Claims:We claim:

1) A compound of the following general formula A

where,
R1 is selected from the group comprising C1-C5 alkyl,
R2 is selected from the group comprising C1-C8 alkyl,
and R3 is selected from the group comprising heterocycloalkyl.

2) A compound as claimed in claim 1 having formula C1 as below

3) A compound as claimed in claim 1 having formula C2 as below

4) A compound as claimed in claim 1 having formula C3 as below

5) A compound as claimed in claim 1 having formula C4 as below

6) A compound as claimed in claim 1 having formula C5 as below

7) A compound as claimed in claim 1 having formula C6 as below

8) A compound as claimed in claim 1 having formula C7 as below

9) A compound as claimed in claim 1 having formula C8 as below

10) A compound as claimed in claim 1-9 wherein R1 is selected from the group comprising methyl and ethyl, R2 is selected from the group comprising propyl, butyl and isobutyl and heterocycloalkyl is selected from the group comprising isopropyl phenyl, m-methylphenyl and m-fluorophenyl.
11) A process for synthesis of compounds as claimed in claims 1-10, wherein the process comprises the steps of :
a) Bromination of xanthine at C8 position,
b) Selective protection of –NH group at N7 position,
c) Alkylation reaction of –NH groups, leading to substitution of alkyl groups at N3 and N1 position,
d) Aromatisation at C8 position,
e) De-protection of selectively protected –NH group
12) The process as claimed in claim 11, wherein the bromination is done at 100°C in presence of H2O.
13) The process as claimed in claim 11-12, wherein the selective protection of –NH group of N7 position is carried out by benzyl chloride.
14) The process as claimed in claim 11-13, wherein the concentration of benzyl chloride is 0.5 equivalents of 8-bromoxanthine.
15) The process as claimed in claim 11-14, wherein the alkylation was carried out with alkyl halides.
16) The process as claimed in claim 11-15, wherein the alkylation was carried out in DMF in presence of scavenger base K2CO3.

17) The process as claimed in claim 11-16, wherein the selective protection and alkylation was carried out by SN2 mechanism.

18) The process as claimed in claim 11-17, wherein the aromatisation is carried out by C8 arylation of substituted xanthine.

19) The process as claimed in claim 11-18, wherein the aromatisation is carried out by coupling of substituted xanthine with aryl boronic acid in presence of Pd (PPh3)4 as catalyst, K2CO3, DMF as solvent at 110oC for 48 h under inert Argon atmosphere.

20) A process for synthesis of compounds as claimed in claims 1-10, wherein the process comprises all the steps as of claim 11 except step (b) which here is:
b) Selective protection of –NH group at both N3 and N7 position,
21) A process for synthesis of compounds as claimed in claim 20, wherein selective protection of –NH group of N7 position is carried out by benzyl chloride.
22) A process for synthesis of compounds as claimed in claim 20, wherein selective protection of –NH group of N3 position is carried out by 4-methoxy benzyl chloride.

23) The process as claimed in claims 11-22, wherein the selective de-protection at N7 position is carried out by catalytic hydrogenation.

24) The process as claimed in claims 11-23, wherein the selective de-protection at N3 position is carried out by acid de-protection.

25) The process as claimed in claims 11-24, wherein the catalytic de-protection is carried out in presence of Pd-catalyst, ammonium formate and methanol at room temperature.

26) The process as claimed in claims 11-25, wherein the acid de-protection is carried out in presence of TFA (Trifloro acetic acid), H2SO4 and anisol with reflux.

27) The compounds and processes as herein described according to text, figures and tables along with reaction schemes and intermediates.
, Description:FIELD OF THE INVENTION
The present invention relates to the field of drug development and pharmaceutical chemistry, specifically to a class of substituted xanthine derivatives, preparation method and the use thereof as therapeutic agents, especially as phosphodiesterases 9A (PDE9A) inhibitors. More particularly the invention pertains to the development of novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material.

BACKGROUND OF THE INVENTION
In recent years, modifications on existing well known drugs have been targeted in drug development process for creating compounds more suitable for their targets in terms of lesser toxicity and increased efficiency of the compound towards a particular target. In human cells, signal transduction is the regulating process of communication between intracellular and extracellular environments of the cell. In this process phosphodiesterases act as key regulating enzymes.
Phosphodiesterase 9A, one of the regulating enzymes in signal transduction pathway involves regulation of cGMP (cyclic guanosine mono phosphate). In some pathophysiological conditions cGMP may get lowered affecting the smooth functioning of signal transduction. Thus inhibition is a key to regulate the level of PDE9A, the absence of which may lead to various diseases such as Schizophrenia, Alzheimer's disease, Parkinson's disease (PD), Creutzfeldt Jakob disease (CJD), diabetes, chronic obstructive pulmonary disease (COPD), obesity, and certain cardiovascular diseases (Oeckl et al., 2012). Inhibition of PDE9A becomes imperative for normalizing the cellular function. No marketed drug is available till date for PDE9A inhibition. Natural Xanthine derivatives such as caffeine, theophylline, theobromine are regarded as non-specific drugs for most of the PDEs (phosphodiesterases) but specific research detail of xanthine derivatives on PDE9A are not available. The structural resemblance with substrate (cGMP) makes xanthine based derivatives good target for PDE9A.
Xanthines and its derivatives are well-known non-specific inhibitors for phosphodiesterases. Xanthine derivatives are significant in various other pharmaceutical applications such as adenosine receptor antagonists, inducers of histone deacetylase activity, antitumor drugs, anti-asthmatic drugs, psycho-stimulant drugs etc [Burbiel et al, 2006; Allwood et al, 2007; Suravajhala et al, 2014]. The modification at different position of the xanthine molecule enhances the size and rigidity of the newly formed compounds.
Earlier studies have proposed ring closure synthetic route for synthesis of xanthine derivatives [Hayallah et al, 2002, Allwood et al, 2007, Bandyopadhyay et al, 2012]. Similar types of schemes are being used for the synthesis of these derivatives. These schemes suffer from numerous bottlenecks, such as use of acid/base or external oxidant, isolation of imine intermediate, use of toxic and expensive reagents/catalysts, high temperature requirement, hazardous solvents, prolonged reaction time, tedious workup, formation of by-products, low yield etc. [Bandyopadhyay et al, 2012]. Thus classical condensation and ring closure methods are not suitable for synthesis of diverse derivatives because these methods require many steps and provide low yield [Kim et al, 2010]. Synthesis of xanthine derivatives from known xanthine based molecules such as theophylline, caffeine, theobromine etc. have been proposed [Sakai et al, 1992; Kim et al, 2010]. The problem with using these compounds as starting material is that it limits the substitution to only those sites which are available for substitution. For instance, in caffeine, all the three –NH groups at N1, N3 and N7 positions are already occupied by methyl groups. Thus only C8 position is available for substitution.
Reference can be made to JPS5668681 (A) which describes the preparation of pentoxifylline having an ameliorant effect on the blood circulation advantageously, by using a 1-(3-halogenated propyl)-theobromine as a starting material, and hydrolysis or alcoholysis of novel 1-(4-acetyl-5-oxohexyl) - theobromine.
Reference can also be made to JPS5594386 (A) which refers to obtaining a xanthine derivative useful as a drug of a circulating organ capable of improving sequela of cerebral thrombosis, by reacting 1-alkyl-4-methylamino-5-N-methylcarboxamido-imidazole with a urea derivative.
Considering the above limitations such as shortcomings of ring closure mechanism, lack of direct route to synthesize xanthine derivatives using xanthine as starting material, and availability of limited binding sites in natural xanthine derivatives, there is an urgent need to find a viable alternative. Thus the inventors propose this present invention for synthesis of compounds which showed significant inhibition activity towards PDE9A.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to overcome all the associated drawbacks and provide novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives to be used in therapeutics.
Another objective of the present invention is to provide novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material.
Yet another objective of the present invention is to synthesize xanthine derivatives which have the potential to inhibit cyclic nucleotide phosphodiesterase 9A.

SUMMARY OF THE INVENTION
The present invention provides xanthine derivatives which have the potential to inhibit cyclic nucleotide phosphodiesterases 9A, the key regulatory enzymes in the signal transduction pathway. Two new schemes have been developed for this synthesis. Both schemes have used xanthine as a starting material. As xanthine derivatives are modified form of xanthine, using xanthine as a starting material for synthesis of derivatives has other benefits, such as easy availability, cost effectiveness, time saving and possibility of large scale synthesis. With this initiative only modification at different positions of xanthine was required without disturbing the scaffold of xanthine.
The synthesized xanthine based inhibitors for PDE9A would be useful for targeting neurodegenerative diseases, as PDE9A is abundant in brain cells and participates in regulating the signal transduction process in brain cells. Phosphodiesterase 9A has highest affinity for cGMP which is involved in myriad of cellular functions including relaxation of smooth muscles, inhibition of platelet aggregation, blunting of cardiac hypertrophy, protection against ischemia/reperfusion damage of the heart, and improvement in cognitive functions etc. [Francis et al, 2010].
Accordingly the present invention provides novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives to be used in therapeutics.
In one general aspect, two novel schemes have been provided for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material.
In another general aspect, two schemes have been provided to synthesize xanthine derivatives which have the potential to inhibit PDE9A.
Accordingly the present invention provides two novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material to synthesize xanthine derivatives which have the potential to inhibit cyclic nucleotide phosphodiesterase 9A, to be used in therapeutics, the said schemes comprising the steps of -
i) Selective bromination of –CH group
ii) Protection of –NH with benzyl group at N7 position in scheme-1 and scheme-2 and N3 position with 4-methoxy benzyl group in scheme-2
iii) Alkylation of –NH groups at N3 and N1 position
iv) Aromatization at C8 position
v) Deprotection of protecting groups (benzyl group and/or 4-methoxy benzyl group)
The details of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description including claims.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig.1 Mechanism of SN2 reaction for benzyl protection
Fig.2 Pathway of Scheme-I
Fig.3 Pathway of Scheme-II
Fig.4 Combined Pathway of Scheme-I and Scheme-II
Fig.5 IC50 graph of synthesized compounds C1-C8

DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the invention as illustrated herein, which would occur to one, skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.
The present inventors have developed two novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives to be used in therapeutics.
In one general aspect, there are provided two novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material.
In another general aspect, there are provided two schemes to synthesize xanthine derivatives which have the potential to inhibit cyclic nucleotide PDE9A.
Accordingly the present invention provides two novel schemes for synthesis of 1, 3, 8- tri substituted xanthine derivatives using xanthine as a starting material to synthesize xanthine derivatives which have the potential to inhibit PDE9A, to be used in therapeutics.
Availability, affordability and accessibility are the three main parameters considered in drug development to reduce the cost of manufacturing. Thus, the selection of starting material is a very crucial step for the synthesis process. Xanthine derivatives are the modified forms of original xanthine molecule. Abundance of xanthine, both biologically and synthetically makes it a great choice as the reaction initiator for organic synthesis of xanthine derivatives. In the present invention, xanthine was used as starting material. Using xanthine as a starting material for synthesis of xanthine derivatives was not an easy task because of the presence of three –NH groups at N1, N3 and N7 positions. These needed to be taken as a challenge in understanding the nature of these –NH groups separately for successful selective reaction. Earlier studies have established substitution at N1, N3 and C8 positions at xanthine as potential binding sites for inhibitor development to target PDE9A [Jacobson et al, 1992; Miyamoto et al, 1994; Bandyopadhyay et al, 2012].
The whole synthesis work is divided into two schemes - Scheme-I and Scheme-II, which simplified the nature of xanthine derivatives. Scheme-I can be applied for those compounds having common N3 position with diverse N1 and C8 substitutions. Likewise scheme-II can be applied for those compounds having common N1 substituent but different C8 and N3 substituent. Thus, these two separate schemes are designed to construct diverse library of xanthine derivatives.
Therapeutic Compounds
Present invention provides compound of general formula A

Where,
R1 is selected from C1 – C5 alkyl,
R2 is selected from C1 – C8 alkyl, and
R3 is selected from heterocycloalkyl.
The compounds synthesized by using formula A are

Compound C1

Compound C2

Compound C3

Compound C4

Compound C5

Compound C6

Compound C7

Compound C8
Schemes Used for Synthesis
i) Bromination of –CH group at C8 position of xanthine (in both scheme-I and scheme-II)

The selective reaction is very crucial in the designing of these two schemes. In this invention, as modification at N1, N3 and C8 positions were selected for synthesis of xanthine derivatives, thus, to make the selective reaction it was imperative to protect N7 position first. For protecting –NH group at N7 position, benzyl chloride was used. Before –NH protection, xanthine was brominated at C8 position in first step for C¬8 aryl substitution to be carried out at 5th step because xanthine has only one hydrogen at C8 position with –CH group. After protection with benzyl group selective bromination at C8 position was not possible due to the presence of methylene (-CH2) group. Therefore, bromination of xanthine was carried out first in both the schemes.

ii) Protection of –NH group
Protection of N7 position of 8-bromo xanthine in scheme-I and scheme-II
The presence of three –NH group at Xanthine represents different properties. The -NH group at all three positions on xanthine has different reactivity because of their surrounded atomic environment. The –NH group at N7 position is highly reactive among all three –NH groups because it faces comparatively less steric hindrance than the other –NH groups. Thus based on different concentration analysis of benzyl chloride for protection targeting N7 position it was found that N7 possessed higher reactivity than N3 while N3 was higher in reactivity than N1 position. N1 was found to be the least reactive because of the presence of carbonyl group on both sides (C2 and C6) which creates high steric hindrance. Coupling of brominated xanthine with one equivalent of benzyl chloride gave two products-one was 7-benzyl 8-bromoxanthine (major) and another was 3, 7-dibenzyl 8-bromoxanthine (minor). When more than one equivalents of the benzyl chloride was used, mixture of compounds was obtained with protection at different position such as 7-benzyl protection, 3, 7-dibenzyl protection and 1, 3, 7-tribenzyl protection. From this mixture, purification of the 7-benzyl 8-bromoxanthine by passing through silica column was very difficult task because of high polarity of the desired product. Hence, presence of higher concentration of benzyl chloride than the concentration required only for the occupancy of N7 position of xanthine was the reason behind obtaining undesired multiple products. Hence, optimization of selective protection was carried out by reducing concentration of benzyl chloride. When benzyl chloride concentration was reduced to 0.5 equivalents of 8-bromoxanthine, it gave a selective protection of N7 position only. After the selective protection of –NH group at N7 position, reaction at N3 position was carried out with optimized concentration of the alkyl halides. The protection of N7 position was carried out by SN2 mechanism.

Scheme-II Step-3b: Protection of N3 position of 7-benzyl 8-bromo xanthine with 4-methoxy benzyl chloride
In this scheme both N3 and N7 positions were protected with different protecting groups. Benzyl group was used for N7 protection while 4-methoxy benzyl chloride was used as protecting group for N3 protection.

(iii) Alkylation of –NH groups at N3 and N1 positions of protected 8-bromo xanthine
In both schemes alkyl groups at both N3 and N1 positions were selected because of their positive biological implications such as inotropic effect, higher blood-brain barrier permeability level and plasma protein binding efficiency [Sanae et al, 1995]. Alkylation both at N3 and N1 positions were also carried out with SN2 mechanism similar to the protection at 7th position with benzyl group. This alkylation reaction is dependent on the concentration of both the reactants (xanthine intermediates and alkyl group). Alkylation reaction was performed in DMF (Dimethylformamide) in the presence of scavenger base K2CO3.
Scheme-I Step-3a: Substitution of alkyl groups at N3 position of 7-benzyl 8-bromoxanthine

Conditions: 0.9 equivalent alkyl iodide, 2 equivalent anhydrous K2CO3, anhydrous DMF, 70°C, 6 hours.
Scheme-I Step-4a Substitution of alkyl groups at N1 position of N3 substituted 7-benzyl 8-bromoxanthine


Condition: 1.5 equivalent alkyl iodide, 2 equivalent anhydrous K2CO3, anhydrous DMF, 70°C, 12 hours

Scheme-II Step-4b: Substitution of alkyl group at N1 position of N3 and N7 protected 8-bromoxanthine

R1= -C2H5
Compound synthesized in scheme-II is

Scheme-II Step-7b: Substitution of alkyl group at N3 position of N1 substituted 7-benzyl 8-bromoxanthine

Here, R2= n-C4H10 (n-butyl), iso-C4H10 (iso-butyl)

(iv) Aromatization of C8 position of xanthine derivatives
Palladium mediated Suzuki coupling reaction is a well-established method for C8 aryl substitution in xanthine derivatives [Vollmann et al, 2002]. C8 arylation of xanthine was carried out with Pd (PPh3)4 (catalyst), K2CO3 (base), DMF (solvent) at 110°C for 48 hours under inert argon atmosphere. The desired products were isolated with yield of 95%. This reaction condition was applied to install C8-phenyl ring with various functional groups and side chains.
Scheme-I: Step-5a coupling of 1, 3 di-substituted xanthine with aryl boronic acid


Condition: 1-R1 3-R2 7-Benzyl 8-Bromo xanthine (1 equivalent), 0.013 equivalents Pd (PPh3)4 (catalyst), 2 equivalent K2CO3 (base), DMF (solvent) at 110°C for 48 hours under inert argon atmosphere.
Scheme-II: Step-5b coupling of N1- substituted xanthine with aryl boronic acid

Here, R3= iso-propyl phenyl

(v) Deprotection of protecting groups of xanthine derivatives
Finally, 7-benzyl protected xanthine derivatives were deprotected. Initially acid deprotection method was used for deprotection of benzyl group but it did not work for benzyl protection at 7th position. Then catalytic hydrogenation was used for deprotection at 7th position of xanthine derivatives in both scheme-I and scheme-II. The catalytic hydrogenation was the best method for selective deprotection at N7 position when benzyl group was used as a protector. It was seen that when benzyl group was used as protector on both N3 and N7 positions, catalytic deprotection occurred only at N7 position while acidic deprotection occurred partially at N3 position only. But when p-methoxy benzyl chloride was used for protection at N3 position selective deprotection occurred at N3 position in acid deprotection environment. Hence, in scheme-II the protection of N3 position was carried out with other protecting group - p-methoxy benzyl group. The presence of methoxy (an electron releasing) group made the deprotection easier. The selective deprotection of p-methoxy benzyl group at N3 position was carried out by acid deprotection method. The acid deprotection was selective for the N3 position both in case of benzyl and p-methoxy benzyl protecting groups but this method was more suitable for deprotection of p-methoxy benzyl group. The acid deprotection method was non-reactive to deprotection of benzyl protecting group at N7 position. Therefore this method was used for selective N3 deprotection in scheme-II.
Catalytic deprotection of benzyl group at N7 position of xanthine derivatives in scheme-I and scheme-II

Selective deprotection of benzyl group at 7th position

Scheme-II Step-6b: Acid deprotection of p-methoxy benzyl (PMB) group at N3 position of xanthine derivative in scheme-II

Here, R1= C2H5 and R3= m-isopropyl phenyl

Scheme-II is the modified version designed for the synthesis of xanthine derivatives. It can be applied for the synthesis of diverse library of xanthine derivatives with common substitution at N1 and C8 positions with different derivatives attached at N3 position. Both step-1 and step-2 are common for scheme-I and scheme-II. From step-3b scheme-II follows another path. Finally, step-6a/step-8b is also common for both scheme-I and scheme-II.

Table 1 Details of synthesized compounds (C1-C8)
Entry R1 R2 R3 Compounds Yield (in %) Molecular weight Melting Point Formula Schemes applied
C1 - CH3 -CH2CH2CH3

93.02 326 793 C18H22N4O2 Scheme-I
C2 - CH¬¬2CH3 -CH2CH2CH3

76.00 340 805.15 C19H22N4O2 Scheme-I
C3 - CH¬¬2CH3 -CH2CH2CH3

77.12 312.66 798 C17H20N4O2 Scheme-I
C4 -CH3 -CH2CH2(CH3)2

81.08 340.42 790 C19H24N4O2 Scheme-I
C5 - CH¬¬2CH3 -CH2CH2(CH3)2

76.00 354.55 801 C20H26N4O2 Scheme-I & Scheme-II
C6 - CH¬¬2CH3 -CH2CH2 CH2CH3

77.38 354.44 816 C20H26N4O2 Scheme-I & Scheme-II
C7 - CH¬¬2CH3 -CH2CH2 CH2CH3

50.00 326.4 808 C18H22N4O2 Scheme-I
C8 - CH¬¬2CH3 -CH2CH2 CH2CH3

53.54 330.35 798 C17H19F N4O2 Scheme-I

EXAMPLE - 1
Step-1 of Scheme-I and Scheme-II
Bromination at C8 position of xanthine (synthesis of 8-bromo-1H-purine-2, 6 (3H, 7H)-dione)
To a mixture of Xanthine (1 g, 657 mmol) in 6.5 ml water in a glass tube 711 µL (13.7 mmol) of concentrated bromine (Br2) solution was added. The glass tube was capped tightly. The reaction was allowed to heat at 100°C for 2h. After 2h of reaction, product mixture was allowed to cool at room temperature and filtered. The solid was washed with water followed by washing with diethyl ether (Et2O). The product was dried under high vacuum. Light yellowish powder was formed with yield of 71.36 %.
1H NMR (600 MHz, DMSO-d6): 14.003(1H, s), 11.667(1H, s), 10.924(1H, s).
13C NMR (600 MHz, DMSO-d6): d 154.54, 151.06, 148.83, 124.00, 109.47.
MS (+ESI) m/z: 231.01, 232.0058(MH+).

EXAMPLE - 2
Step-2 of Scheme-I and Scheme-II
Protection of –NH group at N7 position of 8-bromoxanthine
To a mixture of 8-Bromo xanthine (8-bromo-1H-purine-2, 6 (3H,7H)-dione) (0.3g, 1.298 mmol) in 3 mL anhydrous DMF, 1.298 mmol K2CO3 and 80.6 µL benzyl chloride (0.7 mmol) were added in a 25 mL round bottom flask. Reaction was allowed to run at 70°C for 2.5h on silica bath. After the completion of reaction, product mixture was kept at ice. 10% dilute HCl was added to neutralize the product mixture. White colour precipitate was formed. Product was filtered and washed 2-3 times with water. The product was allowed to vacuum dry. White powder was obtained with 45 % yield.
1H NMR (600 MHz, DMSO-d6): 11.804 (1H, s), 11.061 (1H, s), 7.356 (2H, s), 7.30 (1H, s), 7.23 (2H, s), 5.442 (2H, s).
13C NMR (600 MHz, DMSO-d6): d 155.20, 151.15, 149.13, 136.05, 129.12, 128.82, 128.27, 127.43, 108.86, 49.57,
MS (+ESI) m/z: 321.94, 322.94 (MH+)

EXAMPLE - 3
Step-3b of Scheme – II
Protection of –NH group at N3 position of 7¬-benzyl 8-bromoxanthine
To a mixture of 7-benzyl 8-Bromo xanthine (7-benzyl-8-bromo-1H-purine-2,6 (3H,7H)-dione) (1.07 g, 3.33 mmol) in 10 mL anhydrous DMF, 6.66 mmol of K2CO3 and 40.65 µL of 4-methoxybenzyl chloride (0.9 mmol) were added in a 50 mL round bottom flask. Reaction was allowed to run at 70°C for 2.5 h on silica bath. After the completion of the reaction, the product mixture was kept on ice. 10% HCl was added drop-wise to neutralise the product mixture. Light white coloured precipitate was formed. Product was filtered and washed 2-3 times with water. The product was allowed to vacuum dry. White powder was formed with 70.06 % yield.

1H NMR (600 MHz, DMSO-d6): 11.421 (1H, s, N1-NH), 7.343(2H, J= 7.26, 7.26, Ar), 7.296 (1H, d, J=6.19, Ar), 7.259 (4H, t, J=8.26, 8.26, Ar), 6.863 (2H, d, J=8.43, Ar), 5.455 (2H, s, N7-CH2-), 4.976 (2H, s, N3-CH2-), 3.693 (3H, s, Ar-OCH3).
13C NMR (600 MHz, DMSO-d6): 159.44, 154.23, 150.97, 149.46, 136.19, 129.78, 129.44, 128.64, 127.89, 114.53, 109.65, 55.72, 50.09, 45.12
MS (+ESI) m/z: 441.0397

EXAMPLE - 4
Step-3a1 of Scheme-I
Substitution of propyl group at N3 position of 7-benzyl 8-bromoxanthine (Synthesis of 7-benzyl-8-bromo-3-propyl-1H-purine-2, 6 (3H, 7H)-dione)
To a mixture of 7-benzyl 8-bromo xanthine (7-benzyl-8-bromo-1H-purine-2, 6 (3H,7H)-dione) (307 mg, 0.956 mmol) and anhydrous K2CO3 (132 mg, 0.956 mmol) in a 2 mL anhydrous DMF, 47.36 µL propyl iodide (0.487 mmol) was added and stirred at 70°C for 6 h. After the completion of reaction the reaction flask was kept on ice for 10 minutes. 10% diluted HCl was added drop-wise to neutralize the product mixture. After that water was added in the neutralized solution. White color precipitate was formed which was filtered and washed 3-4 times with water followed by drying in oven at 40°C. The resultant solid powder was the mixture of two compounds-7-benzyl-8-bromo-3-propyl-1H-purine-2, 6 (3H,7H)-dione and 7-benzyl-8-bromo-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione. The products were purified by column chromatography. The major product was 7-benzyl-8-bromo-3-propyl-1H-purine-2, 6 (3H,7H)-dione (Compound 3a1) in white powdered form. The final yield of the compound 3a1 (7-benzyl 8-bromo 3-propyl xanthine) was 77.81 %.

1H NMR (600 MHz, DMSO-d6): 11.33(1H,s), 7.36 (2H, t, J=7.57, 3,5-ArH), 7.31(1H, t, J=7.31, 4-ArH), 7.264 (1H, d, J=7.17, 2,6-ArH), 5.48 (2H,s, -CH2-Ar), 3.83 (2H, t, N3-CH2-CH2-), 1.65 (2H, sextet, -CH2-CH2-CH3 ), 0.874 (3H,t, -CH2CH3)
13C NMR (600 MHz, DMSO-d6): 154.06, 150.27, 149.10, 135.58, 128.76, 128.47, 127.95, 127.18, 108.81, 49.34, 43.41, 20.81, 10.94
MS (+ESI) m/z: 363.0453, 364.0453 (MH+)

Step-3a2 of Scheme-I
Substitution of isobutyl group at N3 position of 7-benzyl 8-bromoxanthine (Synthesis of 7-benzyl-8-bromo-3-isobutyl-1H-purine-2, 6 (3H, 7H)-dione)

To a mixture of 7-benzyl 8-bromo xanthine (7-benzyl-8-bromo-1H-purine-2, 6(3H, 7H)-dione) (385 mg, 0.12 mmol) and anhydrous K2CO3 (0.33 mg, 0.239 mmol) in a 1 mL anhydrous DMF, 137.96 µL isobutyl iodide (0.12 mmol) was added. The reaction mixture was then stirred at 70°C for 6 h. After completion of the reaction, flask was kept on ice for 10 minutes. To neutralize the product mixture 10% HCl was added dropwise followed by addition of water to the neutralized solution. Subsequently, off white colour precipitate was formed which was filtered and washed 3-4 times with water followed by drying in oven at 40°C. The resultant powder was the mixture of two compounds- 7-benzyl-8-bromo-3-isobutyl-1H-purine-2,6 (3H,7H)-dione and 7-benzyl-8-bromo-1,3-diisobutyl-1H-purine-2,6(3H,7H)-dione. Column chromatography was carried out to separate two products. 7-benzyl-8-bromo-3-isobutyl-1H-purine-2,6 (3H,7H)-dione (compound 3a2) was the major product in white powdered form with final yield of 85.2 %.

1H NMR (600 MHz, DMSO-d6): 11.33(1H, s, N1-H), 7.36 (2H, t, J=7.42, 3,5-ArH), 7.31(1H, dd, 2,6-ArH, J=5.44, 9.10), 7.26 (2H, d, 4-ArH, J=7.34), 5.47 (2H, s, N7-CH2-), 3.85 (2H, t, J= 7.48, N3-CH2-), 2.15 (1H, septet, -CH-(CH3)2), 0.87(6H, d, -CH(CH3)2)
13C NMR (600 MHz, DMSO-d6): 154.06, 150.34, 149.32, 128.75, 127.93, 127.15, 108.86, 49.48, 48.81, 26.75, 19.72.
MS (+ESI) m/z: 377.0609

Step-3a3 of Scheme-I
Substitution of n-butyl group at N3 position of 7-benzyl 8-bromoxanthine (Synthesis of 7-benzyl-8-bromo-3-butyl-1H-purine-2, 6 (3H,7H)-dione)

To a mixture of 7-benzyl 8-bromo xanthine (7-benzyl-8-bromo-1H-purine-2, 6 (3H,7H)-dione) (90 mg, 0.28 mmol) and anhydrous K2CO3 (0.39 mg, 0.280 mmol) in 1 mL anhydrous DMF, 22.6 µL propyl iodide (0.199 mmol) was added. The reaction then stirred at 70°C for 6h. After completion of the reaction, the flask was kept on ice for 10 minutes. 10% HCl was added drop-wise to neutralize the product mixture followed by addition of water. Then, white colored precipitate was formed. Precipitated product was filtered and washed 3-4 times with water followed by drying in oven at 40°C. This powder was a mixture of two compounds- 7-benzyl-8-bromo-3-butyl-1H-purine-2, 6 (3H,7H)-dione and 7-benzyl-8-bromo-1,3-dibutyl-1H-purine-2,6(3H,7H)-dione. The product mixture was purified by column chromatography. 7-benzyl-8-bromo-3-butyl-1H-purine-2, 6 (3H,7H)-dione (compound 3a3) was the major product in white powdered form with a final yield of 85.7 %.

1H NMR (600 MHz, DMSO-d6): 11.32(1H, s, N1-H), 7.34 (2H, t, J=7.36, 3,5-ArH), 7.29(1H, t, 2,6-ArH, J=7.05), 7.23 (2H, d, 4-ArH, J=7.87), 5.46 (2H, s, N7-CH2-), 3.85 (2H, t, J= 7.30, N-CH2-), 1.59 (2H, quintet, -CH2-CH2-CH2-), 1.28 (2H, quintet, CH2-CH2-CH3), 0.88 (3H, t, J=7.4 Hz, -CH2CH3)
13C NMR (600 MHz, DMSO-d6): 154.05, 150.23, 149.07, 135.57, 128.76, 128.07, 127.95, 127.19, 108.82, 49.34, 41.65, 29.60, 19.36, 13.60
MS (+ESI) m/z: 377.0629

EXAMPLE - 5
Step-7b of Scheme-II
Synthesis of compound 7b1 (7-benzyl-1-ethyl-3-isobutyl-8-(3-isopropylphenyl)-1H-purine-2,6(3H,7H)-dione) and compound 7b2 (7-benzyl-3-butyl-1-ethyl-8-(3-isopropylphenyl)-1H-purine-2,6 (3H,7H)-dione)
To a mixture of compound 6b1 (0.2 g, 0.514 mmol) and anhydrous K2CO3 (0.142 g, 1.028 mmol) in 2 mL anhydrous DMF, 88 µL isobutyl iodide or butyl iodide (0.77 mmol) was added. The reaction was then stirred at 70°C for 12 h. After completion of the reaction, the reaction flask was kept on ice for 10 minutes. To neutralize the product mixture 10% HCl was added dropwise. Thereafter, water was added to the neutralized solution leading to the formation of off-white colored precipitate. Precipitated product was filtered and washed 3-4 times with water followed by drying in an oven at 40°C. Yellowish oil mixture was obtained. The product was purified by column chromatography. The purified compound was obtained in yellowish oil form with yield of 84.6 %. The compounds (compound 7b1 and compound 7b2) were similar compounds that we got from step-5a5 (compound 5a5) and 5a6 (compound 5a6) in scheme-I.

EXAMPLE - 6
Step-4a1 of Scheme-I
Substitution of methyl group at N1 position of Compound 3a1 (Synthesis of 7-benzyl-8-bromo-1-methyl-3-propyl-1H-purine-2, 6(3H,7H)-dione)

To a mixture of compound 3a1 (630 mg, 1.73 mmol) and anhydrous K2CO3 (480 mg, 3.47 mmol) in 8 mL anhydrous DMF, 216 µL methyl iodide (3.47 mmol) was added. The reaction mixture was then stirred at 70°C for 12 h. After completion of the reaction, flask was allowed to cool at room temperature. The product mixture was diluted with ethyl acetate. Organic part was separated from the aqueous part by using water and brine alternatively. At the end of extraction, the organic part was isolated and dried with sodium sulfate. The yellowish solution obtained was vacuum dried in rotary evaporator. The yellowish mixture obtained was purified by column chromatography with ethyl-hexane (10:90) solvent. Purified whitish powder was obtained with a yield of 89.7 % (7-benzyl-8-bromo-1-methyl-3-propyl-1H-purine-2, 6(3H,7H)-dione).

1H NMR (600 MHz, DMSO-d6): 7.36 (2H, dd, J=4.57, 10.13: 3,5-ArH), 7.31(1H, t, J=1.81, 9.03, 4-ArH), 7.26 (2H, m, 2,6-ArH), 5.48 (2H,s, J=3.76, -CH2-Ar), 3.9 (2H, dd, J=6.80, 7.91 N3-CH2-CH2-), 3.22 (3H, s, J= 3.03, N1-CH3), 1.67 (2H, sextet, -CH2-CH2-CH3 ), 0.88 (3H,t, J=7.45, -CH2CH3).
13C NMR (600 MHz, DMSO-d6): 153.73, 150.34, 147.56, 135.56, 128.74, 128.22, 127.91, 127.12, 108.36, 49.35, 44.43, 27.76, 10.95.
MS (+ESI) m/z: 377.0603

Step-4a2 of Scheme-I
Substitution of ethyl group at N1 position of Compound 3a1 (Synthesis of 7-benzyl-8-bromo-1-ethyl-3-propyl-1H-purine-2,6 (3H,7H)-dione)

To a mixture of compound 3a1 (500 mg, 1.38 mmol) and anhydrous K2CO3 (381 mg, 2.75 mmol) in 5 mL anhydrous DMF, 220 µL ethyl iodide (2.75 mmol) was added. The reaction was allowed to stir at 70°C for 12 h. After completion of the reaction, reaction mixture was allowed to cool on ice for 10 minutes. The product mixture was neutralized with 10% HCl. As white precipitate began to appear, water was added to the neutralized mixture. After addition of water the product was accumulated in a white precipitated form. The whitish precipitate was filtered and washed with water 3-4 time. Product was allowed to dry at 40°C in a hot air oven to obtain white powder (compound 4a2). The final yield of the compound 4a2 (7-benzyl-8-bromo-1-ethyl-3-propyl-1H-purine-2,6(3H,7H)-dione) was 94.8%.

1H NMR (600 MHz, DMSO-d6): 7.35 (2H, t, J=7.40, 7.40), 7.29 (1H, t, J=7.35, 7.35), 7.246 (2H, d, J= 7.31), 5.551 (2H, s, -CH2-C6H5), 3.888 (4H, q, J=6.99, 6.99, 6.81), 1.662 (2H, m, N3-CH2CH2CH3), 1.095 (3H, t, J= 7.00, 7.00, N1-CH2CH3), 0.868 (3H, t, J=7.44, 7.44, N3-CH2CH2CH3).
13C NMR (600 MHz, DMSO-d6): 153.33, 149.88, 147.57, 135.55, 128.33, 127.89, 127.09, 108.36, 49.32, 44.32, 35.75, 20.75, 12.96, 10.93.
MS (+ESI) m/z: 391.0778

Step-4a3 of Scheme-I
Substitution of methyl group at N1 position of compound 3a2 (Synthesis of 7-benzyl-8-bromo-3-isobutyl-1-methyl-1H-purine-2,6 (3H,7H)-dione)

To a mixture of compound 3a2 (812 mg, 2.15 mmol) and anhydrous K2CO3 (595 mg, 4.3 mmol) in 10 mL anhydrous DMF, 268 µL methyl iodide (3.47 mmol) was added. The reaction was then stirred at 70°C for 12 h. After completion of the reaction, flask was allowed to cool at room temperature. The product mixture was diluted with ethyl acetate and transferred to a separating funnel. The organic part was extracted from the aqueous part by washing with water and brine alternatively and dried with sodium sulfate. The product mixture was vacuum dried in a rotary evaporator. Dark yellowish product mixture was obtained. The product mixture was purified by column chromatography using ethyl-hexane (10:90). The white powder (compound 4a3) was obtained. The final yield of the product was 92.6% (7-benzyl-8-bromo-3-isobutyl-1-methyl-1H-purine-2,6(3H,7H)-dione).

1H NMR (600 MHz, DMSO-d6): 7.36 (2H, t, J=7.41, 3,5-ArH), 7.31(1H, t, 2,6-ArH, J=7.31), 7.26 (2H, d, 4-ArH, J=7.31), 5.52 (2H, s, N7-CH2-), 3.85 (2H, d, J= 7.48, N3-CH2-), 3.23 (3H, s, N1-CH3), 2.17 (1H, septet, -CH-(CH3)2), 0.88 (6H, d, -CH(CH3)2).
13C NMR (600 MHz, DMSO-d6): 153.33, 149.88, 147.57, 135.55, 128.33, 127.89, 127.09, 108.36, 49.32, 44.32, 35.75, 20.75, 12.96, 10.93.
MS (+ESI) m/z: 391.0763

Step-4a4 of Scheme-I
Substitution of ethyl group at N1 position of compound 3a2 (Synthesis of 7-benzyl-8-bromo-1-ethyl-3-isobutyl-1H-purine-2,6(3H,7H)-dione)

To a mixture of compound 3a2 (0.224g, 0.646 mmol) in 3 mL anhydrous DMF, 0.178 mmol anhydrous K2CO3 and 104 µL (0.129 mmol) of ethyl iodide was added. Reaction was allowed to run at 70°C for 12 h on silica bath. After completion of the reaction, product was extracted with ethyl acetate and water sequentially. The extracted organic part was dried with sodium sulphate. Yellowish reaction mixture was obtained after vacuum evaporation. Reaction mixture was purified by column chromatography. White powdered compound was obtained with final yield of 90 % (7-benzyl-8-bromo-1-ethyl-3-isobutyl-1H-purine-2,6(3H,7H)-dione).

1H NMR (600 MHz, DMSO-d6): 7.36 (2H, t, J=7.41, 3,5-ArH), 7.31(1H, t, 2,6-ArH, J=7.31), 7.26 (2H, d, 4-ArH, J=7.31), 5.51 (2H, s, N7-CH2-), 3.90 (2H, quartet, N1-CH2-CH3) 3.77 (2H, d, N3-CH2-CH2-), 3.23 (3H, s, N1-CH3), 2.15 (1H, septet, -CH-(CH3)2), 0.86 (6H, d, -CH(CH3)2).
13C NMR (600 MHz, DMSO-d6): 153.37, 150.16, 147.82, 135.59, 128.78, 128.50, 127.92, 127.12, 108.36, 49.36, 42.23, 37.72, 35.81, 26.82, 19.78, 12.98.
MS (+ESI) m/z: 405.0931

Step-4a5 of Scheme-I
Substitution of ethyl groups at N1 position of compound 3a3 (Synthesis of 7-benzyl-8-bromo-3-butyl-1-ethyl-1H-purine-2,6 (3H,7H)-dione)

To a mixture of compound 3a3 (525 mg, 1.39 mmol) and anhydrous K2CO3 (385 mg, 2.78 mmol) in 6 mL anhydrous DMF, 224 µL ethyl iodide (2.78 mmol) was added. The reaction was allowed to stir at 70°C for 12 h. After completion, reaction mixture was allowed to cool on ice for 10 minutes. The product mixture was neutralized with 10% HCl. Then water was added to the neutralized mixture. After addition of water the product was accumulated in white precipitated form. The precipitated product was filtered and washed 3-4 time with water. Product was then allowed to dry at 40°C in the hot air oven overnight. White powdered (compound 4a5) was obtained with final yield of 92.6 % (-benzyl-8-bromo-3-butyl-1-ethyl-1H-purine-2,6 (3H,7H)-dione).

1H NMR (600 MHz, DMSO-d6): 7.36 (2H, t, J=7.43, 3,5-ArH), 7.30 (1H, t, 2,6-ArH, J=7.31), 7.23 (2H, d, 4-ArH, J=7.33), 5.52 (2H, s, N7-CH2-), 3.94 (2H, dd, J=7.08, 14.45, N1-CH2-CH3) 3.89 (2H, t, J= 7.01, N-CH2-), 1.62 (2H, quintet, -CH2-CH2-CH2-), 1.28 (2H, quintet, CH2-CH2-CH3), 1.106(3H, t, J=6.99, N1-CH2CH3), 0.899 (3H, t, J=7.36 Hz, -CH2CH3).
13C NMR (600 MHz, DMSO-d6): 153.86, 150.37, 148.07, 136.08, 129.26, 128.87, 128.42, 127.62, 108.91, 49.85, 42.92, 36.28, 30.05, 19.88, 14.09, 13.50.
MS (+ESI) m/z: 405.0941

EXAMPLE – 7
Step-4b1 of Scheme – II
Substitution of ethyl groups at N1 position of compound 3b (synthesis of 3-(4-methoxybenzyl)-7-benzyl-8-bromo-1-ethyl-1H-purine-2,6(3H,7H)-dione)

To a mixture of compound 3b obtained in step-3b (0.98 g, 2.22 mmol) and anhydrous K2CO3 (0.644 g, 4.66 mmol) in 10 mL anhydrous DMF, 0.3749 µL ethyl iodide (4.66 mmol) was added. The reaction then stirred at 70°C for 12 h. After completion of the reaction, reaction mixture was allowed to cool at room temperature. The product mixture was diluted with ethyl acetate. The organic part was separated from aqueous part by washing with water and brine alternatively. After extraction, the organic part was isolated and dried with sodium sulfate. The yellowish solution obtained was dried under vacuum in a rotary evaporator. Whitish product mixture was obtained. The product mixture was purified by column chromatography with ethyl-hexane (10:90) solvent. Product was obtained in the form of white powder with final yield of 87.4 % (3-(4-methoxybenzyl)-7-benzyl-8-bromo-1-ethyl-1H-purine-2,6(3H,7H)-dione).
1H NMR (600 MHz, DMSO-d6): 7.338 (2H, t, J= 7.40, 7.40, Ar), 7.286 (3H, d, J=7.286, Ar), 7.248 (2H, d, J=7.53, Ar), 6.861 (2H, d, J=8.45, Ar), 5.498 (2H, s, N7-CH2-), 5.042, 3.885 (3H, q, J=6.77, 6.77, 6.86, N1-CH2-CH3) (2H, s, N3-CH2-), 3.686 (3H, s, Ar-OCH3), 1.089 (3H, t, J= 6.94, 6.94, N3-CH2-CH3).
13C NMR (600 MHz, DMSO-d6): 159.34, 153.98, 150.68, 148.13, 136.19, 136.19, 129.92, 129.44, 129.11, 129.08, 128.62, 127.85, 114.52, 114.31, 109.15, 55.69, 50.09, 46.06, 36.60, 13.68
MS (+ESI) m/z: 469.0894

EXAMPLE - 8
Step-5a of Scheme-I
Suzuki coupling reaction for substitution at C8 position of substituted xanthine derivative

A mixture of compound obtained from step-4a (in scheme-I) or step-4b (in scheme-II) (1 equivalent), 3-R3 boronic acid (2 equivalent), anhydrous K2CO3 (2 equivalent) was taken in 25 mL round bottom flask. Then, Tertakis (triphenylphosphine) palladium (0.013 equivalents) was added as a catalyst in the presence of argon atmosphere. The reaction flask was assembled with a condenser. Thereafter, the reaction mixture was degassed by three times evacuation and backfilled with argon. After that anhydrous 5 mL DMF was added to the reaction mixture. The reaction was stirred at 110°C for 2 days. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed. The organic layer was extracted with ethyl acetate. Organic extract was then washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred in a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The purified product formed was of oily nature.

Step - 5a1 of Scheme I
Synthesis of 7-benzyl-8-(3-isopropylphenyl)-1-methyl-3-propyl-1H-purine-2,6(3H,7H) –dione

A mixture of compound 4a1 (226 mg, 0.599 mmol), 3-isopropyl phenyl boronic acid (196 mg, 1.2 mmol), anhydrous K2CO3 (166 mg, 1.2 mmol) was taken in 25 mL round bottom flask. Then tertakis (triphenylphosphine) palladium (36 mg, 0.03 mmol) was added under argon atmosphere in the flask. The reaction was then stirred at 110°C for 2 days. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed, the organic layer was extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction, the organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The product formed was yellowish oily in nature with yield of 44.2%.

1H NMR (600 MHz, DMSO-d6): 7.456 (1H, d, J=5.71), 7.416 (1H, d, J=7.74), 7.35 (2H, t, J=7.69, 7.69: 3,5-ArH), 7.30 (1H, s), 7.26 (2H, d, J=7.33), 7.014 (1H, d, J=7.50), 5.63 (2H,s, -CH2-Ar), 4.02 (2H, t, J=7.18, 7.18, N3-CH2-CH2-), 3.24 (3H, s, N1-CH3), 2.85 (1H, dt, J= 6.30, 6.30, 12.43, Ar-CH(CH3)2), 1.75 (2H, m, -CH2-CH2-CH3 ), 1.097 (3H,s, -CH(CH3)2), 1.086 (3H, s, -CH(CH3)2), 0.916 (3H,t, J=7.39, 7.39, -CH2CH3)
13C NMR (600 MHz, DMSO-d6):154.54, 151.87, 150.67, 148.97, 147.69, 137.15, 128.94, 128.78, 127.48, 126.70, 126.41, 125.98, 107.44, 48.75, 44.31, 33.19, 27.62, 23.53, 20.88, 11.07.

Step - 5a2 of Scheme I
Synthesis of 7-benzyl-1-ethyl-8-(3-isopropylphenyl)-3-propyl-1H-purine-2,6(3H,7H)-dione

A mixture of compound 4a2 (283 mg, 0.7233 mmol), 3-isopropyl phenyl boronic acid (237 mg, 1.45 mmol), anhydrous K2CO3 (200 mg, 1.45 mmol) was taken in 25 mL round bottom flask. Then, Tertakis (triphenylphosphine) palladium (45 mg) was added under argon atmosphere in the flask. The reaction was carried out in 5 mL DMF. The reaction was stirred at 110°C for 2 days. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed, the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction of organic phase it was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The product formed was whitish semisolid in nature (compound 5a2) with a yield of 63.4 %.

1H NMR (600 MHz, DMSO-d6): 7.44 (1H, t, J=6.74, 6.74), 7.416 (1H, d, J=8.29), 7.34(1H, s), 7.30 (2H, t, J=7.31: 3,5-ArH), 7.25 (1H, t, J=7.24, 4-ArH), 7.008 (2H, d, 2,6-ArH), 5.63 (2H,s, -CH2-Ar), 4.02 (2H, t, J=7.18,N3-CH2-CH2-), 3.92 (2H, q, J=6.83, N1-CH2CH3) 2.85 (1H, septet, Ar-CH(CH3)2), 1.75 (2H, sextet, -CH2-CH2-CH3 ), 1.14 (3H, s, N1-CH2CH3),1.092 (6H,d, J= 6.89, -CH(CH3)2), 0.912 (3H,t, J=7.42, -CH2CH3)
13C NMR (600 MHz, DMSO-d6): 154.13, 151.71, 150.36, 148.79, 147.72, 137.06, 128.93, 128.74, 128.61, 127.49, 126.71, 126.42, 125.92, 107.45, 48.78, 44.22, 35.65, 3319, 23.54, 20.89, 13.11, 11.07.
MS (+ESI) m/z: 431.2457

Step-5a3 of Scheme – I
Synthesis of 7-benzyl-1-ethyl-3-propyl-8-m-tolyl-1H-purine-2,6(3H,7H)-dione
A mixture of compound 4a2 (218 mg, 0.557 mmol), 3-methyl phenyl boronic acid (151 mg, 1.14 mmol), anhydrous K2CO3 (73.5 mg, 1.14 mmol) was taken in 25 mL round bottom flask. Tertakis (triphenylphosphine) palladium (34 mg, 0.003 mmol) was added in the presence of argon atmosphere. The reaction was carried out in 5 mL DMF. The reaction was stirred at 110°C for 2 days. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed, the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The product obtained was semisolid and light yellow with yield of 67.85%.

1H NMR (600 MHz, DMSO-d6): 7.35 (2H, d, J=6.92), 7.288 (2H, m), 7.24(2H, d, J=8.55), 7.06 (1H, d, J=5.79), 7.002 (2H, m), 5.63 (2H,s, -CH2-Ar), 4.02 (2H, t, J=7.18,N3-CH2-CH2-), 3.92 (2H, q, J=6.83, N1-CH2CH3) 2.85 (1H, septet, Ar-CH(CH3)2), 2.29 (3H, s, Ar-CH3)1.75 (2H, sextet, -CH2-CH2-CH3 ), 1.14 (3H, s, N1-CH2CH3).
1H NMR (600 MHz, DMSO-d6): 154.59, 152.06, 151.73, 150.97, 149.03, 148.04, 137.15, 128.99, 128.78, 127.51, 126.76, 126.39, 125.97, 107.39, 49.77, 48.77, 33.21, 27.71, 26.90, 23.55, 19.93, 19.23.
MS (+ESI) m/z: 431.2465

Step-5a4 of Scheme – I
Synthesis of 7-benzyl-3-isobutyl-8-(3-isopropylphenyl)-1-methyl-1H-purine-2,6(3H,7H)-dione

A mixture of compound 4a3 (417 mg, 1.07 mmol), 3-isopropyl phenyl boronic acid (350 mg, 2.13 mmol) and anhydrous K2CO3 (295 mg, 2.13 mmol) was taken in 50 mL round bottom flask. Tertakis (triphenylphosphine) palladium (64 mg, 0.006 mmol) was added under argon atmosphere in the flask. The reaction was carried out in 10 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion formed on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to the separating funnel. Two layers were formed; the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oily form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The product formed was semisolid and yellowish in colour (compound 5a4) with yield of 65.5 %.

1H NMR (600 MHz, DMSO-d6): 7.538(1H, s), 7.43 (2H, m, ArH), 7.39 (1H, d, J=2.18), 7.319 (1H, s), 7.29 (2H,t, J=7.40, 7.40), 7.239 (1H, t, J=7.25,7.25, ArH), 6.997 (2H, d, ArH), 5.62 (2H, s, N7-CH2-), 3.8 (2H, d, J= 7.48, N3-CH2-), 3.23 (3H, s, N1-CH3), 2.88 (1H, hept, -CH-(CH3)2), 2.23 (1H, ddq, N3-CH2-CH(CH3)2), 1.07 (Ar-CH(CH3)2), 0.90 (6H, d, N3-CH2-CH(CH3)2)
13C NMR (600 MHz, DMSO-d6): 154.59, 152.06, 151.73, 150.97, 149.03, 148.04, 137.15, 128.99, 128.78, 127.51, 126.76, 126.39, 125.97, 107.39, 49.77, 48.77, 33.21, 27.71, 26.90, 23.55, 19.93, 19.23.
MS (+ESI) m/z: 431.2465

Step-5a5 of Scheme – I
Synthesis of 7-benzyl-1-ethyl-3-isobutyl-8-(3-isopropylphenyl)-1H-purine-2,6(3H,7H)-dione

A mixture of compound 4a4 (315 mg, 0.778 mmol), 3-isopropyl phenyl boronic acid (268 mg, 1.63 mmol), anhydrous K2CO3 (225 mg, 1.63 mmol) was taken in 50 mL round bottom flask. Tertakis (triphenylphosphine) palladium (60 mg, 0.005 mmol) was added under argon atmosphere in the flask. The reaction was carried out in 6 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL of water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed, the organic layer was re-extracted with ethyl acetate. Organic layer was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was then purified by column chromatography (10% ethyl acetate: 90% Hexane). The product formed was semisolid and yellowish in colour (compound 5a5) with a yield of 71%.

1H NMR (600 MHz, DMSO-d6): 7.538(1H, s), 7.43 (2H, m, 3,5-ArH), 7.39 (1H, t, 2,6-ArH, J=7.31), 7.32 (1H, s)7.29(1H,t, J=7.40), 6.99 (2H, d, 4-ArH, J=7.31), 5.63 (2H, s, N7-CH2-), 3.92 (2H, q, (J=7.10, 7.10, 6.99) N1-CH2- CH3), 3.88 (2H, d, J= 7.44, N3-CH2-), 2.99 (1H, hept, -CH-(CH3)2), 2.24 (1H, ddq, N3-CH2-CH(CH3)2), 1.15 (Ar-CH(CH3)2), 1.11(3H, t, N1-CH2- CH3), 1.08 (6H, d, N3-CH2-CH(CH3)2)
13C NMR (600 MHz, DMSO-d6): 154.70, 152.47, 151.13, 150.45, 149.63, 148.69, 137.83, 129.80, 129.61, 129.40, 128.37, 128.15, 128.15, 127.37, 127.01, 126.56, 107.76, 50.24, 49.40, 36.34, 34.00, 27.58, 24.52, 24.52, 24.19, 20.59, 13.76.
MS (+ESI) m/z: 445.2631

Step-5a6 of Scheme – I
Synthesis of 7-benzyl-3-butyl-1-ethyl-8-(3-isopropylphenyl)-1H-purine-2,6 (3H,7H)-dione

To a mixture of compound 4a5 (201 mg, 0.496 mmol), 3-isopropyl phenyl boronic acid (163 mg, 0.992 mmol), anhydrous K2CO3 (137 mg, 0.992 mmol) in 25 mL round bottom flask, Tertakis (triphenylphosphine) palladium (35 mg, 0.003 mmol) was added in the presence of argon atmosphere. The reaction was carried out in 4 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed the organic layer was re-extracted with ethyl acetate. The organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product as oil. The product was then purified by column chromatography (10% ethyl acetate: 90% Hexane). The product obtained was semisolid in nature and pale yellow in colour (compound 5a6) with yield of 98.6%.

1H NMR (600 MHz, DMSO-d6): 7.355 (2H, d, J=7.18), 7.34 (2H, m), 7.33 (1H, d, J=7.82), 7.283 (1H, m, J=7.67), 7.164 (1H, s, J=1.79), 7.13 (1H, s, J=7.67), 7.078 (1H, d, J=8.05), 7.03 (2H, t, J= 7.77), 5.41 (2H, s, N7-CH2-), 3.90 (2H, q, N1-CH2-CH3) 3.82 (2H, t, J= 7.14, N3-CH2-), 2.88 (1H, J=7.00, 6.99, 13.81, heptet, Ar-CH(CH3)2), 2.75 (2H, quintet, -CH2-CH2-CH2-), 1.6 (2H, sextet, CH2-CH2-CH3), 1.13 (Ar-CH(CH3)2), 1.11(3H, t, N1-CH2- CH3), 1.10(3H, t, J=7.05, N1-CH2CH3), 0.808 (3H, t, J=7.36 Hz, -CH2CH3) (600 MHz,
13C NMR (600 MHz, DMSO-d6): 154.59, 152.06, 151.73, 150.97, 149.04, 148.04, 137.15, 128.99, 128.78, 127.51, 126.76, 126.39, 125.97, 107.39, 49.77, 48.77, 33.21, 27.71, 26.90, 23.90, 23.55, 19.93, 19.86, 19.23.
MS (+ESI) m/z: 445.2622

Step-5a7 of Scheme – I
Synthesis of 7-benzyl-3-butyl-1-ethyl-8-m-tolyl-1H-purine-2,6 (3H,7H)-dione
To a mixture of compound 4a5 (183 mg, 0.452 mmol), 3-methyl phenyl boronic acid (129 mg, 0.903 mmol), anhydrous K2CO3 (125 mg, 0.903 mmol) was taken in 25 mL round bottom flask, Tertakis (triphenylphosphine) palladium (35 mg, 0.003 mmol) was added under argon atmosphere in the flask. The reaction was carried out in 4 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion formed on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to the separating funnel. Two layers were formed, the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product as oil. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane). The product formed was semisolid in nature and light yellow in nature (compound 5a7) with yield of 85.5%.

1H NMR (600 MHz, DMSO-d6): 7.403 (1H, s), 7.376 (2H, m), 7.341 (1H, t, J=7.53, 7.53 Hz), 7.27 (2H, t, J=7.43, 7.43 Hz), 7.226 (1H, t, J=7.31, 7.31 Hz), 5.6 (2H, s, N7-CH2-), 4.03 (2H, t, N3-CH2-) 3.89 (2H, q, J= 6.93, 6.93, 6.99, N1-CH2-CH3), 2.3 (3H, s, Ar- CH3), 2.15 (2H, quintet, -CH2-CH2-CH2-), 1.3 (2H, dq, J= 7.32, 7.32, 7.19, 14.63 Hz, CH2-CH2-CH3), 1.10(3H, t, J=6.98 Hz, N1-CH2CH3), 0.903 (3H, t, J=7.36 Hz, -CH2CH3).
13C NMR (600 MHz, DMSO-d6): 157.07, 154.42, 151.85, 150.10, 147.54, 138.29, 129.58, 129.37, 128.87, 128.68, 128.29, 126.13, 125.89, 126.13, 125.89, 107.44, 48.13, 42.06, 35.56, 29.56, 20.76, 19.53, 13.40, 13.40, 12.98.
MS (+ESI) m/z: 417.2288

Step-5a8 of Scheme – I
Synthesis of 7-benzyl-3-butyl-1-ethyl-8-(3-fluorophenyl)-1H-purine-2,6(3H,7H)-dione
A mixture of compound 4a5 (130 mg, 0.321 mmol), 3-floro phenyl boronic acid (94 mg, 0.674 mmol), anhydrous K2CO3 (93 mg, 0.674 mmol) was taken in 25 mL round bottom flask. Tertakis (triphenylphosphine) palladium (25 mg, 0.002 mmol) was added under argon atmosphere in the flask. The reaction was carried out in 3 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed, the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred in a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane).The product formed was semisolid in nature and light green in colour (compound 5a8) with yield of 74.6%.

1H NMR (600 MHz, , DMSO-d6): 7.536 (1H, dd, J=8.06, 13.95), 7.445 (2H, dd, 4.74, 13.85 Hz), 7.378 (1H, td, J=2.39, 8.75, 8.75 Hz), 7.272 (2H, t, J=7.37, 7.37 Hz), 7.223 (1H, t, J=7.26, 7.26 Hz), 6.982 (2H, d, J=7.35), 5.691 (2H, s, N7-CH2-), 4.03 (2H, t, J=7.26, 7.26, N3-CH2-) 3.906 (2H, q, J= 6.96, 6.96, 6.98, N1-CH2-CH3), 1.69 (2H, m, CH2-CH2-CH2-CH3), 1.32 (2H, m, CH2-CH2-CH2-CH3 ), 1.101 (3H, t, J=7.00, 7.00 Hz, N1-CH2CH3), 0.906 (3H, t, J=7.36, 7.36, -CH2CH3)
13C NMR (600 MHz, DMSO-d6): 163.33, 161.70, 154.68, 150.81, 149.00, 137.40, 131.86, 131.04, 129.45, 128.29, 126.79, 125.80, 118.22, 116.48, 107.77, 49.29, 43.14, 36.38, 30.31, 20.08, 14.29, 13.76.
MS (+ESI) m/z: 421.213

EXAMPLE - 9
Step-5b1 of Scheme - II
Synthesis of 3-(4-methoxybenzyl)-7-benzyl-1-ethyl-8-(3-isopropylphenyl)-1H-purine-2,6 (3H,7H)-dione

To the mixture of compound 4b1 (1.66 g, 3.55 mmol), 3-isopropyl phenyl boronic acid (1.22 g, 7.45 mmol), anhydrous K2CO3 (1.03 g, 7.45 mmol) taken in 50 mL round bottom flask. Tertakis (triphenylphosphine) palladium (260 mg, 0.2 mmol) was added under argon atmosphere in the flask. The reaction was carried out in 10 mL DMF at 110°C for 48 h. After completion of the reaction, product mixture was allowed to cool at room temperature. 10 mL water was added to the product mixture and stirred for 10 minutes. Upon cooling, the reaction mixture darkened and black emulsion appeared on the upper layer of the solution. The reaction mixture was then diluted with ethyl acetate and transferred to a separating funnel. Two layers were formed; the organic layer was re-extracted with ethyl acetate. Organic extract was washed with 5% sodium carbonate solution and brine sequentially. After extraction organic phase was transferred to a 250 mL Erlenmeyer flask equipped with a magnetic stir bar. Activated charcoal (0.50 g) and sodium sulfate (2g) were added to the flask. This mixture was stirred for 10 min. The solution was then filtered through 1 cm celite bed. The resulting pale yellow solution was concentrated under reduced pressure to yield the crude product in oil form. The product was purified by column chromatography (10% ethyl acetate: 90% Hexane).The product formed was light yellow and semisolid in nature (compound 5b1) with yield of 72.2 %.

1H NMR (600 MHz, DMSO-d6): 7.455(1H, t, J=8.58, 8.58, Ar-H), 7.409 (2H, dd, J=5.98, 13.53, Ar-H), 7.374 (2H, d, J=8.35, Ar-H), 7.345 (1H, s, Ar-H), 7.289(2H, t, J=7.33, 7.33), 7.244 (1H, d, J=7.26, Ar-H), 7.007 (2H, d, J=7.30, Ar-H), 6.875 (2H, d, J=8.13, Ar-H), 5.623 (1H, s, N7-CH2-), 5.149 (1H, s, N3-CH2-), 3.897 (2H, dd, J=6.69, 13.63, N1-CH2CH3), 3.688(1H, s, Ar-OCH3), 2.834 (1H, dt, J=6.72, 6.72, 13.55, -CH(CH)2), 1.096 (3H, t, J=6.55, 6.55, N1-CH2CH3), , (6H, d, J=6.92, -CH(CH)2).
13C NMR (600 MHz, DMSO-d6): 159.35, 154.75, 152.54, 150.93, 149.61, 148.25, 137.77, 130.20, 129.66, 129.44, 127.35, 126.63, 114.49, 107.40, 60.43, 55.68, 49.21, 46.19, 36.45, 33.85, 24.20, 21.35, 14.73, 13.79.
MS (+ESI) m/z: 509.2611

EXAMPLE - 10
Step - 6a of Scheme - I (or) step - 8b of Scheme – II
Deprotection at N7 position of substituted xanthine derivatives
1-R1 3-R2 7-Benzyl 8- R3 xanthine (125 mg) was taken in a 25 mL flask equipped with magnetic bead. 3 mL methanol was added into the flask. Then the solution was degassed and backfilled with argon alternatively for three times. 10% Pd/H (100 mg) was taken into 2nd round bottom flask (25 mL) and dissolved with 5mL methanol. The flask mixture was degassed three times by evacuation and backfilled with argon. The content of 1st flask was poured into the 2nd flask while stirring via syringe. The 2nd flask was then purged with H2 gas. Then the reaction was allowed to stir at room temperature for 48 h. The resultant product mixture was passed through celite (1 cm). The solution obtained was concentrated under reduced pressure. Product formed was yellowish powder which was washed with 1mL diethyl ether and filtered. The final product formed was pure white in color.

Step-6a1 of Scheme I
Synthesis of Compound C1
1H NMR (600 MHz, DMSO-d6):13.78 (1H, s, -NH), 8.033 (1H, s, Ar-H), 7.924 (1H, d, J=7.69 Hz, Ar-H), 7.396(1H, m), 7.35 (1H, d, J=7.68, Ar-H), 4.018 (2H, m, N3-CH2-CH2, 3.26 (1H, s, N1-CH3), 2.945 (1H, ddd, J=5.19, 8.58, 10.31, Ar-CH(CH3)2), 1.739 (2H, m, -CH2-CH2-CH3 ), 1.245 (3H,d, J= 3.57, -CH(CH3)2), 1.234 (3H, d, J= 3.34, -CH(CH3)2), 0.900 (3H,t, J=7.43, 7.43, -CH2CH3)
600 MHz 13C NMR in DMSO-d6: 154.88, 151.55, 150.75, 149.82, 148.91, 129.59, 129.33, 129.08, 128.37, 128.00, 124.84, 108.27, 45.14, 34.11, 28.45, 24.41, 21.51, 11.72
MS (+ESI) m/z: 327.18

Step-6a2 of Scheme – I
Synthesis of Compound C2
1H NMR (600 MHz, DMSO-d6):13.82 (1H, s, -NH), 8.04 (1H, s, Ar-H), 7.9 (1H, d, J=7.56 Hz, Ar-H), 7.42(1H, t, J=7.67 Hz), 7.37 (1H, d, J=7.64, Ar-H), 4.03 (2H, t, J=7.18,N3-CH2-CH2, 2.96 (1H, Ar-CH(CH3)2), 1.75 (2H, sextet, -CH2-CH2-CH3 ), 1.26 (6H,d, d, J= 6.70, -CH(CH3)2), 1.14 (3H, t, -CH2-CH2CH3) 0.906 (3H,t, -CH2CH3)
13C NMR (600 MHz, DMSO-d6): 154.50, 151.12, 149.81, 148.56, 129.58, 129.35, 129.08, 124.89, 124.85, 108.24, 45.04, 38.68, 36.41, 34.11, 24.41, 21.41, 21.52, 13.85, 11.70
MS (+ESI) m/z: 341.2002

Step-6a3 of Scheme – I
Synthesis of Compound C3
1H NMR (600 MHz, DMSO-d6): 13.76 (1H, s, -NH), 7.945 (1H, d, J=5.12 Hz, Ar-H), 7.899 (1H, d, J=7.6 Hz, Ar-H), 7.37 (1H, t, J=7.66, 7.66 Hz), 7.279 (1H, d, J=7.52, Ar-H), 4.001 (2H, m, -Ar-CH2-CH2-CH3, 3.93(2H, q, J= 7.00, 7.00, 7.02 Hz, N- CH2-CH3), 2.356 (3H, s, Ar-CH3), 1.727 (2H, m, -CH2-CH2- CH3 ), 1.123 (3H, td , J=2.39, 6.95, 7.02,N-CH2CH3), 0.891 (3H, t, J=7.43,7.43 Hz, -CH2-CH2CH3).
13C NMR (600 MHz, DMSO-d6): 154.47, 151.11, 150.83, 150.57, 148.92, 138.87, 131.54, 129.50, 129.27, 127.57, 124.25, 108.27, 45.05, 36.41, 21.64, 21.53, 13.87, 13.85, 11.71.
MS (+ESI) m/z: 313.1684

Step-6a4 of Scheme – I
Synthesis of Compound C4
1H NMR (600 MHz, DMSO-d6): 8.046 (1H, s, ArH), 7.9 (1H, d, J=2.64), 3.891 (2H, d, J= 7.37, N3-CH2- CH-(CH3)2), 3.274 (3H, s, N1-CH3), 2.954 (1H, dt, J=6.87, 6.87, 13.78 Hz, -CH-(CH3)2), 2.23 (1H, dt, J= 7.01, 7.01, 13.71 Hz, N3-CH2-CH(CH3)2), 1.250 (6H, d, J= 6.89 Hz, Ar-CH(CH3)2), 0.908 (6H, d, J= 6.66 Hz, N3-CH2-CH(CH3)2). Note [A broader peak came it may probably submerged NH peak, two aryl peaks]
13C NMR (600 MHz, DMSO-d6): 154.78, 151.76, 150.68, 149.81, 149.06, 129.60, 129.36, 129.10, 124.85, 108.22, 50.61, 34.10, 28.51, 27.51, 24.42, 20.56.
MS (+ESI) m/z: 341. 1999

Step-6a5 of Scheme – I
Synthesis of Compound C5
1H NMR (600 MHz, DMSO-d6): 13.80 (1H, s,-NH), 8.024 (1H, s, ArH), 7.911 (1H, d, J=7.62), 7.407 (1H, t, J=7.68, 7.68, Ar-H), 7.347 (1H, d, J=7.67), 3.941 (2H, q, J=6.95, 6.95, 6.97, N1-CH2-CH3), 3.876 (2H, d, J= 7.45, N3-CH2-), 2.94 (1H, m, -CH-(CH3)2), 2.244 (1H, dp, J= 6.88, 6.88, 6.87, 6.87, 13.76 Hz, N3-CH2-CH(CH3)2), 1.237 (6H, d, J=6.92, Ar-CH(CH3)2), 1.125(3H, t, J= 7.00, 7,00 Hz, N1-CH2-CH3), 0.892 (6H, d, J=6.71, N3-CH2-CH(CH3)2)
13C NMR (600 MHz, DMSO-d6): 154.51, 151.34, 150.69, 149.81, 149.21, 129.60, 129.10, 128.21, 128.08, 124.87, 108.24, 50.49, 36.43, 34.11, 27.55, 24.42, 20.56, 13.85.
MS (+ESI) m/z: 354.2182

Step-6a6 of Scheme – I
Synthesis of Compound C6
1H NMR (600 MHz, DMSO-d6): 8.017 (1H, s, ArH), 7.906 (1H, d, J=7.63 Hz), 7.385 (1H, t, J=7.64, 7.64 Hz, Ar-H), 7.314 (1H, d, J=7.55 Hz), 3.941 (2H, t, J=7.12, 7.12 Hz, N3-CH2-CH2-), 3.929 (2H, q, J= 6.89, 6.89, 6.92 Hz, N1-CH2-CH3), 2.93 (1H, dp, J=6.72, 6.72, 6.57, 6.57, 13.42, Ar-CH-(CH3)2), 1.686 (2H, m, N3-CH2-CH2- CH2-CH3), 1.314 (2H, dq, J=7.41, 7.41, 7.46, 14.88 Hz, N3-CH2-CH2- CH2-CH3), 1.236 (6H, d, J=6.90, Ar-CH-(CH3)2), 1.119(3H, t, J= 6.96, 6.96 Hz, N1-CH2-CH3), 0.913 (3H, t, N3-CH2-CH2- CH2-CH3),
13C NMR (600 MHz, DMSO-d6): 154.76, 151.18, 151.13, 149.67, 149.07, 130.05, 129.48, 128.73, 124.73, 124.73, 109.10, 43.17, 36.33, 34.11, 30.28, 24.43, 20.02, 14.25, 13.92
MS (+ESI) m/z: 355.2142

Step-6a7 of Scheme – I
Synthesis of Compound C7
1H NMR (600 MHz, DMSO-d6): 7.930 (1H, s, ArH), 7.889 (1H, d, J=7.65 Hz), 7.336 (1H, t, J=7.57, 7.57 Hz, Ar-H), 7.220 (1H, d, J=7.33 Hz), 4.030 (2H, t, J=6.95, 6.95 Hz, N3-CH2-CH2-), 3.929 (2H, q, J= 6.58, 6.58, 6.62 Hz, N1-CH2-CH3), 3.15 (1H, s, -NH), 2.348 (3H, s, Ar-CH3), 1.682 (2H, m, N3-CH2-CH2- CH2-CH3), 1.315 (2H, dq, J=7.22, 7.22, 7.46, 14.29 Hz, N3-CH2-CH2- CH2-CH3), 1.107 (3H, t, J=6.91, 6.91, N1-CH2-CH3), 0.909 (3H, t, J= 7.29, 7.29 Hz, N3-CH2-CH2- CH2-CH3),
13C NMR (600 MHz, DMSO-d6):154.22, 151.10, 149.93, 148.17, 138.85, 131.52, 129.50, 127.57, 124.27, 108.24, 43.23, 36.40, 30.30, 21.65, 20.03, 14.27, 13.85.
MS (+ESI) m/z: 327.1841

Step-6a8 of Scheme – I
Synthesis of Compound C8
1H NMR (600 MHz, DMSO-d6): 7.981 (1H, d, J= 7.75 Hz, ArH), 7.925 (1H, d, J=10.07 Hz), 7.567 (1H, dd, J=7.70, 14.21 Hz, Ar-H), 7.331 (1H, t, J=8.30, 8.30 Hz, Ar-H), 4.05 (2H, t, J=7.02, 7.02 Hz, N3-CH2-CH2-), 3.944 (2H, q, J= 6.83, 6.83, 6.84 Hz, N1-CH2-CH3), 1.699 (2H, m, N3-CH2-CH2- CH2-CH3), 1.324 (2H, m, N3-CH2-CH2- CH2-CH3), 1.134 (3H, t, J=6.93, 6.93, N1-CH2-CH3), 0.926 (3H, t, J= 7.32, 7.32 Hz, N3-CH2-CH2- CH2-CH3),
13C NMR (600 MHz, DMSO-d6): 163.78, 162.16, 154.63, 151.05, 131.91, 131.85, 127.08, 123.24, 117.63, 117.52, 113.62, 113.46, 43.27, 36.46, 30.26, 20.02, 14.38, 14.38, 14.27, 13.84.
MS (+ESI) m/z: 331.1575

EXAMPLE 11
Step - 6b1 of Scheme - II
Deprotection of 4-methoxy benzyl at N3 position of N1 and C8 di-substituted xanthine derivative in scheme-II

Synthesis of 7-benzyl-1-ethyl-8-(3-isopropylphenyl)-1H-purine-2,6(3H,7H)-dione
A solution of Compound 5b1 (R1=Et) (1.257 g, 2.47 mmol), concentrated sulfuric acid (10 drop), anisol (375 µL, 3.4 mmol) in TFA (5 mL) was taken in 25 mL flask equipped with magnetic bead. The flask was degassed and backfilled with argon alternatively for three times. The reaction mixture was refluxed for 22h. Oily residue was formed which was diluted with water and isopropyl ether. This was followed by neutralization with 20% NaOH till pH 5 was obtained. The resultant precipitate was filtered, washed with water and isopropyl ether, and dried. The product (compound 6b1) was obtained in greenish powdered form.

1H NMR (600 MHz, DMSO-d6): 12.036(1H, s, N1-H), 7.395(1H, d, J=5.12, Ar-H), 7.36 (3H, d, J=6.38, 6.38, Ar-H), 7.285 (2H, t, J=7.30, 7.30), 7.232 (1H, m, Ar-H), 6.989(2H, d, J=7.27, Ar-H), 5.604 (1H, s, N7-CH2-), 3.845(2H, q, J=6.69, 6.69, 6.70), 2.832 (1H, dt, J=6.76, 6.76, 13.58, CH(CH3)2), 1.079 (6H, d, J= 7.01, CH(CH3)2.
13C NMR (600 MHz, DMSO-d6): 154.95, 152.09, 150.62, 149.02, 147.29, 137.33, 128.92, 128.80, 128.64, 127.49, 126.45, 126.37, 125.93, 107.44, 48.64, 23.79, 23.59, 13.23
MS (+ESI) m/z: 389.199
The 1H Spectra of compounds C1, C2, C3, C4, C5, C6, C7 and C8 are presented below.

1H Spectra of C1
1H Spectra of C2

1H Spectra of C3

1H Spectra of C4

1H Spectra of C5

1H Spectra of C6

1H Spectra of C7

1H Spectra of C8

EXAMPLE 12
Biological Studies
With the above synthesis methodology a series of compounds were synthesized and analysed for their biological activity with PDE9A. To measure the inhibitory effect of the synthesized compounds, Malachite Green Spectrophotometric Assay was conducted. It has been reported earlier that IBMX (1-methyl 3-isobutyl xanthine) is a nonspecific inhibitor for most of the phosphodiesterases but it does not inhibit the PDE9A [Huai et al; 2004]. Hence, in the present invention IBMX was used as a reference compound. Among all synthesized compounds, compound C6 showed best inhibition result towards PDE9A in a dose dependent manner (IC50= 38.27 µM). The compound C5 showed similar binding affinity (IC50= 38.55 µM) towards PDE9A. The presence of isomeric fragment at N3 position of these compounds might be a reason for such similarity.
Table - 2 Experimental IC50 and predicted Ki values of synthesized compounds
Entry IC50 in PDE9A (in µM) Predicted Ki (in µM)
C1 91.83 ± 1.98 30.84
C2 50.46 ± 2.21 16.92
C3 86.86 ± 2.43 29.16
C4 76.19 ± 1.60 25.57
C5 38.55 ± 1.90 12.91
C6 38.28 ± 1.63 12.82
C7 62.60 ± 2.6 21
C8 51.82 ± 2.25 17.37
The predicted Ki (inhibition constant) was calculated by using the web tool [https://botdb-abcc.ncifcrf.gov/]. The equation used for calculating Ki was IC50 = Ki (1 + [S]/KM), where [S] = 12 µM and KM = 6.085 µM.
It was observed that both at N1 and N3 positions in the xanthine derivatives with increasing chain length of alkyl groups increased the inhibition activity against PDE9A. However, increasing chain length at N1 position was comparatively more effective than increasing chain length at N3 position. For instance, in compound C1 which consist of methyl group at N1 position was nearly two fold less reactive (IC50= 91.83 µM) than compound C2 (IC50= 50.46 µM) which consist of ethyl group at N1 position. Similar results were obtained in the case of compound C4 (IC50=76.188 µM) and compound C5 (IC50=38.55 µM). Substitution with fragments of same molecular weight but different structure has created very less difference in inhibitory efficiency. For instance, branching (isobutyl chain) at N3 position of compound C5 showed comparatively less inhibition than compound C6 that consist of n-butyl side chain at N3 position.
Similarly, at C8 position aryl substitution created significant change in inhibitory effect. As IBMX (1-methyl 3-isobutylxanthine) was non-reactive towards to PDE9A, the addition of 3-isopropyl phenyl ring at C8 position of xanthine in compound C4 (1-methyl 3-isobutyl 8-(3- isopropyl) phenylxanthine) significantly increased the inhibitory efficiency (IC50= 76.19 µM) of the compound. The meta-position of aryl ring also had impact on the inhibition efficiency of compound. With increasing chain length at meta-position of phenyl ring increased the inhibitory activity of the compounds. Using functional group like floro group at m-position of phenyl ring increased the inhibition efficiency of compound (C8) towards PDE9A. However, increasing carbon chain length in alkyl group at meta-position of phenyl ring had better binding affinity than using functional group with phenyl ring at C8 position. Thus, by analysing all the facts, compound C5 and C6 were proved to be potent inhibitors for PDE9A. Table-2 represents the experimental IC50 values of all synthesized compounds. This table also shows the predicted Ki values derived from experimental IC50 values and Km of the PDE9A.

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