thin-layer chromatography followed by quenching process;
extracting and purifying said first reaction mixture by ethyl acetate with at least three successive quantities and drying over anhydrous sodium sulphate to obtain arylpentan-1, 4-diones followed by column chromatography to remove traces of impurities from said arylpentan-1, 4-diones;
adding at least one primary aromatic amine to said arylpentan-1, 4-diones and adding glacial acetic acid to obtain a second reaction mixture wherein said second reaction mixture refluxed under sand bath for about a period of 6 to 8 hours and monitored by thin-layer chromatography;
extracting and purifying said second reaction mixture by ethyl acetate with at least three successive quantities to obtain diarylpyrrole followed by column chromatography to remove traces of impurities from said diarylpyrrole;
dissolving said diarylpyrrole in chloroform to obtain a diarylpyrrole solution and adding said diarylpyrrole solution to a vilsmeier reagent while stirring on a water bath to obtain a third reaction mixture wherein said third reaction mixture stirred at room temperature for about 2 to 3 hours and monitored using thin-layer chromatography followed by quenching process;
extracting and purifying said third reaction mixture by ethyl acetate with at least three successive quantities and drying over anhydrous sodium sulphate to obtain diarylpyrrole aldehyde followed by column chromatography to remove traces of impurities from said diarylpyrrole aldehyde;
dissolving said diarylpyrrole aldehyde to ethanol to obtain a diarylpyrrole aldehyde solution and adding methylamine to said diarylpyrrole aldehyde solution while stirring about 3 to 4 hours followed by addition of sodium borohydride to said diarylpyrrole aldehyde solution to obtain a fourth reaction mixture;
stirring said fourth reaction mixture at room temperature for about 6 to 12 hours and monitoring said fourth reaction mixture by thin-layer chromatography followed by quenching process, and
extracting said fourth reaction mixture by ethyl acetate and dried over anhydrous sodium sulphate to obtain a pyrrole derivative-based antidepressant composition followed by washing with diethylether to remove traces of impurities from said pyrrole derivative-based antidepressant composition.
6. A method to synthesize pyrrole derivative-based antidepressant composition as claimed claim 4, wherein said catalyst comprises either 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride or Imidazolium or thiazolium salts or cyanides or alkylthiazolium based ionic liquids or any other catalyst thereof.
7. A method to synthesize pyrrole derivative-based antidepressant composition as claimed claim 4, wherein said catalyst and said solvent are utilized in the presence of triethylamine and sodium acetate in a specified concentration of about 1.5 millimoles and 0.12 millimoles respectively.
8. The method to synthesize pyrrole derivative-based antidepressant composition as claimed claim 4, wherein said second reaction mixture is neutralized in the presence of dilute sodium bicarbonate solution.
9. The method to synthesize pyrrole derivative-based antidepressant composition as claimed claim 4, wherein said vilsmeier reagent is prepared by adding dimethyl formamide to phosphorus pentachloride followed by stirring on an ice bath for a few minutes.
10. The method to synthesize pyrrole derivative-based antidepressant composition as claimed claim 4, wherein said diarylpyrrole aldehyde comprises 1, 5- diarylpyrrole-3-carbaldehyde in pure form.