FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, exhibiting therapeutic activity in management of inflammatory diseases. The present invention further relates to 4-glucosamine quinoline analogs with different substituents at position-2 of quinoline.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer property. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. On the other hand, Nitric Oxide (NO) also possesses various pharmacological activities like anti-hypertensive, analgesic, long-acting anaesthetic, anti-inflammatory, smooth-muscle relaxation, immuno-suppressant, anti-diabetic, anti-cancer etc. and also has low solubility in water and is unstable in the presence of various oxidants. It makes it difficult to introduce as such into biological systems in a controlled or specific fashion.
[0004] Therefore, development of chemical agents that release NO is important, which may be associated with high therapeutic activity, less toxic effects and may show synergistic effects with increased absorption.
[0005] There is, therefore, a need to develop Nitric oxide releasing compound which can overcome deficiencies associated with the known arts.

OBJECTS OF THE INVENTION
[0006] An object of the present invention is to provide novel compounds useful for management of inflammatory diseases.
[0007] Yet another object of the present invention is to develop Nitric oxide releasing compounds which can overcome deficiencies associated with the known arts.
[0008] Another object of the present invention is to provide novel compounds which show synergistic effects with increased absorption.
[0009] Another object of the present invention is to provide novel compounds with high therapeutic activity and less toxic effects.

SUMMARY OF THE INVENTION
[0010] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0011] The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, exhibiting therapeutic activity in management of inflammatory diseases.
[0012] In one aspect, the present invention relates to 4-glucosamine quinoline analogs with different substituents at position-2 of quinoline.
[0013] In one aspect, the present invention relates to compounds of Formula I, and their pharmaceutically acceptable salts thereof,

wherein:
R1 can be selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -ORa, -NH2, -NRaRb, -CO(Ra), -CHO, -NO2, -F, -Cl, -Br, -I, -COOH, -CONH2 or –COORa; wherein the said C1-6alkyl, C3-7cycloalkyl, C6-10aryl may optionally be substituted at any available position by one or more suitable substituents selected from R2;
Ra and Rb can be independently selected from H, C1-6alkyl, C3-7cycloalkyl or C6-10aryl;
R2 can be selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -NH2, -CHO, -NO2, -F, -Cl, -Br, -I, -COOH or -CONH2.
[0014] In another aspect, the present invention relates to compounds of Formula I, wherein R1 can be selected from H, C1-6alkyl, C6-10aryl, -OH, -ORa, -NH2, -CO(Ra), -CHO, -F, -Cl, -Br or -I.
[0015] In yet another aspect, the present invention relates to compounds of Formula I, wherein R1 can be selected from H, CH3, C6H5, -OH, -OCH3, -NH2, -COCH3 or –Cl.
[0016] In another aspect, the present invention relates to a composition comprising the compound of Formula I, and their pharmaceutically acceptable salts, along with excipients.
[0017] In still another aspect, the invention also relates to the processes for the synthesis of novel compounds of Formula I and their pharmaceutically acceptable salts thereof.
[0018] In one aspect, the present invention relates to novel compounds of Formula I useful as anti-inflammatory, analgesic, ulcerogenic potential, anti-oxidant and antimicrobial agents.
[0019] Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0020] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
[0021] Figure 1: Standardization plot for sodium nitrate for Griess Test.
[0022] Figure 2: DPPH free-radical scavenging activity

DETAILED DESCRIPTION
[0023] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0024] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0025] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0026] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0027] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0028] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0029] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0030] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[0031] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0032] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0033] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0034] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0035] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0036] The present invention relates to pharmaceuticals. Specifically, the present invention relates to novel compounds of Formula I, exhibiting therapeutic activity in management of inflammatory diseases.
[0037] In one embodiment, the present invention further relates to 4-glucosamine quinoline analogs with different substituents at position-2 of quinoline.
[0038] In one embodiment, the present invention relates to compounds of Formula I, and their pharmaceutically acceptable salts thereof

wherein:
R1 can be selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -ORa, -NH2, -NRaRb, CO(Ra), -CHO, -NO2, -F, -Cl, -Br, -I, -COOH, -CONH2 or –COORa; wherein the said C1-6alkyl, C3-7cycloalkyl, C6-10aryl may optionally be substituted at any available position by one or more suitable substituents selected from R2;
Ra and Rb can be independently selected from H, C1-6alkyl, C3-7cycloalkyl or C6-10aryl;
R2 can be selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -NH2, -CHO, -NO2, -F, -Cl, -Br, -I, -COOH or -CONH2.
[0039] In another embodiment, the present invention relates to compounds of Formula I, wherein R1 can be selected from H, C1-6alkyl, C6-10aryl, -OH, -ORa, -NH2, -CO(Ra), -CHO, -F, Cl, -Br or -I.
[0040] In a preferred embodiment, the present invention relates to compounds of Formula I, wherein R1 can be selected from H, CH3, C6H5, -OH, -OCH3, -NH2, -COCH3 or –Cl.
[0041] In another embodiment, the present invention relates to a composition comprising a compound of Formula I, and their pharmaceutically acceptable salts, along with excipients. The suitable excipients are well known to a person of skill in the art and they include, but are not limited to, sweeteners, food colors, preservatives, binders, buffers, wetting agents and disintegrants. A pharmaceutical composition of the compound of Formula I may be administered via oral, topical, nasal, pulmonary, intravenous, transdermal, subcutaneous, or intramuscular routes.
[0042] In an embodiment, the composition may be present in the form of a capsule, tablet, powder, pill, suspension, dispersion, solution, aerosol or patches.
[0043] In another embodiment, the compounds of Formula I exhibit pharmacological properties.
[0044] In an embodiment, the compounds have increased water solubility and Nitric oxide releasing properties in physiological conditions. The claimed compound therefore has enhanced biological activity.
[0045] In yet another embodiment, the present invention relates to compounds of Formula I useful as anti-inflammatory, analgesic, ulcerogenic potential, anti-oxidant and antimicrobial agents.
[0046] These compounds are associated with high therapeutic activity with less toxic effects. The compounds of present invention may show synergistic effects with increased absorption.
[0047] In another embodiment, the present invention relates to a method of treating, especially an inflammatory disease, using a compound of Formula I, and their pharmaceutically acceptable salts or any composition comprising a compound of Formula I, and their pharmaceutically acceptable salts.
[0048] The present invention also relates to the use of the compound of Formula I in manufacture of a medicament for treatment or prevention of inflammatory diseases.
Definitions
[0049] Relative to the above description of the compounds of the present invention, the following definitions apply.
[0050] The term “alkyl” as used herein alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon chain, having from 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, t-butyl and the like. Alkyl groups may further be substituted with one or more suitable substituents.
[0051] The term “cycloalkyl” refers to cyclic alkyl groups constituting of 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups may further be substituted with one or more suitable substituents. The term “cycloalkyl” may optionally contain one or more unsaturated bonds.
[0052] The term “aryl” herein refers to six to ten membered monocyclic aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with one or more suitable substituents. The aryl group may optionally be fused with one or two cycloalkyl group(s) or other aryl group(s) resulting in polycyclic ring system. The fused group may be further substituted with one or more suitable substituents.
[0053] A “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, for example glucosamine sulphates. A “pharmaceutically acceptable salt” also encompasses any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on a compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
[0054] In yet another embodiment, particularly useful examples of the present invention include but are not limited to the compounds selected from Table 1:
Table 1
Compound No. Structure
1
2
3
4
5
6
7
8

[0055] In another embodiment, the invention also relates to the processes for the synthesis of novel compounds of Formula I and their pharmaceutically acceptable salts thereof.
[0056] The compounds of the present invention may be prepared by the following reaction sequence as depicted in for example Scheme No 1. The compounds disclosed may also be prepared by techniques known in the art and familiar to a skilled organic chemist. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry.

[0057] In an embodiment, the present invention relates to a method of preparing a compound of Formula I comprising the following steps:
a) reacting a compound of Formula III with a glucosamine to give a compound of Formula II; and
b) nitration of the compound of Formula II to give a compound of Formula I.
[0058] In one embodiment, compounds of Formula I and their pharmaceutically acceptable salts thereof, can be synthesized from compounds of Formula II by nitration reaction. Nitration can be achieved using any method known in the art, preferably by using acetic anhydride/HNO3/NaNO2. The nitration process is preferably carried out in cold conditions.
[0059] Compounds of Formula II can be synthesized by reaction of compounds of Formula III with glucosamine using standard coupling reagents.
[0060] The obtained product is re-crystallized in alcohol to give solids preferably in the color range of light yellow to brown.
[0061] The compounds formed may contain chiral carbons, each of which may be R or S or their mixtures. Therefore, the product obtained may have stereochemically active centers.
[0062] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.
EXAMPLE 1: PREPARATION OF COMPOUNDS
[0063] For synthesis, the starting compounds of Formula III (2-substituted, 6-chloroquinoline) are treated with glucosamine (equimolar) which on dehydration gives 2-substituted-6-chloro-4-glucosoamino quinoline. This compound was further nitrated with acetic anhydride (23mg) in the presence of fuming nitric acid and sodium nitrite (60mg). The reaction mixture was stirred for 1 hour and then was kept for 3 hours to give the final compounds 1-8 with their respective substitutions at position 2.
EXAMPLE 2:
2.1 Identification Test :
[0064] On treatment with Griess reagent a light purple color developed in the titled compounds.
2.2 Quantification of the product:
[0065] The conversion of 4-glucosamino quinoline to nitric oxide derivatives of 4-glucosamino quinoline was quantified by means of sodium nitrite standard curve. The various standard solutions of concentrations i.e. 0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 ?g/ml of sodium nitrite were prepared by serial dilutions in water and a standardization curve was prepared at 549nm (refer Table 1 and Figure 1).
TABLE 1: Absorbance values for standardization plot of sodium nitrate
S. No. Conc.(?g/ml) Absorbance
1. 0 0.000
2. 2 0.092
3. 4 0.150
4. 6 0.217
5. 8 0.273
6. 10 0.333
7. 12 0.399
8. 14 0.465
9. 16 0.524
10. 18 0.591
11. 20 0.641

[0066] The quantity of nitroso derivative formed was determined with the help of sodium nitrite standard curve. In order to determine the same, 26 mg of the claimed compounds was dissolved in 9 ml buffer solution of pH 7.0 and was incubated with 1ml Griess Reagent at 25?C in the incubator for 30 minutes and was observed. After 30 minutes a purple color was seen in the mixture which indicated the formation of nitroso derivative of the claimed compounds. Then UV absorbance after the filtration of solution was taken at 549 nm which came out to be 0.251.With the help of the absorbance values, concentration of the sample was found from the standard curve of sodium nitrite to be 7.2 µg per ml.
[0067] Nitric oxide (NO) is an effective vasodilator that also inhibits platelet aggregation. Anti-inflammatory effect was quantified spectrometrically using Griess method by measuring nitric oxide (NO) production after the addition of Griess reagent.
EXAMPLE 3: In vitro antioxidant assays
DPPH radical scavenging activity:
[0068] Radical scavenging action of synthesized compounds against the stable 1, 1-diphenyl-2-picrylhydrazyl radical (DPPH) was measured using spectrophotometer. In order to measure the DPPH scavenging activity of the claimed compounds, DPPH solution was prepared by adding 12.5 mg of DPPH in 50 mL of methanol. Absorbance of this stock solution was measured at 517 nm. The DPPH solution was then diluted with methanol to an absorbance of 0.99 and stored in an amber colored bottle ready for use. An aliquot of 100 µL of the claimed compounds (1-8) at different concentrations (20, 40, 60, 80 and 100 µg/mL each prepared in methanol) was added to 1 mL of DPPH solution. The reaction mixture was incubated at 37 °C in darkness for 20–30 minutes. Decrease in absorbance was determined at 517 nm. As a standard, ascorbic acid/ 0.2 mM NaNO2 was used. The reaction was performed in triplicate. Scavenging activity was the calculated by using the Eq.1; where Q represents the DPPH scavenging activity and results are shown in table (also refer Figure 2).
Q (%) = Absorbance of control-Absorbance of sample/Absorbance of control×100 (Eq. 1)

TABLE 2: Showing DPPH free radical scavenging activity
Synthesized Compounds DPPH Scavenging Activity
Concentration in µg/mL 20 40 60 80 100
Compound 1 18 30 49 61 88
Compound 2 17 28 51 63 91
Compound 3 19 31 52 71 94
Compound 4 18 31 54 74 93
Compound 5 16 28 53 68 87
Compound 6 18 30 50 70 90
Compound 7 20 31 55 76 95
Compound 8 19 28 49 71 90
Standard (Ascorbate/NaNO2) 22 33 57 79 97

[0069] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.

ADVANTAGES OF THE PRESENT INVENTION
[0070] The present invention provides novel compounds useful for management of inflammatory diseases.
[0071] The present invention provides novel nitric oxide releasing compounds.
[0072] The present invention provides nitric oxide releasing compound which can overcome deficiencies associated with the known arts.
[0073] The present invention provides novel compounds which show synergistic effects with increased absorption.
[0074] The present invention provides novel compounds with high therapeutic activity and less toxic effects.

CLAIMS:
A compound of Formula I, and their pharmaceutically acceptable salts thereof

wherein:
R1 is selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -ORa, -NH2, -NRaRb, -CO(Ra), -CHO, -NO2, -F, -Cl, -Br, -I, -COOH, -CONH2 or –COORa; and
Ra and Rb are independently selected from H, C1-6alkyl, C3-7cycloalkyl or C6-10aryl.
2. The compound as claimed in claim 1, wherein the C1-6alkyl, C3-7cycloalkyl, C6-10aryl are substituted by one or more suitable substituents selected from R2;
wherein R2 is selected from H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, -OH, -NH2, -CHO, -NO2, -F, -Cl, -Br, -I, -COOH or -CONH2.
3. The compound as claimed in claim 1, wherein R1 is selected from H, C1-6alkyl, C6-10aryl, -OH, -ORa, -NH2, -CO(Ra), -CHO, -F, -Cl, -Br or -I.
4. The compound as claimed in claim 1, wherein R1 is selected from H, CH3, C6H5, -OH, -OCH3, -NH2, -COCH3 or –Cl.
5. A composition comprising a compound of Formula I, and their pharmaceutically acceptable salts, along with excipients.
6. A method of preparing a compound of Formula I comprising the following steps:
a) reacting a compound of Formula III with a glucosamine to give a compound of Formula II; and
b) nitration of the compound of Formula II to give a compound of Formula I
7. The method as claimed in claim 6, wherein the nitration is performed using a mixture of acetic anhydride, nitric acid and sodium nitrate.