1. Novel Tetrazole annulated Benzopyridodiazepinone compounds of Formula I Formula I Wherein R’ is selected from C1-C10 straight chain or cyclic alkyl group, wherein each of the group can be substituted or unsubstituted with one or more halogen, nitro, amino, oxo, alkyl , aryl, heteroaryl, heterocyclyl group, alkoxy or phenoxy group. R’’ is selected from methyl, ethyl, propyl, methylamine, ethyl amine, propyl amine, phenyl tetrazole, benzyl tetrazole, phenyl, benzyl, benzene, nitrobenzene, methyl benzene, methoxy benzene, methyl benzoate, methyl, ethyl, cyclopropyl.

2. The compounds as claimed in claim 1 wherein R3 is selected from hydrogen or methyl group.

3. The compounds as claimed in claim 2 wherein R2 is cyclopropane.

4. The compounds as claimed in claim 2 wherein R2 is benzene, aniline, toluene, nitrobenzene, methoxybenzene and methyl benzoate.

5. The compounds as claimed in claim 2 wherein R2 is selected from phenyl tetrazole or benzyl tetrazole.

6. The compounds as claimed in claim 2 wherein R2 is selected from methyl, ethyl or ethyl amine group.

7. The compounds as claimed in claim 1 wherein the compound is selected from, 9-cyclopropyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-cyclopropyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 6-methyl-9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 6-methyl-9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-methoxyphenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-methoxyphenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; Methyl-4-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate; Methyl-4-(6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate; 9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 6-methyl-9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(3-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(3-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(2-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(2-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-ethyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-ethyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 6-methyl-9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine; 2-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)ethan-1-amine;

8. A process for preparing novel tetrazole annulated Benzopyridodiazepinone compounds of formula I, said process comprising (ix) Reacting 2-chloro-3-aminopyridyl amine (II) with 2-chlorobenzoyl chloride to obtain the amide of formula III, (II) (III) (x) Treating the amide (III) with an amine of formula R’ (NH2) of formula (IV) in the presence of a solvent and base to obtain the diazepinone of formula V, (V) (xi) Treating a solution of diazepinone of formula V in solvent with phosphorous oxychloride and stirring at 50- 70C (xii) Adding an azide source to the solution of step (iii) and refluxing for 6-10 hrs to obtain the crude compound of formula I.

9. The process as claimed in claim 8, wherein the solvent is selected from methanol, ethanol, dichloromethane, tetrachloromethane, chloroform, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide, isopropanol.

10. The process as claimed in claim 8, wherein the base is selected from caesium carbonate, potassium carbonate and sodium carbonate.

11. The process as claimed in claim 8, wherein the azide source is selected from sodium azide and trimethylsilyl azide.

12. The process as claimed in claim 8, further comprising purifying the crude product with column chromatography or HPLC. Dated this the 26th day of November 2024.

Description:Field of the invention
The present invention relates to novel tetrazole annulated Benzopyridodiazepinone compounds and a process for preparing the same. The present invention also provides pharmaceutical composition comprising the same.

Background of the invention
Benzodiazepine such as diazepam, clobazam and clonazepam have been found effective in managing different types of epilepsy. Besides, diazepam has shown promising outcomes in the treatment of anxiety, acute recurring seizure, alcohol detoxification and severe muscle spasm and stiffness associated with neurological disease.

Diazepam Clobazam Clonazepam
In recent year, tetrazole-containing compounds such cilostazol, pranlukast and losartan are in clinical trials for the management of different neurological disorders.

Cilostazol Losartan

Pranlukast
Although, Benzodiazepine and tetrazole appear to show promising role in the management of varied neurological issues, there are no literature on any hybrid molecule having these structures.

Dysregulation of the Tropomyosin Kinase B (TrkB) pathway has been implicated in different neurological and neurodegenerative conditions, including epilepsy, stroke, Huntington's Disease, Parkinson's Disease, Amyotrophic lateral sclerosis, and stress-related disorders

It is therefore important to generate the library of novel molecules having Tropomyosin Kinase B inhibitory activity and evaluate their potential in the management of various neurological disorders.

Object of the invention
It is an object of the present invention to provide novel compounds having Tropomyosin Kinase B inhibitory activity.

It is another object of the present invention to provide process for preparing novel compounds for having Tropomyosin Kinase B inhibitory activity.

It is another object of the present invention to provide a pharmaceutical composition comprising novel compounds having Tropomyosin Kinase B inhibitory activity.

It is another object of the present invention to provide a pharmaceutical composition comprising novel compounds for the treatment of Tropomyosin Kinase B mediated condition such as epilepsy, cancer and related issues.

Summary of the invention
Accordingly, the present invention provides novel Tetrazole annulated Benzopyrido diazepinone compounds of formula I

Formula I
Wherein R’ is selected from C1-C10 straight chain or cyclic alkyl group, wherein each of the group can be substituted or unsubstituted with one or more halogen, nitro, amino, oxo, alkyl, aryl, heteroaryl, heterocyclyl group, alkoxy or phenoxy group; R” is selected from hydrogen, methyl, ethyl or propyl, group.

The present invention also provides a process for the preparation of novel Tetrazole annulated Benzopyridodiazepinone compounds of formula I by introducing the tetrazole to the benzodiazepine through the condensation of imidoyl chloride with trimethylsilyl azide.

The present invention provides a process for preparing novel tetrazole annulated Benzopyridodiazepinone compounds of formula I, said process comprising
(i) reacting 2-chloro-3-aminopyridyl amine (II) with 2-chlorobenzoyl chloride to obtain the amide of formula III,

(II) (III)

(ii) treating the amide (III) with an amine of formula R’ (NH2) of formula (IV) in the presence of a solvent and base to obtain the diazepinone of formula V,

(V)
(iii) treating a solution of diazepinone of formula V in solvent with phosphorous oxychloride and stirring at 50- 70°C, and
(iv) adding an azide source to the solution of step (iii) and refluxing for 6-10 hrs to obtain the crude compound of formula I.

Detailed description of the invention
The present invention relates to novel compounds for the treatment of Tropomyosin Kinase B mediated condition. In particular, the present invention provides novel compounds for the treatment of Tropomyosin Kinase B mediated conditions such as epilepsy, seizures and related issues.
The present invention provides novel tetrazole annulated Benzopyridodiazepinone compounds of formula I

Formula I
Wherein R’ is selected from C1-C10 straight chain or cyclic alkyl group, wherein each of the group can be substituted or unsubstituted with one or more halogen, nitro, amino, oxo, alkyl , aryl, heteroaryl , heterocyclyl group, alkoxy or phenoxy group; R” is selected from hydrogen, methyl, ethyl or propyl, group.
In one embodiment the present invention provides compounds of formula I wherein the compound is selected from,
9-cyclopropyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-cyclopropyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-methoxyphenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-methoxyphenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
Methyl-4-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate;
Methyl-4-(6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate;
9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(3-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(3-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(2-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(2-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-ethyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-ethyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
2-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)ethan-1-amine;

The present invention also provides a process for preparing novel tetrazole annulated Benzopyridodiazepinone compounds of formula I, said process comprising
(v) reacting 2-chloro-3-aminopyridyl amine (II) with 2-chlorobenzoyl chloride to obtain the amide of formula III,

(II) (III)

(vi) treating the amide (III) with an amine of formula R’ (NH2) of formula (IV) in the presence of a solvent and base to obtain the diazepinone of formula V,

(V)
(vii) treating a solution of diazepinone of formula V in solvent with phosphorous oxychloride and stirring at 50- 70°C, and
(viii) adding an azide source to the solution of step (iii) and refluxing for 6-10 hrs to obtain the crude compound of formula I.

The solvents used in the process are methanol, ethanol, dichloromethane, tetrachloromethane, chloroform, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide, isopropanol. The base is selected from caesium carbonate, potassium carbonate and sodium carbonate. The azide source at step (iv) is selected from sodium azide and trimethylsilyl azide. The crude product obtained in the above process is further purified using conventional techniques such as column chromatography or HPLC.

The process for preparing novel tetrazole annulated Benzopyridodiazepinone compounds of formula I involves introducing the tetrazole to the benzodiazepine through the condensation of imidoyl chloride with trimethylsilyl azide. The commercially available 2-chloro-3-aminopyridyl amine were reacted with 2-chlorobenzoyl chloride in the presence of base sodium hydrogen orthophosphate (Na2HPO4) to afford amide (4-5) as depicted in Scheme 1.
Scheme 1

The two-chlorine atoms in intermediate (4-5) will undergo amination reaction with cyclopropylamine (6), substituted aniline (9), various aminobenzonitrile (12) and substituted alkylamine (15) to yield series of benzopyridodiazepinone derivatives. These intermediate (4-5) is suitable for the intermolecular cyclization with various set of amines for the formation of seven-membered diazepinones ring Scheme 2. The seven-membered diazepinones ring is privileged and crucial for the anti-convulsant activity, as evidenced from the approved drug diazepam, clopazam and clonazepam.

Scheme 2

The present invention has been made for the conversion secondary amide in diazepinone 7(a-b), 10(a-j), 13(a-h) and 16(a-f) to the imidoyl chloride followed by treatment with an azide source to achieve tetrazole derivatives. In all targeted series, imidoyl chloride is achieved by the reaction of POCl3 which further engaged in the cyclization reaction with azide to give 8(a-b), 11(a-j), 14(a-h) and 17(a-f) shown in Scheme 3-6.

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Example 1: Preparation of compounds 4 and 5
To a solution of 2-chloro-3-amino pyridine (0.03 mol) in DMSO (30 ml), the base sodium hydrogen orthophosphate (10.01g, 0.06 mol) and 2-chlorobenzoyl chloride (3.79ml, 0.03 mol) was added. The reaction mixture was stirred for 6h at room temperature. The reaction mixture was extracted with chloroform (30ml x 3). The organic layer was washed with brine, dried with anhydrous sodium sulphate to obtain crude which is purified by column chromatography (ethylacetate and hexane (25:100 v/v).

Example 2: Preparation of compounds 7(a-b)
To a solution of appropriate carboxamide (0.00187 mol) in dichloromethane was added in equimolar quantities of cyclopropylamine (0.1ml, 0.00187 mol) and caesium carbonate (1.21g, 0.00374 mol). The reaction mixture was heated under reflux for about 24-30 h and the reaction completion was monitored by thin layer chromatography. After completion, the organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate and hexane as eluent.

Example 3: Preparation of compounds 10(a-j)
To a solution of appropriate carboxamide (0.00187 mol) in dichloromethane was added in equimolar quantities of substituted aniline (0.00187 mol) and caesium carbonate (1.21g, 0.00374 mol). The reaction mixture was heated under reflux for about 24-30 h and the reaction completion was monitored by thin layer chromatography. After completion, the organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate and hexane as eluent.

Example 4: Preparation of compounds 13(a-h)
To a solution of appropriate carboxamide (0.00187 mol) in dichloromethane was added in equimolar quantities of 4-aminobenzonitrile (0.00187 mol) and caesium carbonate (1.21g, 0.00374 mol). The reaction mixture was heated under reflux for about 24-30 h and the reaction completion was monitored by thin layer chromatography. After completion, the organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate and hexane as eluent.

Example 5: Preparation of compounds 16(a-h)
To a solution of appropriate carboxamide (0.00187 mol) in dichloromethane was added in equimolar quantities of substituted alkylamine (0.00187 mol) and caesium carbonate (1.21g, 0.00374 mol). The reaction mixture was heated under reflux for about 24-30 h and the reaction completion was monitored by thin layer chromatography. After completion, the organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate and hexane as eluent.

Example 6: Preparation of compounds 8(a-b)
A phosphorous oxychloride (0.29g, 0.0019 mol) was added to the solution of appropriate diazepinones 7(a-b) (0.0019 mol) in DCM and stir for 2 h at 60 oC. After 2 h, trimethyl silyl azide (0.12g, 0.0019 mol) was added, and the resulting mixture was refluxed for 8 h. The excess solvent was then vacuum evaporated, and ethylacetate was added. The organic phase was washed with water and dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate/hexane as eluent.

Example 7: Preparation of compounds 11(a-j)
A phosphorous oxychloride (0.26g, 0.0017 mol) was added to the solution of diazepinones 10(a-j) (0.0017 mol) in DCM and stir for 2 h at 60 oC. After 2 h, trimethylsilyl azide (0.22g, 0.0034 mol) was added, and the resulting mixture was refluxed for 8 h. The excess solvent was then vacuum evaporated, and ethylacetate was added. The organic phase was washed with water and dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate/hexane as eluent.

Example 8: Preparation of compounds 14(a-h)
A phosphorous oxychloride (0.26g, 0.0017 mol) was added to the solution of diazepinones 13(a-h) (0.0017 mol) in DCM and stir for 2 h at 60oC. After 2 h, trimethylsilyl azide (0.22g, 0.0034 mol) was added, and the resulting mixture was refluxed for 8 h. The excess solvent was then vacuum evaporated, and ethylacetate was added. The organic phase was washed with water and dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate/hexane as eluent.

Example 9: Preparation of compounds 17(a-f)
A phosphorous oxychloride (0.26g, 0.0017 mol) was added to the solution of diazepinones 16(a-f) (0.0017 mol) in DCM and stir for 2 h at 60 oC. After 2 h, trimethylsilyl azide (0.22g, 0.0034 mol) was added, and the resulting mixture was refluxed for 8 h. The excess solvent was then vacuum evaporated, and ethylacetate was added. The organic phase was washed with water and dried over sodium sulphate and concentrated to dryness. The crude products were purified by column chromatography using ethylacetate/hexane as eluent.

Table 1: Structure of the synthesized tetrazole annulated benzopyridodiazepine derivatives
Structure IUPAC Name

9-cyclopropyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-cyclopropyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

6-methyl-9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

6-methyl-9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-methoxyphenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-methoxyphenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine
Methyl-4-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate
Methyl-4-(6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate
9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine
6-methyl-9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(3-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(3-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(2-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(2-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-ethyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-ethyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

6-methyl-9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine

2-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)ethan-1-amine

Example 10: Molecular docking and Invitro Tropomyosin Receptor Kinase B TRKB inhibitory activity
The synthesized compounds 8(a-b), 11(a-j), 14(a-h), 17(a-e) were docked to determine their affinity of molecules with Tropomyosin Kinase B and their utility in convulsant disorder. The docking score of synthesized compounds are presented in Table 2. All the compounds exhibited good docking scores i.e. -8.1 to -11.3 Kcal/mol. Among all, 14h and 14g showed the highest docking score -11.3 and -11.0 Kcal/mol, which revealed that tetrazole ring in both compounds involved in hydrogen bond interaction (H-Met636), whereas benzodiazepine ring in 14h and 14g involved in pi-sigma interaction with amino acid Leu 560, Leu699 and pi-alkyl interaction Ala586, further methyl bearing pyridine ring in 14h compounds involved in alkyl interaction with Lys 643 available in catalytic site of TRKB. Notably, benzyl-linked tetrazole in 14h and 14g involved pi-pi stacked interaction with Phe565 and pi-alkyl interaction with Val568.
Further, in vitro results from enzyme-based assay of test compounds revealed that the compounds 14h>14g>14b>14a possess potent TRKB inhibitory activity with an IC50 of 2.32>2.54=2.54>2.72 respectively, as shown in Table 2.

Table 2: Molecular docking and IC50 values of synthesized compounds for inhibiting Tropomyosin Receptor Kinase B (TRKB)
Compounds Docking score IC50 (nM)
14h -11.3 2.32
14g -11.0 2.54
14b -10.9 2.54
14a -10.7 2.72
11h -10.2 2.81
11j -10.1 2.83
11c -10.0 2.92
11d -10.2 3.00
11f -9.7 3.08
14d -9.9 3.16
11g -10.0 3.18
11b -9.8 3.21
14c -9.5 3.15
11e -9.5 3.19
11a -9.6 3.21
17b -9.1 3.35
14e -9.5 3.38
11i -9.9 3.46
17d -8.9 3.47
14f -8.6 3.76
17a -8.6 3.57
8b -8.6 3.71
17f -8.5 3.78
17c -8.5 3.73
8a -8.3 3.58
17e -8.1 4.06

, C , Claims:We claim
1. Novel Tetrazole annulated Benzopyridodiazepinone compounds of Formula I

Formula I
Wherein R’ is selected from C1-C10 straight chain or cyclic alkyl group, wherein each of the group can be substituted or unsubstituted with one or more halogen, nitro, amino, oxo, alkyl , aryl, heteroaryl, heterocyclyl group, alkoxy or phenoxy group.
R’’ is selected from methyl, ethyl, propyl, methylamine, ethyl amine, propyl amine, phenyl tetrazole, benzyl tetrazole, phenyl, benzyl, benzene, nitrobenzene, methyl benzene, methoxy benzene, methyl benzoate, methyl, ethyl, cyclopropyl.
2. The compounds as claimed in claim 1 wherein R3 is selected from hydrogen or methyl group.
3. The compounds as claimed in claim 2 wherein R2 is cyclopropane.
4. The compounds as claimed in claim 2 wherein R2 is benzene, aniline, toluene, nitrobenzene, methoxybenzene and methyl benzoate.
5. The compounds as claimed in claim 2 wherein R2 is selected from phenyl tetrazole or benzyl tetrazole.
6. The compounds as claimed in claim 2 wherein R2 is selected from methyl, ethyl or ethyl amine group.
7. The compounds as claimed in claim 1 wherein the compound is selected from,
9-cyclopropyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-cyclopropyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-phenyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-(p-tolyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-methoxyphenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-methoxyphenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
Methyl-4-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate;
Methyl-4-(6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)benzoate;
9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-(4-nitrophenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(3-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(3-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(2-(1H-tetrazol-5-yl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(2-(1H-tetrazol-5-yl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-(4-((1H-tetrazol-5-yl)methyl)phenyl)-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-ethyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-ethyl-6-methyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
6-methyl-9-propyl-9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepine;
2-(9H-benzo[f]pyrido[2,3-b]tetrazolo[1,5-d][1,4]diazepin-9-yl)ethan-1-amine;
8. A process for preparing novel tetrazole annulated Benzopyridodiazepinone compounds of formula I, said process comprising
(ix) Reacting 2-chloro-3-aminopyridyl amine (II) with 2-chlorobenzoyl chloride to obtain the amide of formula III,

(II) (III)

(x) Treating the amide (III) with an amine of formula R’ (NH2) of formula (IV) in the presence of a solvent and base to obtain the diazepinone of formula V,

(V)
(xi) Treating a solution of diazepinone of formula V in solvent with phosphorous oxychloride and stirring at 50- 70C
(xii) Adding an azide source to the solution of step (iii) and refluxing for 6-10 hrs to obtain the crude compound of formula I.

9. The process as claimed in claim 8, wherein the solvent is selected from methanol, ethanol, dichloromethane, tetrachloromethane, chloroform, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide, isopropanol.

10. The process as claimed in claim 8, wherein the base is selected from caesium carbonate, potassium carbonate and sodium carbonate.

11. The process as claimed in claim 8, wherein the azide source is selected from sodium azide and trimethylsilyl azide.

12. The process as claimed in claim 8, further comprising purifying the crude product with column chromatography or HPLC.

Dated this the 26th day of November 2024.