FIELD OF THE INVENTION
The invention relates to the field of xanthine derivatives and more particularly to a pharmaceutical compound which is 8-substituted xanthine derivative acting as adenosine A2A receptor ligands.
BACKGROUND OF THE INVENTION
Adenosine is a naturally occurring nucleoside which exhibits potent physiological actions in cardiovascular, nervous, pulmonary, renal and immune systems. The development of potent and selective ligands of adenosine receptors (ARs) has been the subject of medicinal chemistry research for decades. The expression and activation of the four adenosine receptor subtypes A1, A2A, A2B, and A3 are associated with control of gene expression, cell growth, intestinal function, neurosecretion, vascular tone and asthma.
A2A receptor subtype represents a fascinating target for the development of small molecules as antiasthmatic agents as these receptors are expressed in lungs and in inflammatory cells involved in asthma. Therefore selective ligands of this subtype are being widely explored by a large number of research bodies to generate novel therapies for asthma and chronic obstructive pulmonary disease (COPD).

Substituted xanthines represent the first potent class of adenosine receptor antagonists reported till date. It has been established that appropriate substitutions as well as location of 8-phenyl substituents affects the potency and selectivity of xanthines toward ARs and thus their pharmacological effects.
There have been a number of solutions provided for use of adenosine receptor antagonists. Few of them have been discussed below:
WO1995011681A1 describes use of compounds, identified through the use of recombinant human adenosine receptors A1, A2a, A2b and A3, and functional assays. The pharmacology of these compounds is characterized through the use of cloned human adenosine receptors of the Al, A2a, A2b and A3 class and their subtypes.

US5861405A describes 8-substituted 1,3,7-trialkylxanthine derivatives useful as A2-selective adenosine receptor antagonists and compositions comprising such compounds.

The aforesaid documents and similar disclosures which talk about use of several adenosine receptor antagonists comprises number of shortcomings and drawbacks such as, but not limited to, restriction of adenosine receptors on their use in human and veterinary therapy for conditions associated with the cell surface effects. Further, specific adenosine receptor subtype responsible for such responses is not disclosed. Also, subtype specificity of these compounds are not described. The existing xanthine compounds are described as potent and/or selective adenosine receptor antagonists wherein the potency and/or the selectivity is not very significant. For example, the AR antagonist such as ZM241385 is unselective and has poor bioavailability.
Accordingly, there remains a need in the prior art to have an improved xanthine derivative to overcome the aforesaid problems and shortcomings.
However, there remains a need in the art for a pharmaceutical compound which is 8-substituted xanthine derivative. The compound acts as adenosine A2Areceptor ligands and thus, useful as anti-inflammatory and anti-asthmatic drugs.

OBJECT OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical compound comprising 8-substituted xanthine. Another object of the present invention is to provide the pharmaceutical compound comprising 8-substituted xanthine of formula (I) which acts as adenosine A2A receptor ligands. Another object of the present invention is to provide the 8-substituted xanthine of formula (I) which has high affinity and potency towards adenosine A2A receptors. Another object of the present invention is to provide the pharmaceutical compound comprising 8-substituted xanthine of formula (I) which acts as an anti-inflammatory and anti-asthmatic drug.
SUMMARY OF THE INVENTION
Embodiments of the present invention aim to provide a pharmaceutical compound comprising 8-substituted xanthine of formula (I). The 8-substituted xanthine has high affinity and potency towards adenosine A2A receptors and thus acts as adenosine A2A receptor ligands. Further, the pharmaceutical compound is useful in the treatment of diseases such as, but not limited to, asthma, COPD and Parkinson’s disease.
In accordance with an embodiment of the present invention, the pharmaceutical compound comprising 8-substituted xanthine of formula (I). Further, R1 and R2 are methyl groups. R3 is selected from, but not limited to, a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.
In accordance with an embodiment of the present invention, the xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.
In accordance with an embodiment of the present invention, the xanthine is selected from a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.
In accordance with an embodiment of the present invention, the 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 140-145°C.
In accordance with an embodiment of the present invention, the 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 165-170°C.

In accordance with an embodiment of the present invention, the 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthineis having a melting point in a range of, but not limited to, 160-162°C.
In accordance with an embodiment of the present invention, the 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 170-176°C.
In accordance with an embodiment of the present invention, the 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 160-162°C.

In accordance with an embodiment of the present invention, the 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point of, but not limited to, 280°C or above.

In accordance with an embodiment of the present invention, the xanthine possesses affinity and potency of, but not limited to, 0.01µm towards adenosine A2A receptors.

In accordance with an embodiment of the present invention, the process of preparing the pharmaceutical compound comprising the steps of mixing N, N’-dipropylurea, cyanoacetic acid and acetic anhydride to form a first mixture, adding a solution of sodium hydroxide in the first mixture resulting in precipitation of a first compound, adding a solution of sodium nitrite in the first compound and acidifying with acetic acid to form a second mixture, washing and drying the second mixture to form a second compound, dissolving the second compound in concentrated ammonium hydroxide followed by adding sodium dithionite to form a third mixture, washing and drying the third mixture to form a third compound, adding a plurality of amines in a suspension of hydroxybenzaldehyde in ethyl methyl ketone to form a fourth mixture, filtering the fourth mixture to form a fourth compound, adding the fourth compound in the third compound and refluxed, adding an ice cold solvent in the mixture of fourth compound and the third compound to obtain a fifth compound and refluxing the fifth compound in thionyl chloride and filtering the refluxed mixture to obtain 8-substituted xanthine.

In accordance with an embodiment of the present invention, the xanthine is having a formula (I). Further, R1 and R2 are methyl groups. R3 is selected from, but not limited to, a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.

In accordance with an embodiment of the present invention, the xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.

In accordance with an embodiment of the present invention, the xanthine is selected from, but not limited to, a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.

In accordance with an embodiment of the present invention, the first mixture is refluxed at a temperature in range of, but not limited to, 70-80°C for 3 hours and thereafter cooled at a temperature in range of, but not limited to, 0-5°C.

In accordance with an embodiment of the present invention, the sodium hydroxide is having a concentration of 5% (w/v).

In accordance with an embodiment of the present invention, the first compound is 6-amino-1, 3-dipropyluracil.

In accordance with an embodiment of the present invention, the acetic acid is added dropwise for a period of, but not limited to, 1 hour resulting in red-violet precipitates.
In accordance with an embodiment of the present invention, the second mixture is stirred at room temperature for overnight. Further, the second mixture is cooled, filtered and washed with, but not limited to, water and diethyl ether.

In accordance with an embodiment of the present invention, the second compound is 6-amino-1, 3-dipropyl-5-nitrosouracil. Further, the second compound is having a melting point in a range of, but not limited to, 215-220°C.

In accordance with an embodiment of the present invention, the third mixture is stirred for, but not limited to, 2 hours at room temperature followed by cooling in an ice bath. Further, the third mixture is filtered and washed with cool water followed by drying.

In accordance with an embodiment of the present invention, the third compound is 5, 6-diamino-1, 3-dipropyluracil. Further, the third compound is having a melting point in a range of, but not limited to, 128-132°C.

In accordance with an embodiment of the present invention, the plurality of amines are selected from, but not limited to, a group consisting of 4-(2-chloroethyl)-amino hydrochlorides, 4-(2-chloroethyl)-morpholine hydrochloride, 4-(2-chloroethyl)-piperidine hydrochloride, 2-chloro-N,N’-dimethyl ethanamine, 1-(2-chloroethyl)-pyrrolidine, 2-chloro-N,N’-diethyl ethanamine and 1-(2-chloroethyl)-phthalimide.

In accordance with an embodiment of the present invention, the step of adding a plurality of amines further comprises a step of addition of dried potassium carbonate in the fourth mixture to avoid incorporation of moisture.

In accordance with an embodiment of the present invention, the step of adding the fourth compound involves the fourth compound provided in ethanol and the third compound provided in ethanol and acetic acid. Further, ethanol and acetic acid are provided in a ratio of, but not limited to, 8:2.

In accordance with an embodiment of the present invention, the ice cold solvent is, but not limited to, water.

In accordance with an embodiment of the present invention, the fifth compound is a Schiff base.

In accordance with an embodiment of the present invention, the step of refluxing is performed at a temperature in range of, but not limited to, 70-80°C for 1 hour.

In accordance with an embodiment of the present invention, the step of refluxing further comprises a step of crystallization of the 8-substituted xanthine from a mixture of chloroform and methanol present in a ratio of, but not limited to, 1:2.

BRIEF DESCRIPTION OF THE DRAWINGS
So that the manner in which the above recited features of the present invention can be understood in detail, a more particular to the description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawing. It is to be noted, however, that the appended drawing illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, the invention may admit to other equally effective embodiments.

These and other features, benefits and advantages of the present invention will become apparent by reference to the following text figure, with like reference numbers referring to like structures across the views, wherein:

Fig. 1 is a flow chart illustrating a process of preparing a pharmaceutical compound in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS
The present invention is described hereinafter by various embodiments with reference to the accompanying drawing, wherein reference numerals used in the accompanying drawing correspond to the like elements throughout the description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiment set forth herein. Rather, the embodiment is provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. In the following detailed description, numeric values and ranges are provided for various aspects of the implementations described. These values and ranges are to be treated as examples only, and are not intended to limit the scope of the claims. In addition, a number of materials are identified as suitable for various facets of the implementations. These materials are to be treated as exemplary, and are not intended to limit the scope of the invention. As used throughout this description, the word "may" is used in a permissive sense (i.e. meaning having the potential to), rather than the mandatory sense (i.e. meaning must). Further, the words "a" or "an" means "at least one” and the word “plurality” means “one or more” unless otherwise mentioned. Furthermore, the terminology and phraseology used herein is solely used for descriptive purposes and should not be construed as limiting in scope. Language such as "including", "comprising", "having", "containing", or "involving" and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents, and additional subject matter not recited, and is not intended to exclude other additives, components, integers or steps. Likewise, the term "comprising" is considered synonymous with the terms "including" or "containing" for applicable legal purposes. Any discussion of documents, acts, materials, devices, articles and the likes are included in the specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention.

In this disclosure, whenever an element or a group of elements is preceded with the transitional phrase “comprising”, it is understood that we also contemplate the same composition, element or group of elements with transitional phrases “consisting of”, “consisting”, “selected from the group of consisting of”, “including”, or “is” preceding the recitation of the composition, element or group of elements and vice versa.

In accordance with an embodiment of the present invention, a pharmaceutical compound comprising 8-substituted xanthine of formula (I).

In accordance with an embodiment of the present invention, R1 and R2 are methyl groups. Further, R3 is selected from a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.

In accordance with an embodiment of the present invention, the xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.

In accordance with an embodiment of the present invention, the xanthine is selected from a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.

In accordance with an embodiment of the present invention, 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 140-145°C. 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthineis having a melting point in a range of, but not limited to, 165-170°C. 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 160-162°C. 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 170-176°C. 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point in a range of, but not limited to, 160-162°C. Further, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point of 280°C or above.

In accordance with an embodiment of the present invention, the xanthine is having high affinity towards adenosine A2A receptors. In particular, xanthine of formula (I) possesses affinity and potency in a range of 0.01µm towards adenosine A2A receptors.

Figure 1 is a flow chart illustrating a process (100) of preparing a pharmaceutical compound in accordance with an embodiment of the present invention.

At step 102, as shown in figure 1, N, N’-dipropylurea, cyanoacetic acid and acetic anhydride are mixed to form a first mixture.

In accordance with an embodiment of the present invention, the first mixture is refluxed at a temperature in range of, but not limited to, 70-80°C for 3 hours to exclude moisture. The excess anhydride and acetic acid formed during the reaction is removed under vacuum. Thereafter, the residual first mixture is cooled at a temperature in range of, but not limited to, 0-5°C.

At step 104, a solution of sodium hydroxide is added in the first mixture resulting in precipitation of a first compound.
In accordance with an embodiment of the present invention, the sodium hydroxide is having a concentration of 5% (w/v). Further, the first compound formed is 6-amino-1, 3-dipropyluracil.

At step 106, a solution of sodium nitrite is added in the first compound and acidified with acetic acid to form a second mixture.

In accordance with an embodiment of the present invention, the acetic acid is added dropwise for a period of, but not limited to, 1 hour resulting in red-violet precipitates. The second mixture was then kept on stirring at room temperature for a period of overnight.

At step 108, the second mixture is washed and dried to form a second compound.

In accordance with an embodiment of the present invention, the second mixture obtained at step 106 is cooled, filtered and washed with, but not limited to, water and diethyl ether followed by drying to get the second compound. The second compound is 6-amino-1, 3-dipropyl-5-nitrosouracil. Further, the second compound is having a melting point in a range of, but not limited to, 215-220°C.

At step 110, the second compound is dissolved in concentrated ammonium hydroxide followed by addition of sodium dithionite to form a third mixture.

In accordance with an embodiment of the present invention, the sodium dithionite dissolved and underwent a series of color changes. Further, the third mixture is stirred for, but not limited to, 2 hours at room temperature followed by cooling in an ice bath.

At step 112, third mixture is washed and dried to form a third compound.

In accordance with an embodiment of the present invention, the third mixture formed in the step 110 is filtered and washed with few drops of cool water followed by drying to get the third compound. The third compound is 5, 6-diamino-1, 3-dipropyluracil. Further, the third compound is having a melting point in a range of, but not limited to, 128-132°C.

At step 114, a plurality of amines are added in a suspension of hydroxybenzaldehyde in ethyl methyl ketone to form a fourth mixture.

In accordance with an embodiment of the present invention, the plurality of amines are selected from, but not limited to, a group consisting of 4-(2-chloroethyl)-amino hydrochlorides, 4-(2-chloroethyl)-morpholine hydrochloride, 4-(2-chloroethyl)-piperidine hydrochloride, 2-chloro-N,N’-dimethyl ethanamine, 1-(2-chloroethyl)-pyrrolidine, 2-chloro-N,N’-diethyl ethanamine and 1-(2-chloroethyl)-phthalimide.
In accordance with an embodiment of the present invention, the step 114 further comprises a step of addition of dried potassium carbonate in the fourth mixture to avoid incorporation of moisture.

At step 116, the fourth mixture is filtered to form a fourth compound.

In accordance with an embodiment of the present invention, the mixture obtained from step 114 is filtered and reduced on rotary evaporator to afford the targeted compounds or the fourth compound. Further, varying fourth compounds may be obtained depending on the amine used in the fourth mixture.

At step 118, the fourth compound is added in the third compound and refluxed.

In accordance with an embodiment of the present invention, the fourth compound is provided in ethanol and the third compound is provided in ethanol and acetic acid. Ethanol and acetic acid are provided in a ratio of, but not limited to, 8:2. Further, excess amount of solvent is recovered using rotary evaporator.

At step 120, an ice cold solvent is added in the mixture of fourth compound and the third compound to obtain a fifth compound.

In accordance with an embodiment of the present invention, the ice cold solvent is, but not limited to, water. Further, the fifth compound is a Schiff base.

At step 122, the fifth compound is refluxed in thionyl chloride and filtering the refluxed mixture to obtain 8-substituted xanthine.

In accordance with an embodiment of the present invention, the fifth compound is refluxed in thionyl chloride for 1 hour at a temperature in range of, but not limited to, 70-80°C. Excess solvent is reduced under vacuum and residue so obtained is neutralized to result in precipitation. The reaction mixture is cooled, filtered off and washed with cold water to obtain various 8-substituted xanthines of formula (I).

In accordance with an embodiment of the present invention, R1 and R2 are methyl groups. Further, R3 is selected from, but not limited to, a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.

In accordance with an embodiment of the present invention, the step 122 further comprises a step of step of crystallization of the 8-substituted xanthine from a mixture of chloroform and methanol present in a ratio of, but not limited to, 1:2.

In accordance with an embodiment of the present invention, xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.

In accordance with an embodiment of the present invention, xanthine is selected from, but not limited to, a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.

In accordance with an embodiment of the present invention, the pharmacological activity of the pharmaceutical compound is tested in both in vivo and in vitro.

Hereinafter, non-limiting examples of the present invention will be provided for more detailed explanation which is not meant to limit the scope of the invention in any manner.

Examples
Materials and methods
1. Preparation of 8-substituted xanthine compound
Step 1: A mixture of N, N’-dipropylurea (1.0 g, 6.94 mmol), cyanoacetic acid (1.5 g, 17.64 mmol) and acetic anhydride (2.5 ml) was refluxed at 70-80°C for 3 hours excluding moisture. The excess anhydride and acetic acid formed during the reaction were removed under vacuum. The residue was then cooled at 0-5°C and a solution of 5 % sodium hydroxide (40 ml) was added with stirring resulting in precipitation of 6-amino-1, 3-dipropyluracil.

Step 2: A sodium nitrite solution (1.0 g, 14.49 mmol in 8 ml of water) was added to cool, stirred mixture of 6-amino-1, 3-dipropyluracil and acidified with acetic acid dropwise (2 ml) over a period of one hour resulting in red-violet precipitates. The mixture was then kept on stirring at room temperature for a period of overnight. The mixture so obtained was then cooled, filtered off, washing was done with water and diethyl ether followed by drying to get 6-amino-1, 3-dipropyl-5-nitrosouracil (1.33 g, 63.63%).

Step 3: The 6-amino-1,3-dipropyl-5-nitrosouracil (1g, 4.16 mmol) was dissolved in 8 ml ammonium hydroxide concentrated. The sodium dithionite (2.74 g, 15.73 mmol) was then added slowly with stirring. The salt dissolved and underwent a series of color changes. The solution was kept on stirring for further two hours at room temperature followed by cooling in an ice bath. The precipitates so obtained were filtered off, washing was done with few drops of cool water followed by drying to get 5, 6-diamino-1, 3-dipropyluracil (0.76 g, 80.85%).

Step 4: Various amines such as 4-(2-chloroethyl)-amino hydrochlorides (1 g), [4-(2-chloroethyl)-morpholine hydrochloride (5.36 mmol), 4-(2-chloroethyl)-piperidine hydrochloride (5.42 mmol), 2-chloro-N,N’-dimethyl ethanamine (6.93 mmol), 1-(2-chloroethyl)-pyrrolidine (5.88 mmol), 2-chloro-N,N’-diethyl ethanamine (5.82 mmol) and 1-(2-chloroethyl)-phthalimide (4.77 mmol)] were added to the refluxing suspension of 4-hydroxy-benzaldehyde (1 g, 6.56 mmol) in ethyl methyl ketone (20 ml). 3.0 g of dried potassium carbonate was added to avoid incorporation of any moisture. After completion, suspension was filtered and reduced on rotary evaporator to afford the targeted compounds or fourth compound.

Step 5: To the stirred solution of fourth compound in ethanol (5 ml), added 5, 6-diamino-1,3-dipropyluracil (1g, 4.42 mmol) with ethanol and acetic acid (8:2, 10 ml) and refluxed. After completion, excess amount of solvent was recovered using rotary evaporator. Added ice cold water in to the reaction mixture, filtered-off and washed to fifth compound (Schiff base).

Step 6: The Schiff bases (1 g) were refluxed in thionyl chloride (15 ml) for 1 hour at 70-80 °C. Excess solvent was reduced under vacuum and residue so obtained was neutralized to result in precipitation. The reaction mixture cooled, filtered off and washed with cold water to obtain various 8-(4-(2-aminoethoxy)-phenyl)-1,3-dipropylxanthine derivatives such as, 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine (Ia), 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine (Ib), 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine (Ic), 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine (Id), 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine (Ie) and 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine (If).

2. Experimental animals
Guinea-pigs (Male; Dunkin Hartley) of 220-280 g, were obtained from Lala Lajpat Rai University of Animal Sciences, Hisar. The experimental animals so procured were kept in standard conditions as prescribed with proper food and water. They were monitored for 12 hours day and night cycle for experimentation.

3. Drugs used
Histamine hydrochloride (bronchospasm agent), theophylline (standard drug), carboxymethyl cellulose (suspending agents) and test compounds (synthesized pharmaceutical compound).

4. Experimental protocol
Guinea pigs (n= 5) were designated as A for control animals (fed with carboxymethyl cellulose and water); B for positive animals (carboxymethyl cellulose, theophylline and water) and C for test animals (carboxymethyl cellulose, test drug and water). The assigned animal groups were allowed for fasting before treatment.

5. Radioligand binding assays at adenosine receptors
The various pharmaceutical compounds were evaluated using in vitro radioligand binding studies at cloned adenosine receptors. In this study all human subtypes were stably transfected into Chinese Hamster Ovary (CHO) cells to study their pharmacological profile in an identical cellular background utilizing radioligand binding studies (A1, A2A, A3) or adenyl cyclase activity assays (A2B).
Results
1. Bronchospasmolytic activity (in vivo)
The bronchospasmolytic activity of pharmaceutical compounds was determined by histamine aerosol induced bronchospasm model. The experimental animals were exposed to histamine aerosol in histamine chamber for 5 mins after 1 hour of dosing. Prior to exposure, animals received test drug (50 mg/kg), theophylline (50 mg/kg) and carboxymethyl cellulose orally, respectively. Difference in in vivo pharmacological behaviors of each animal was observed such as bronchospasm, jerks, death or survival. The animals were allowed to remain in the chamber for 15 min, if survived, animals were removed from the chamber and placed in fresh atmosphere with proper diet. The pharmacological behaviors so monitored were tabulated in Table 1.

Table 1: Protection by xanthine derivatives against bronchospasm induced by histamine aerosol (5 ml of 1% w/v aerosoled in 1 min) in guinea pigs
Number of animals in each group (N) = 5
*Newman-Keuls Multiple Comparison Test; p<0.05 as compare to normal control
#Newman-Keuls Multiple Comparison Test; p<0.05 as compare to theophylline
Dose of standard and tested compounds = 50 mg/kg

2. Radioligand binding assays at adenosine receptors
Affinities of various newly synthesized xanthine derivatives for adenosine A1, A2A and A3 receptors have been summarized in Table 2.

Table 2: Binding affinities of various xanthine derivatives at adenosine receptors.
*Preliminary Values
Shown values are geometric means from 3 to 5 experiments in µM with 95% confidence intervals in parentheses, where:
a Displacement of specific (3H)CCPA binding in CHO cells, stably transfected with human recombinant A1 adenosine receptor, expressed as Ki (nM).
b Displacement of specific (3H)NECA binding in CHO cells, stably transfected with human recombinant A2A adenosine receptor, expressed as Ki (nM).
c Antagonist affinities were determined by inhibition of NECA-stimulated adenylyl cyclase activity in membrane preparations.
d Displacement of specific (3H)HEMADO binding in CHO cells, stably transfected with human recombinant A3 adenosine receptor, expressed as Ki (nM)

3. Characterization data
Various derivatives of the pharmaceutical compound comprising 8-substituted xanthine having formula (I) have been described separately below.

(i) 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine (RY-091, Ia)
Yield: 0.90 g, 90.54%, melting point (mp) 140-145°C (decomposition)
Spectral and elemental analysis:
FT-IR ?max (KBr) cm-1: 3179 (NH), 2962 (Ali-CH), 1696 (C=O), 1646 (C=N), 1558 (NH), 1469 (Ar-C=C), 1247 (C-N), 1178 (C-O)
¹HNMR (400MHz, CDCl3): d 12.75 (s, 1H, -NH), 8.35 (d, 1H, Ar-H, Jortho=8.6), 8.21 (m, 1H, Ar-H), 7.48 (d, 1H, Ar-H, Jortho=8.8), 7.00 (m, 1H, Ar-H), 4.10 (m, 10H, 5 x -NCH2), 3.70 (s, 6H, 3 x -OCH2-), 1.83 (m, 4H, 2 x -CH2-) and 0.89-1.03 ppm (m, 6H, 2 x -CH3)
13C-NMR (100 MHz, CDCl3): d 11.23 (CH3), 11.45 (CH3), 20.01 (CH2), 21.35 (CH2), 44.39 (2 x N-CH2), 54.02 (3 N-CH2), 65.64 (2 x O-CH2), 66.08 (O-CH2), 111.10 -156.41 (2 ArC) and 162.75 (C=O) and 168.05 ppm (C=O)
Cal. for C23H31N5O4: C 62.57%, H 7.08%, N 15.86%, O 14.49%, Found: C 60.57%, H 6.18%, N 14.16%
(ii) 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine (RY-093, Ib)
Yield:0.99 g, 99%, mp 165-170°C (decomposition)
Spectral and elemental analysis:
FT-IR?max (KBr)cm-1: 3168 (NH), 2960 (Ali-CH), 1696 (carbonyl), 1648 (C=N), 1526 (NH-bend), 1468 (Ar-C=C), 1250 (C-O), 1180 (C-N)
¹H-NMR (400 MHz, CDCl3): d 8.15 (d,2H, Ar-H, Jortho=7.76Hz), 6.92 (d, 2H, Ar-H, Jortho=7.24Hz), 4.37 (s, 1H, -NH-), 4.16-4.01 (m, 2H, -OCH2-), 3.15-2.77 (m,10H, -5 x -NCH2-), 1.85-1.55 (m, 10H, 5 x -CH2-), 1.01-0.89 (m, 6H, 2xCH3)
13CNMR (100MHz, CDCl3): d 10.20-10.38 (CH3), 20.30 (CH2), 25.52 (CH2), 44.56 (N-CH2), 53.75 (N-CH2), 65.64 (O-CH2), 108.23-151.41 (Ar-C), 155.75 (C=O) and 159.05 ppm (C=O)
Cal. for C24H33N5O3: C 65.58%, H 7.57%, N 15.93%, O 10.92%, Found: C 64.98%, H 7.01%, N 14.97%

(iii) 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine(RY-095, Ic)
Yield:0.99 g, 99%, mp 160-162°C (decomposition)
Spectral and elemental analysis:
FT-IR ?max (KBr)cm-1: 3564 (NH), 3110 (Ar-CH), 2961 (Ali-CH), 1696 (C=O), 1645 (C=N), 1540 (NH), 1459 (H-C=C-H), 1255 (C-N), 1176 (C-O)
¹H-NMR (400 MHz, CDCl3): d 13.01 (s, 1H,-NH), 8.20 (s, 2H, Ar-H), 7.45 (s, 1H, Ar-H), 6.98 (s, 1H, Ar-H), 4.06 (s, 6H, 2 x -NCH3), 3.14 (m, 2H, -OCH2-), 1.77 (s, 6H, 3 x -NCH2-) and 0.60-0.92 ppm (s, 10H, 2 x -CH2-, 2 x CH3)
13CNMR (100MHz, CDCl3): d 10.37 (CH3), 11.53 (CH3), 21.24 (2 CH2), 43.66 (2 N-CH2), 45.80 (2 N-CH3), 57.70 (N-CH2), 65.64 (O-CH2), 115.23 (Ar-C), 121.67 (Ar-C), 150.89 (Ar-C), 152.41 (2 Ar-C), 119.10 (2 Ar-CH), 132.90 (2 Ar-CH), 151.75 (C=O) and 156.05 ppm (C=O)
Cal. for C21H29N5O3: C 63.14%, H 7.32%, N 17.53%, O 12.01%, Found: C 60.14%, H 6.82%, N 16.83%

(iv) 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine (RY-097, Id)
Yield:0.99 g, 99%, mp 170-176°C (decomposition)
Spectral and elemental analysis:
FT-IR ?max (KBr)cm-1: 3564 (NH), 3175 (CH), 2960 (CH), 1695 (C=O), 1648 (C=N), 1523 (NH), 1470 (Ar-C=C), 1248 (C-O), 1179 (C-N)
¹HNMR (400MHz, CDCl3): d 8.19 (s, 2H, Ar-H), 6.98 (s, 2H, Ar-H), 4.31 (s, 1H, -N H), 4.15-4.05 (m, 10H, 5 x -NCH2-), 3.20-2.98 (m, 2H, -OCH2), 1.96 (s, 4H, 2 x -CH2-), 1.84 (m, 2H, -CH2-), 1.71 (m, 2H, -CH2-) and 1.01-0.94 ppm (m,6H, 2xCH3)
13CNMR (100MHz, CDCl3): d 11.25 (CH3), 11.49 (CH3), 20.08 (CH2), 21.36 (CH2), 25.56 (2 CH2), 44.05 (2 N-CH2), 54.08-56.67 (3 N-CH2), 66.07 (O-CH2), 108.31 (Ar-C), 114.67 (2 Ar-CH),128.89 (2 Ar-CH), 121.45 (Ar-C), 149.96 (Ar-C), 152.87 (C=O), 156.08 (2 Ar-C) and 156.78 ppm (C=O)
Cal. forC23H31N5O3: C, 64.93%, H 7.35%, N 16.47%, O 11.29%, Found: C 65.34%, H 8.31%, N 15.12%

(v) 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine (RY-099, Ie)
Yield:0.99 g, 99%, mp 160-162°C (decomposition)
Spectral and elemental analysis:
FT-IR ?max(KBr) cm-1: 3647 (NH), 3174 (Ar-CH), 2961 (Ali-CH), 1695 (C=O), 1648 (C=N), 1554 (NH), 1468 (Ar-C=C), 1249 (C-O), 1178 (C-N)
¹H-NMR (400 MHz, CDCl3): d 12.75 (s, 1H, -NH), 8.16 (m, 2H, Ar-H), 6.95 (m, 2H, Ar-H), 4.48 (s, 2H,-OCH2-), 4.30-3.86 (m, 4H, 2 x -NCH2-), 3.45-3.23 (s, 2H, -NCH2), 1.84-1.69 (m, 4H, 2 x -NCH2-), 1.39-1.25 (s, 4H, 2 x -CH2-) and 0.99 ppm (m, 12H, 4xCH3)
13CNMR (100MHz, CDCl3): d 10.08-11.24 (2 CH3), 13.08 (2 CH3), 20.08 (CH2), 21.34 (CH2), 44.03-53.78 (5 N-CH2), 66.07 (O-CH2), 107.89 (Ar-C), 114.67 (2 Ar-CH), 121.45 (Ar-C), 128.89 (2 Ar-CH), 150.04 (Ar-C), 152.87 (C=O), 156.08 (2 Ar-C) and 156.78 ppm (C=O)
Cal. for C23H33N5O3: C 64.61%, H 7.78%, N 16.38%, O 11.23%, Found:C 62.61%, H 8.08%, N 16.38%

(vi) 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine (RY-101, If)
Yield:0.99 g, 99%, mp> 280°C
Spectral and elemental analysis:
FT-IR ?max (KBr) cm-1: 3316 (NH), 3192 (CH), 2963 (CH), 1693 (carbonyl), 1644 (C=N), 1560 (NH), 1476 (H-C=C-H), 1271 (C-O), 1178 (C-N)
¹H-NMR (400 MHz, DMSO-d6): d 13.28 (s, 1H, -NH-), 7.98 (s, 4H, Ar-H), 6.84 (s, 4H, Ar-H), 4.05 (s, 2H, -OCH2-), 3.91 (s, 6H, 3 x -NCH2-), 1.79-1.63 (m, 4H, -2CH2-), 0.94 (t, 6H, 2 x -CH3, J1=6.16, J2=6.12)
13C-NMR (100 MHz, DMSO-d6): d 10.8-11.01 (2 CH3), 20.02 (2 CH2), 39.04-44.89 (3 N-CH2), 66.04 (O-CH2), 114.32 (2 Ar-CH, Ar-C), 123.76 (Ar-C), 128.05 (4 Ar-CH), 131.44 (2 Ar-CH), 132.24 (2 Ar-C), 150.78 (Ar-C), 152.04 (C=O), 156.04 (2 Ar-C), 156.87 (C=O) and 167.09 ppm (2 C=O)
Cal. for C27H27N5O5: C 64.66%, H 5.43%, N 13.96%, O 15.95%, Found: C 66.59%, H 5.76%, N 14.72%

Conclusion
A pharmaceutical compound comprising 8-substituted xanthine has been successfully obtained. All the animals used in the study survived against histamine exposure (in vivo) and also showed excellent binding affinity to adenosine A2A receptors (in vitro) in a range of about 0.01 µg. Further, the disclosed pharmaceutical compound is useful as anti-inflammatory and anti-asthmatic drug and thus, useful in the treatment of diseases such as, but not limited to, asthma, COPD and Parkinson’s disease.

The exemplary implementation described above is illustrated with specific structure, ingredients, and other characteristics, but the scope of the invention includes various other structures, ingredients, and characteristics. Also, the pharmaceutical compound as described above could be fabricated in various other ways and could include various other materials, including various other functional groups etc. to provide various pharmaceutical compounds with various 8-substituted xanthines.

Various modifications to these embodiments are apparent to those skilled in the art from the description and the accompanying drawings. The principles associated with the various embodiments described herein may be applied to other embodiments. Therefore, the description is not intended to be limited to the embodiments shown along with the accompanying drawings but is to be provided broadest scope consistent with the principles and the novel and inventive features disclosed or suggested herein. Accordingly, the invention is anticipated to hold on to all other such alternatives, modifications, and variations that fall within the scope of the present invention and appended claims.

Claims:We Claim:
1. A pharmaceutical compound, comprising:
8-substituted xanthine of formula (I);
wherein R1 and R2 are methyl groups;
wherein R3 is selected from a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.

2. The pharmaceutical compound as claimed in claim 1, wherein said xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.

3. The pharmaceutical compound as claimed in claim 1, wherein said xanthine is selected from a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.

4. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of 140-145°C.

5. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of 165-170°C.

6. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point in a range of 160-162°C.

7. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine is having a melting point in a range of 170-176°C.

8. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point in a range of 160-162°C.

9. The pharmaceutical compound as claimed in claim 3, wherein said 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine is having a melting point of 280°C or above.
10. The pharmaceutical compound as claimed in claim 1, wherein said xanthine possesses affinity and potency of 0.01µm towards adenosine A2A receptors.

11. A process (100) of preparing a pharmaceutical compound as claimed in claim 1, comprising the steps of:
mixing (102) N, N’-dipropylurea, cyanoacetic acid and acetic anhydride to form a first mixture;
adding (104) a solution of sodium hydroxide in said first mixture resulting in precipitation of a first compound;
adding (106) a solution of sodium nitrite in said first compound and acidifying with acetic acid to form a second mixture;
washing and drying (108) said second mixture to form a second compound;
dissolving (110) said second compound in concentrated ammonium hydroxide followed by adding sodium dithionite to form a third mixture;
washing and drying (112) said third mixture to form a third compound;
adding (114) a plurality of amines in a suspension of hydroxybenzaldehyde in ethyl methyl ketone to form a fourth mixture;
filtering (116) said fourth mixture to form a fourth compound;
adding (118) said fourth compound in said third compound and refluxed;
adding (120) an ice cold solvent in said mixture of fourth compound and said third compound to obtain a fifth compound;
refluxing (122) said fifth compound in thionyl chloride and filtering said refluxed mixture to obtain 8-substituted xanthine.
12. The process (100) as claimed in claim 11, wherein said xanthine is having a formula (I):

wherein R1 and R2 are methyl groups;
wherein R3 is selected from a group consisting of morpholino moiety, piperidino moiety, dimethylamino moiety, pyrrolidino moiety, diethylamino moiety and pthalimido moiety.

13. The process (100) as claimed in claim 12, wherein said xanthine is 8-[4-(2-aminoethoxy) phenyl]-1, 3-dipropyl xanthine.

14. The process (100) as claimed in claim 12, wherein said xanthine is selected from a group consisting of 8-[4-(2-morpholinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-(2-piperidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(dimethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-(2-pyrrolidinoethoxy)-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(diethylamino)-ethoxy}-phenyl]-1,3-dipropylxanthine, 8-[4-{2-(phthalimido)-ethoxy}-phenyl]-1,3-dipropylxanthine and combinations thereof.

15. The process (100) as claimed in claim 11, wherein said first mixture is refluxed at a temperature in range of 70-80°C for 3 hours and thereafter cooled at a temperature in range of 0-5°C.

16. The process (100) as claimed in claim 11, wherein said sodium hydroxide is having a concentration of 5% (w/v).

17. The process (100) as claimed in claim 11, wherein said first compound is 6-amino-1, 3-dipropyluracil.

18. The process (100) as claimed in claim 11, wherein said acetic acid is added dropwise for a period of 1 hour resulting in red-violet precipitates.

19. The process (100) as claimed in claim 11, wherein said second mixture is stirred at room temperature for overnight.

20. The process (100) as claimed in claim 19, wherein said second mixture is cooled, filtered and washed with water and diethyl ether.

21. The process (100) as claimed in claim 11, wherein said second compound is 6-amino-1, 3-dipropyl-5-nitrosouracil.

22. The process (100) as claimed in claim 11, wherein said second compound is having a melting point in a range of 215-220°C.

23. The process (100) as claimed in claim 11, wherein said third mixture is stirred for 2 hours at room temperature followed by cooling in an ice bath.

24. The process (100) as claimed in claim 23, wherein said third mixture is filtered and washed with cool water followed by drying.

25. The process (100) as claimed in claim 11, wherein said third compound is 5, 6-diamino-1, 3-dipropyluracil.

26. The process (100) as claimed in claim 11, wherein said third compound is having a melting point in a range of 128-132°C.

27. The process (100) as claimed in claim 11, wherein said plurality of amines are selected from a group consisting of 4-(2-chloroethyl)-amino hydrochlorides, 4-(2-chloroethyl)-morpholinehydrochloride, 4-(2-chloroethyl)-piperidine hydrochloride,2-chloro-N,N’-dimethyl ethanamine, 1-(2-chloroethyl)-pyrrolidine, 2-chloro-N,N’-diethyl ethanamine and 1-(2-chloroethyl)-phthalimide.

28. The process (100) as claimed in claim 11, wherein said step of adding (114) further comprises a step of addition of dried potassium carbonate in said fourth mixture to avoid incorporation of moisture.

29. The process (100) as claimed in claim 11, wherein said step of adding (118) involves said fourth compound provided in ethanol and said third compound provided in ethanol and acetic acid.
30. The process (100) as claimed in claim 29, wherein said ethanol and acetic acid are provided in a ratio of 8:2.

31. The process (100) as claimed in claim 11, wherein said ice cold solvent is water.

32. The process (100) as claimed in claim 11, wherein said fifth compound is a Schiff base.

33. The process (100) as claimed in claim 11, wherein said step of refluxing (122) is performed at a temperature in range of 70-80°C for 1 hour.

34. The process (100) as claimed in claim 11, wherein said step of refluxing (122) further comprises a step of crystallization of said 8-substituted xanthine from a mixture of chloroform and methanol present in a ratio of 1:2.