1. A compound of formula I or formula II: Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted either 2 or 3 position of the furan ring; “R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring. Wherein the compound exhibits inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

2. The compound as claimed in claim 1, wherein when R is selected as methyl group at the 3rd position of the furan ring, represents a compound 5a:

3. The compound as claimed in claim 1, wherein when R is selected as phenyl group at the 3rd position of the furan ring, represents a compound 5b:

4. The compound as claimed in claim 1, wherein when R is selected as phenyl group at 2nd position of furan ring, represents the compound 5c.

5. The compound as claimed in claim 1, wherein when R is selected as carboxymethyl group at 2nd position of furan ring, represents compound 5d:

6. The compound as claimed in claim 1, wherein when R’ is selected as five membered, represents compound 5e:

7. The compound as claimed in claim 1, wherein when R’ is selected as tetrahydrofuran, represents compound 5f:

8. The compound as claimed in claim 1, wherein when R’ is selected as five membered ring with one oxo group, represents compound 5g:

9. The compound as claimed in claim 1, wherein when R’ is selected as 2-methyl furan, represents compound 5h:

10. The compound as claimed in claim 1, wherein when R’ is selected as cyclohexane, represents a compound 5i:

11. The compound as claimed in claim 1, wherein when R’ is selected as cyclohex-2-ene, represents a compound 5j:

12. The compound as claimed in claim 1, wherein when R’ is selected as cyclohex-3-ene, represents a compound 5k:

13. The compound as claimed in claim 1, wherein when R’ is selected as methyl substituted cyclohexene, represents compound 5l

14. The compound as claimed in claim 1, wherein when R’ is selected as six-membered heterocyclic ring with oxygen atom, represents compound 5m;

15. The compound as claimed in claim 1, wherein when R’ is selected as hexahydroisobenzofuran-1,3-dione, represents compound 5n:

16. A process of preparation of compounds of formula I and formula II, where in the process comprises the steps of: (i) 3+2 cycloaddition reaction with dimedone and cyclic and acyclic diene: (ii) ring expansion via Beckmann rearrangement: wherein the formula I and formula II are Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted either 2 or 3 position of the furan ring; “R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring. Wherein the compound exhibits inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

17. The process as claimed in claim 16, wherein solvent is selected from a list comprising of methanol, ethanol, dichloromethane, chloroform, tetrachloromethane, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide and isopropanol.

18. A pharmaceutical composition comprising a compound of formula I or formula II and a pharmaceutically acceptable excipient.

Description:FIELD OF INVENTION
The present invention relates to the field of medicinal chemistry and neuropharmacology. Particularly, the present invention relates to novel azepinone-based compounds. More particularly, the present invention relates to furano-annulated azepinone compounds for inhibition of acetylcholinesterase enzyme responsible for Alzheimer's disease. The present invention also relates to method of synthesis of novel azepinone-based compounds.

BACKGROUND OF THE INVENTION
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by memory impairment, cognitive decline and behavioural disturbances. It is most common cause of dementia in the elderly population. Current treatment strategies primarily aim at symptomatic relief rather than halting or reversing disease progression.

At the molecular level Alzheimer’s disease is associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to neuronal dysfunction and synaptic loss. Key enzymes such as acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) play crucial role in disease pathology. AChE is responsible for the breakdown of acetylcholine, a neurotransmitter essential for learning and memory.

Although several AChE inhibitors such as donepezil, rivastigmine and galantamine have been developed, they often suffer from limitations such as poor blood-brain barrier penetration, off-target effects, hepatotoxicity, and short duration of action. Therefore, there is need for novel compounds with improved enzyme selectivity, potency, safety profile and CNS bioavailability.

Azepinone, a seven-membered heterocyclic scaffold containing a ketone functionality, has shown promising biological activity in central nervous system disorders. Seven-membered nitrogen heterocycles, particularly the azepinone framework, found in various FDA-approved drugs and natural products such as hymenialdisine, paullone, rucaparib, oxazepam, and temocapril, have shown proven pharmacological importance in medical treatment, such as anti-cancer, neurological diseases, anti-HIV, etc.
Several patent and non-patent literature discloses a number of chemical scaffolds for targeting these enzymes.

US6143886A discloses unsaturated and cyclopropyl-Substituted azepinone compounds which are useful either as selective angiotensin converting enzyme inhibitors, or as dual inhibitors of both angiotensin converting enzyme and neutral endopeptidase. It is also directed to pharmaceutical compositions containing such selective or dual action inhibitors and to methods of using such compositions, as well as to processes for preparing the inhibitors, intermediates, and processes for preparing such intermediates.

ZA898741 (B) relates to the use of certain azepinone derivatives as agents for the treatment of acute and chronic obstructive disorders of the respiratory tract. It is known that non-selective anti-muscarinic such as, for example, atropine can be used to treat asthma attacks and also chronic bronchitis and emphysema. The systemic use of non-selective anti-muscarinic is greatly disadvantaged by the high rate of non-tolerable anticholinergic side effects such as mydriasis, inhibition of salivation, constipation and serious CNS effects.

Despite the growing interest in heterocyclic compounds, there remains a clear unmet need for novel azepinone derivatives with enhanced potency, selectivity and CNS bioavailability for Alzheimer’s therapy. The present invention addresses the limitations of prior art by providing novel azepinone-based compounds tailored for optimized enzyme inhibition.

OBJECT OF THE INVENTION:
To address the foregoing problems, in whole or in part, and/or other problems that may have been observed by persons skilled in the art, the present disclosure provide a series of novel compounds as described by way of example as set forth below.

The principal object of the present invention is to provide novel compounds for inhibition of acetylcholinesterase enzyme responsible for Alzheimer's disease.

Another object of the present invention is to provide a process for preparing novel compounds for having acetylcholinesterase inhibitory activity.

Another object of the present invention is to provide a facile two-step process for preparing novel compounds for having acetylcholinesterase inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition comprising novel compounds having acetylcholinesterase inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition comprising novel compounds for the treatment of acetylcholinesterase mediated condition such as Alzheimer Diseases.

SUMMARY OF THE INVENTION
This summary is intended to introduce, in simplified form, a selection of concepts that are further described in the detailed description. This summary is merely presented as a brief overview of the subject matter described and claimed herein and does not aid in determining the scope of the claimed subject matter.

The present invention provides novel furano-annulated azepinone compounds of formula I and formula II.

Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted either 2 or 3 position of the furan ring;
“R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring.

In one aspect, the present invention provides compounds that exhibit inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

In another aspect, when is selected when R is selected as methyl group at the 3rd position of the furan ring, represents a compound 5a:


In yet another aspect, when R is selected as phenyl group at the 3rd position of the furan ring, represents a compound 5b:


In another aspect, when R is selected as phenyl group at 2nd position of furan ring, represents the compound 5c.

In another aspect, when R is selected as carboxymethyl group at 2nd position of furan ring, represents compound 5d:

In another aspect, when R’ is selected as five membered cyclic ring or cyclopentane in formula II, represents compound 5e:

In another aspect, when R’ is selected as tetrahydrofuran in formula II, represents compound 5f:


In another aspect, when R’ is selected as five membered cyclic ring with one oxygen atom in formula II, represents compound 5g:

In another aspect, when R’ is selected as 2-methyl furan, represents compound 5h:

In yet another aspect, when R’ is selected as cyclohexane, represents a compound 5i:

In another aspect, when R’ is selected as cyclohex-2-ene, represents a compound 5j:

In another aspect, when R’ is selected as cyclohex-3-ene, represents a compound 5k:

In another aspect, wherein when R’ is selected as methyl substituted cyclohexene, represents compound 5l

In another aspect, when R’ is selected as six-membered cyclic ring “tetrahydropyrane” , represents compound 5m;

In yet another aspect, when R’ is selected as hexahydroisobenzofuran-1,3-dione, represents compound 5n:

In yet another aspect, the present invention provides a process of preparation of compounds of formula I and formula II, where in the process comprises steps of:
i) 3+2 cycloaddition reaction with dimedone and cyclic and acyclic diene; and
ii) ring expansion via Beckmann rearrangement.

In yet another aspect, the present invention discloses that solvent used in the preparation method is selected from a list comprising of methanol, ethanol, dichloromethane, chloroform, tetrachloromethane, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide and isopropanol.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or formula II and a pharmaceutically acceptable excipients targeting the AchE enzyme.

BRIEF DESCRIPTION OF THE DRAWINGS
In order to facilitate a comprehensive understanding and practical implementation of the disclosure, reference will now be made to exemplary embodiments illustrated in the accompanying figures. The figures together with detailed description below, are incorporated into and form part of the specification, and serve to further illustrate the embodiments and explain various principles and advantages, in accordance with the present disclosure:

FIG. 1 illustrates 2D and 3D docking poses of 5n and galantamine on the active site of AChE.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides compounds novel furano-annulated azepinone compounds that exhibit inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.
The present disclosure can be understood more readily by reference to the following description, taken in conjunction with the accompanying Figures and Examples, all of which form a part of this disclosure
At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of the invention covered in the present disclosure. However, such a particular form is only an exemplary embodiment, and without intending to imply any limitation on the scope of the invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.

Before the present disclosure or methods of the present disclosure are described in greater detail, it is to be understood that the specific products, methods, processes, conditions or parameters, are not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. For example, "about" can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

It is appreciated that certain features of the methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and/or composites/scaffolds.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

As used herein, the term "comprises", "comprising", or “comprising of” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. The term "comprises", "comprising", or “comprising of” when placed before the recitation of steps in a process or method means that the process or method encompasses one or more steps that are additional to those expressly recited, and that the additional one or more steps may be performed before, between, and/or after the recited steps.

Reference throughout this specification to “certain embodiments”, “further embodiments”, “specific embodiments”, “further specific embodiment”, “one embodiment”, “a non-limiting embodiment”, “an exemplary embodiment”, “some instances”, or “further instances”, means that a particular feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure.

As used herein, the terms ‘include’, ‘have’, ‘comprise’, ‘contain’ etc. or any form of said terms such as ‘having’, ‘including’, ‘containing’, ‘comprising’ or ‘comprises’ are inclusive and will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

As used herein, the term “invention”, “present invention”, “disclosure” or “present disclosure” as used herein is a non-limiting term and is not intended to refer to any single embodiment of the particular invention but encompasses all possible embodiments as described in the specification.

The terms “process(es)” and “method(s)” are considered interchangeable within this disclosure.

For convenience, certain terms used in the specification and examples are collected in this section below:
HOSA: hydroxylamine-O-sulfonic acid
AChE: acetylcholinesterase
CAN: Ceric ammonium nitrate
TLC: Thin layer chromatography
TRKB: Tropomyosin Receptor Kinase B
nM: nanomolar

In one specific embodiment, the present invention provides novel furano-annulated azepinone compounds of formula I and formula II:

Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted on either 2nd or 3rd position of the furan ring;
“R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring.
In yet another embodiment, the present invention provides compounds that exhibit inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

In yet another embodiment, the present invention discloses that when is selected when R is selected as methyl group at the 3rd position of the furan ring, represents a compound 5a:


In yet another embodiment, the present invention discloses that when R is selected as phenyl group at the 3rd position of the furan ring, represents a compound 5b:


In yet another embodiment, the present invention discloses that when R is selected as phenyl group at 2nd position of furan ring, represents the compound 5c.


In yet another embodiment, the present invention discloses that when R is selected as carboxymethyl group at 2nd position of furan ring, represents compound 5d:

In yet another embodiment, the present invention discloses that when R’ is selected as five membered cyclic ring in formula II, represents compound 5e:


In yet another embodiment, the present invention discloses that when R’ is selected as tetrahydrofuran in formula II, represents compound 5f:

In yet another embodiment, the present invention discloses that when R’ is selected as five membered ring with one oxygen atom in formula II, represents compound 5g:


In yet another embodiment, the present invention discloses that when R’ is selected as 2-methyl furan, represents compound 5h:


In yet another embodiment, the present invention discloses that when R’ is selected as cyclohexane, represents a compound 5i:

In yet another embodiment, the present invention discloses that when R’ is selected as cyclohex-2-ene, represents a compound 5j:

In yet another embodiment, the present invention discloses that when R’ is selected as cyclohex-3-ene, represents a compound 5k:


In yet another embodiment, the present invention discloses that when R’ is selected as methyl substituted cyclohexene, represents compound 5l

In yet another embodiment, the present invention discloses that when R’ is selected as six-membered tetrahydropyrane ring represents compound 5m;

In yet another embodiment, the present invention discloses that when R’ is selected as hexahydroisobenzofuran-1,3-dione, represents compound 5n:

In yet another embodiment, the present invention provides a facile synthesis of furano-azepinone derivatives and evaluation of their invitro and insilico inhibitory potential to acetylcholinesterase enzyme.

In another embodiment, the present invention discloses that the present invention provides a process of preparation of compounds of formula I and formula II, where in the process comprises steps of:
i) 3+2 cycloaddition reaction with dimedone and cyclic and acyclic diene; and
ii) ring expansion via Beckmann rearrangement.

In another embodiment, the present invention discloses that 3+2 cycloaddition reaction with dimedone and cyclic and acyclic diene comprises steps of:
Step 1: Activation of Dimedone (keto-enol form);
Step 2: 3+2 Cycloaddition with Diene (cyclic or acyclic); and
Step 3: Formation of Five-Membered Ring.
In another embodiment, the present invention discloses that Beckmann rearrangement comprises steps of:
Step 1: Formation of Oxime;
Step 2: Migration and rearrangement;
Step 3: Ring expansion
Step 4: Nucleophilic Attack by Water;
Step 5: Deprotonation;
Step 5: tautomerization.
In yet another embodiment, the present invention discloses that solvent used in the preparation method is selected from a list comprising of methanol, ethanol, dichloromethane, chloroform, tetrachloromethane, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide and isopropanol.
In yet another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or formula II and a pharmaceutically acceptable excipient.
In yet another embodiment, the present invention discloses that pharmaceutically acceptable excipients include fillers, diluents, binders, lubricants, surfactants, coating agents etc.
In yet another embodiment, the present invention discloses that pharmaceutically acceptable excipients are selected from a group comprising of starch, magnesium stearate, talc, polyethylene glycol, buffers, cellulose, lactose monohydrate.
Even though we have explained the invention of the present disclosure using specific examples, this explanation is not meant to limit how you understand it. People who are skilled in this field may think of various changes and different versions of the invention after reading this description. We expect that such changes can be made without straying from the main idea or purpose of the invention as defined in the claims.

The present disclosure is further described with reference to the following examples, which are only illustrative in nature and should not be construed to limit the scope of the present disclosure in any manner.

EXAMPLES
Example 1:
The inventors exploited the innate ability and inherent potential of one of its carbonyl function along with its adjacent active methylene group to the annulation of 1 with the acyclic alkene/alkyne and cyclic alkene 2(a-n) to form condensed furano derivatives 3(a-n) in generally scheme 1 and particularly in Scheme 1.1 to 1.14 and the second carbonyl function to the expansion its six membered ring to the seven-membered azepinone ring 5(a-n) by applying a one pot Beckmann rearrangement technique on ketones 3a-n which occurred on its reaction with hydroxylamine-O-sulfonic acid (HOSA) reagent 4 with the involvement of ZnCl2 catalyst at room temperature in aqueous media The HOSA assisted the insitu oxime formation which undergo intramolecular rearrangement to the conversion of six-membered to seven-membered ring in mild condition with high yield as shown in scheme 2 and scheme 2.1 to 2.14.

Scheme 1:

Scheme 1.1

Scheme 1.2

Scheme 1.3

Scheme 1.4

Scheme 1.5

Scheme 1.6

Scheme 1.7

Scheme 1.8

Scheme 1.9

Scheme 1.10

Scheme 1.11

Scheme 1.12

Scheme 1.13

Scheme 1.14

Scheme 2:

Scheme 2.1

Scheme 2.2

Scheme 2.3

Scheme 2.4

Scheme 2.5

Scheme 2.6

Scheme 2.7

Scheme 2.8

Scheme 2.9

Scheme 2.10

Scheme 2.11

Scheme 2.12

Scheme 2.13

Scheme 2.14

Example 2: Preparation of compounds 3(a-n):
A solution of ceric ammonium nitrate (CAN) (3.15g, 5.75 mmol) in ethanol (25 ml) was dropwise added to an ice-cooled stirred mixture of the diene 2(a-d) (0.5 g, 0.1 mmol) and dimedone 1 (1.0 g, 7.13 mmol) in ethanol (10 ml). The reddish-brown colour of CAN was disappeared in 15-45 min. The reaction progress was checked using TLC (chloroform: methanol 9:1). After reaction completion, reaction mixture was diluted with 150 ml of water and extracted three times with 30 ml of dichloromethane. The combined organic layers were washed with water, followed by brine, and then dried over anhydrous Na2SO4. The solvent is evaporated in rotatory evaporator below 45oC yielded a pale-yellow solid. The crude product was purified using column chromatography with 2.2:7.8 methanol in chloroform as mobile phase to furnish pure compounds 3(a-d). Similarly, ice-cooled solution of five-membered diene 2(e-h) and six-membered diene 2(i-n) (0.5 g, 0.1 mmol) with dimedone (1.0 g, 7.13 mmol) in ethanol (10 ml) was stirred by the drop wise addition of ceric ammonium nitrate (CAN) (3.15g, 5.75 mmol). The progress of reaction was monitored and checked, upon completion product was extracted and purified by column chromatography to furnish five-membered fused furano ring 3(e-h) and six-membered fused furano ring 3(i-n).

Example 3: Preparation of compounds 5(a-n)
The mixture of 3(a-n) (0.005 mmol), hydroxylamine-O-sulfonic acid (0.0006 mmol) and zinc chloride (0.003 mmol) in water was stirred at 60oC under inert atmosphere for 42h. The reaction progress and completion were monitored using TLC (chloroform: methanol 9:1) until all benzohydrofuran had been consumed. The mixture was extracted by three times washing with 20 ml of ethyl acetate and combined organic layer washed with brine and dried with anhydrous Na2SO4. The pure product was obtained after the removal of solvent and washed with n-hexane to remove minor nonpolar impurities. The solvent was evaporated in vacuo and the residue was purified using a chromatographic column (chloroform 8.2: methanol 1.8).
Table 1: Structure of the synthesized tetrazole annulated furano-annulated azepinone derivatives
Structure IUPAC Name

3,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-furo[3,2-b]azepin-5-one

9-cyclopropyl-6- 7,7-dimethyl-3-phenyl-2,3,4,6,7,8-hexahydro-5H-furo[3,2-b]azepin-5-one

7,7-dimethyl-2-phenyl-4,6,7,8-tetrahydro-5H-furo[3,2-b]azepin-5-one

methyl 7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-2H-furo[3,2-b]azepine-2-carboxylate

4,4-dimethyl-3,4,5,6a,7,8,9,9a-octahydrocyclopenta[4,5]furo[3,2-b]azepin-2(1H)-one


7,7-dimethyl-2,3,3a,4,6,7,8,9a-octahydro-5H-furo[3',2':4,5]furo[3,2-b]azepin-5-one

7,7-dimethyl-3a,4,6,7,8,9a-hexahydro-5H-furo[3',2':4,5]furo[3,2-b]azepin-5-one


2,7,7-trimethyl-3a,4,6,7,8,9a-hexahydro-5H-furo[3',2':4,5]furo[3,2-b]azepin-5-one

4,4-dimethyl-1,3,4,5,6a,7,8,9,10,10a-decahydro-2H-benzofuro[3,2-b]azepin-2-one


4,4-dimethyl-1,3,4,5,6a,9,10,10a-octahydro-2H-benzofuro[3,2-b]azepin-2-one


4,4-dimethyl-1,3,4,5,6a,7,10,10a-octahydro-2H-benzofuro[3,2-b]azepin-2-one


4,4,9-trimethyl-1,3,4,5,6a,7,10,10a-octahydro-2H-benzofuro[3,2-b]azepin-2-one


8,8-dimethyl-3,4,4a,5,7,8,9,10a-octahydro-2H,6H-pyrano[3',2':4,5]furo[3,2-b]azepin-6-one

4,4-dimethyl-4,5,6a,7,7a,10a,11,11a-octahydro-1H-furo[3',4':5,6]benzofuro[3,2-b]azepine-2,8,10(3H)-trione

Example 4: Molecular docking and Invitro Tropomyosin Receptor Kinase B TRKB inhibitory activity:
Molecular docking analysis is a commonly employed approach to assess the affinity of synthesized compounds for a specific target protein. In this study, docking was carried out using MOE (2015) to investigate the active sites of AchE from Homo sapiens (PDB: 4MOE) and predict their binding interactions. The compounds were docked in the active site of AchE and analysed for binding affinities. The compounds 5(a-n) showed key interactions with the active sites of AchE with docking scores ranging from 91.942 to 123.115 Kcal/mol showed in Table 2.
Amongst all, compounds 5n, 5l, and 5b showed the highest affinity and maximum interactions with the catalytic site of the target enzyme. In compound 5n shows a good docking score of 123.115, more than the standard drug galantamine (119.78), and specific binding interactions crucial for their biological activity. In compound 5n, carbonyl of tetrahydrofuran and azepinone involved in hydrogen bond interaction with Gly126, Ala102, Ser203 amino acids whereas methyl and pyran ring involve in hydrophobic interaction with Trp86, Tyr124, Phe338, Phe297 amino acids of AchE. Similarly, 5l and 5b showed hydrogen and hydrophobic interaction with the various residues of amino acid of AchE showed in Supplementary Information. The reference drug galantamine showed hydrogen bond interaction with Asn87, Trp86, His447, Gly120, Ala127 and hydrophobic interaction with Tyr337 amino residue. The 2D and 3D docking poses of 5n and galantamine showed in Fig. 1.

Example 5: In vitro AchE inhibitory activity:
All the synthesized set of furano-azepinone derivatives 5(a-n) are screened for the inhibition of AchE enzyme isolated from the mice via Ellman method. The galantamine (GLM) was used as the reference drugs. The bioassay results revealed that improved inhibitory activity was observed by the replacement of methyl group in 5a (IC50 = 1.3724±0.007 nM) to phenyl ring in 5b (IC50 = 1.2870±0.05 nM) and 5c (1.3071±0.01 nM). The introduction of methoxycarbonyl substituent in 5d showed moderate activity. However, fusion of five-membered ring to furano-azepinone 5e, 5f, 5g and 5h decrease the activity whereas fusion of six-membered cyclohexyl ring in 5l and 5n showed good inhibitory activity. The maximum inhibitory effects were recorded for compounds 5n and 5b with IC50 values 1.2571±0.043 nM and 1.2870±0.05 nM, respectively, which may be attributed to the presence of hexahydroisobenzofuran-1,3-dione and phenyl ring. Notably, tetracyclic ring in 5n showed potent inhibitory potential to AchE enzyme.
Table 2 summarized the invitro AchE inhibitory activity and docking score of synthesized derivatives:
Table 2: Molecular docking and IC50 values of synthesized compounds for inhibiting acetylcholinesterase enzyme
Compounds Docking score IC50 (nM)
5a 1.3724±0.007 83.199
5b 1.2870±0.05 104.317
5c 1.3071±0.01 101.761
5d 1.4320±0.01 101.91
5e 1.3891±0.013 91.942
5f 1.4118±0.01 90.5116
5g 1.3953±0.008 92.5756
5h 1.3818±0.01 96.055
5i 1.3994±0.1 95.7204
5j 1.4744±0.009 97.2989
5k 1.3571±0.043 94.1345
5l 1.4245±0.01 104.296
5m 1.4500±0.01 94.0613
5n 1.2571±0.043 123.115
GLM 1.6261±0.09 119.78

, Claims:We claim
1. A compound of formula I or formula II:

Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted either 2 or 3 position of the furan ring;
“R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring.
Wherein the compound exhibits inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

2. The compound as claimed in claim 1, wherein when R is selected as methyl group at the 3rd position of the furan ring, represents a compound 5a:

3. The compound as claimed in claim 1, wherein when R is selected as phenyl group at the 3rd position of the furan ring, represents a compound 5b:

4. The compound as claimed in claim 1, wherein when R is selected as phenyl group at 2nd position of furan ring, represents the compound 5c.

5. The compound as claimed in claim 1, wherein when R is selected as carboxymethyl group at 2nd position of furan ring, represents compound 5d:

6. The compound as claimed in claim 1, wherein when R’ is selected as five membered, represents compound 5e:

7. The compound as claimed in claim 1, wherein when R’ is selected as tetrahydrofuran, represents compound 5f:

8. The compound as claimed in claim 1, wherein when R’ is selected as five membered ring with one oxo group, represents compound 5g:

9. The compound as claimed in claim 1, wherein when R’ is selected as 2-methyl furan, represents compound 5h:

10. The compound as claimed in claim 1, wherein when R’ is selected as cyclohexane, represents a compound 5i:

11. The compound as claimed in claim 1, wherein when R’ is selected as cyclohex-2-ene, represents a compound 5j:

12. The compound as claimed in claim 1, wherein when R’ is selected as cyclohex-3-ene, represents a compound 5k:

13. The compound as claimed in claim 1, wherein when R’ is selected as methyl substituted cyclohexene, represents compound 5l

14. The compound as claimed in claim 1, wherein when R’ is selected as six-membered heterocyclic ring with oxygen atom, represents compound 5m;

15. The compound as claimed in claim 1, wherein when R’ is selected as hexahydroisobenzofuran-1,3-dione, represents compound 5n:

16. A process of preparation of compounds of formula I and formula II, where in the process comprises the steps of:
(i) 3+2 cycloaddition reaction with dimedone and cyclic and acyclic diene:
(ii) ring expansion via Beckmann rearrangement:
wherein the formula I and formula II are

Wherein “R” is selected from a group comprising of cyclic aromatic ring, phenyl or acyclic group methyl and carboxymethyl group, wherein each group is substituted either 2 or 3 position of the furan ring;
“R’” is selected from a group comprising a five-membered ring or a six-membered cyclic ring wherein each group ring optionally comprises an oxygen atom in the ring.
Wherein the compound exhibits inhibitory activity against acetylcholinesterase (AChE) which is responsible for Alzheimer’s disease.

17. The process as claimed in claim 16, wherein solvent is selected from a list comprising of methanol, ethanol, dichloromethane, chloroform, tetrachloromethane, dimethylsulphoxide, ethylacetate, toluene, benzene, acetone, acetic acid, acetonitrile, dimethylformamide and isopropanol.

18. A pharmaceutical composition comprising a compound of formula I or formula II and a pharmaceutically acceptable excipient.