Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“ANTHRAQUINONE DERIVATIVES TO TREAT CYTOKINE-RELATED DISORDERS”

We, ZYDUS LIFESCIENCES LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Corporate Park, Scheme No. 63, Survey No. 536, Plot No. 103, Khoraj (Gandhinagar), Nr. Vaishnodevi Circle, Sarkhej - Gandhinagar Highway, Ahmedabad – 382481, Gujarat, India,

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to novel compounds of the general formula (I) having the potential to treat cytokine-related disorders especially osteoarthritis, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

BACKGROUND OF THE INVENTION
Osteoarthritis (OA) is the most common form of arthritis. Its prevalence is increasing markedly because of an ageing population. OA is a chronic degenerative disease that is characterized by the gradual and progressive destruction of the cartilage that coats the articular surface of knees, hips, shoulders, hands, ankles and the spinal column. Disease is further characterized by the inflammation of the synovial membrane as well as damage to menisci, tendons, muscles and nerves associated with the affected joint. For individuals, the burden of OA also includes persistent background pain (aching) and intermittent but generally more intense pain. Together with disability, pain contributes to a significant reduction in quality of life. The management of OA includes pharmacological therapies, which are mostly symptomatic. Paracetamol is the first-line oral analgesic, whilst oral non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, are the mainstay of therapy. These drugs control pain but do not have known disease modifying effects. Treatment with NSAIDs is limited by their negative side effects on the gastrointestinal tract. Symptomatic slow-acting drugs for OA such as glucosamine, chondroitin sulphate and diacerein are used for non-acute treatment. IL-1 plays a major role in OA pathophysiology. Diacerein has been shown to inhibit, in vitro and in vivo, the production and activity of IL-1 and the secretion of metalloproteinases, without affecting the synthesis of prostaglandins; therefore, diacerein does not have a deleterious effect on the upper gastrointestinal tract the amino monosaccharide glucosamine is a major component of the glycosaminoglycan in articular cartilage. Its effects include stimulation of physiologic proteoglycan synthesis and decrease in the activity of catabolic enzymes such as metalloproteases. Diacerein has shown a potential for the treatment of OA, however, because of its side effects such as liver toxicity and diarrhea, its use is highly restricted. As of now, OA is a condition that is lacking in cost effective interventions and has no cure.
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SUMMARY OF THE INVENTION
The present invention relates to novel compounds of the general formula (I) having potential to treat cytokine related disorders especially osteoarthritis. The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of cytokine production. The compounds of this invention are therefore suitable for the treatment of cytokine related disorders such as osteoarthritis.

EMBODIMENTS OF THE INVENTION
The main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of cytokine related disorders such as osteoarthritis.
In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
In another embodiment is provided pharmaceutical compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of cytokine related disorders such as osteoarthritis, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
In one of the embodiments certain specific compounds which is useful for the treatment of cytokine related disorders.

DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general formula (I),

wherein,
X = hydroxy or -NR3R4,
R3 and R4 are independently selected from hydrogen, an optionally substituted group selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, -OR5 and haloalkyl; R3 and R4 together with the N atom to which they are attached may form a 5-8 membered cyclic ring;
R1 and R2 independently represent hydrogen, hydroxy, cyano, halo, nitro, haloalkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR5, -COOR5, -OR5, -OSO2CH3, -OCOR5, -S(O)pR5, -NR5R6, -CONR5R6, -N(R5)COR6, -N(R5)COOR6, -N(R5)CONR5R6, -SO2NR5R6, -N(R5)SO2R6;
R5 and R6 are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aralkyl, heterocyclylalkyl and haloalkyl; R5 and R6 together with the N atom to which they are attached may form a 5-8 membered cyclic ring;
When any of the above-defined groups is substituted the substitutions on them may be selected from hydrogen, hydroxy, cyano, halo, nitro, oxo, imino, haloalkyl, optionally substituted groups selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C8)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl and heterocyclylalkyl, alkylsulfonyloxy, -COR5, -COOR5, -OR5, -NR5R6, -CONR5R6, -N(R5)COR6, -N(R5)COOR6, -OCH2COR5, -N(R5)CH2COR6, -N(R5)CONR5R6, -S(O)pR5 derivatives; wherein, R5 and R6 are as defined earlier;
p = 0-2;
In a further embodiment the groups, radicals described above may be selected from:
- the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like;
- the “alkenyl” group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the “alkenyl” group includes dienes and trienes of straight and branched chains;
- the “alkynyl” group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like. The term “alkynyl” includes di- and tri-ynes;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
- the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
- the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
- the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 4-methylpiprrazinyl, 4-hydroxypiperidinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, p = 0-2;
- the “heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
- the “aralkyl” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an alkyl radical, as define above, more preferably groups selected from benzyl, phenethyl, and the like;
- the “heterocyclylalkyl” group used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl radical, as defined above, attached directly to an alkyl radical, as define above;
- the “alkylsulfonyloxy” group used either alone or in combination, refers to an alkylsulfonyl group attached directly to an oxygen atom, wherein a suitable alkyl group as defined above is attached to a sulfonyl radical;
- the “oxo” or “carbonyl” group used either alone (-C=O-) or in combination with other radicals such as alkyl described above, for e.g. “alkylcarbonyl”, denotes a carbonyl radical (–C=O-) substituted with an alkyl radical described above such as acyl or alkanoyl;
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
Preferred compounds according to the present invention include but are not limited to:
N-(2-hydroxyethyl)-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N, N-bis(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(benzyloxy)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(2-(ethyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(2-(methyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-hydroxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-((1-(methyl sulfonyl) cyclopropyl) methyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
1-(9,10-dioxo-9,10-dihydroanthracene-2-carbonyl) piperidine-4-carbonitrile;
2-(4-methyl-1H-pyrazole-1-carbonyl) anthracene-9,10-dione;
1-methoxy-6-(4-methylpiperazine-1-carbonyl) anthracene-9,10-dione;
5-(methylsulfonyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
N-(2-hydroxyethyl)-5-methoxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide.
In one of the embodiments certain specific compounds which is useful for the treatment of cytokine-related disorders especially osteoarthritis. Some of the compounds are as below with their IUPAC name:
N-(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
2-(morpholine-4-carbonyl) anthracene-9,10-dione;
9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
5-chloro-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
4-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid.
All the above listed compounds are prepared as per the method given in example no. 1, 16 and 18.
The compounds 1, 12-14 and 17-18 can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds 1, 12-14 and 17-18, or pharmaceutical compositions containing them are useful as a medicament for the cytokine related disorders especially osteoarthritis and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
The quantity of active component, that is, compounds 1, 12-14 and 17-18 according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
The novel compounds 1, 12-14 and 17-18 of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The pharmaceutical compositions further comprise an effective amount of an IL inhibitor. The dosage of IL inhibitors may vary within wide limits and should be adjusted, in each particular case, to the individual conditions.
In some embodiments, the cytokine related disorders include but not limited to osteoarthritis, rheumatoid arthritis, osteoporosis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn’s disease, psoriasis, scleroderma, atopic dermatitis, periodontal disease, gingivitis, diabetic nephropathy, lupus nephritis, IgA nephropathy, glomerulonephritis, systemic lupus erythematosus, graft vs host disease.
In some embodiments, the present invention includes a method for the treatment of at least one of but not limited to osteoarthritis, rheumatoid arthritis, osteoporosis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn’s disease, psoriasis, scleroderma, atopic dermatitis, periodontal disease, gingivitis, diabetic nephropathy, lupus nephritis, IgA nephropathy, glomerulonephritis, systemic lupus erythematosus, graft vs host disease administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of formula 1, 12-14 and 17-18.
The novel compounds of this invention may be prepared using the reactions and techniques as shown in the scheme below and described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and de-protected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers and/or diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention.

Scheme 1: Synthesis of compounds of general formula (I)

The compound of the general formula (IV) can be prepared by Friedel craft acylation reaction between (II) and (III) with appropriate modifications of starting materials and reagents. The compound of the general formula (V) can be obtained by acid-mediated cyclization of (IV). Compound (V) can be converted into corresponding carboxylic acid derivatives (I, when X = OH) using general techniques available for the oxidation of the aromatic alkyl group. The carboxylic acid derivative can be coupled with compounds of the general formula (VI) to prepare (I, when X = NR3R4) using various amide bond formation techniques known in the art such as described in Tetrahedron 2005, 61, 10827 with appropriate modifications as necessary. The preferred method involves the formation of acid chloride by reacting the acid with thionyl chloride followed by a reaction with (VI) in presence of organic bases such as triethyl amine, DIPEA etc. and using solvents such as DCM, THF etc.
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
The 1H NMR spectra were recorded on a Brucker Avance-400 spectrometer (400 MHz). The chemical shifts (d) are reported in parts per million (ppm) relative to Tetramethyl silane (TMS), in either CDCl3 or DMSO-d6 solution. Mass spectra (ESI-MS) were obtained on Shimadzu LC-MS 2010-A spectrometer.

List of Abbreviations
CDCl3: Deuterated chloroform
DMF: Dimethyl formamide
DCM: Dichloromethane
DMSO-d6: Hexadeuterodimethyl sulfoxide
TEA: Triethyl amine
THF: Tetrahydrofuran
DIPEA: Diisopropyl amine
1H NMR: Proton Nuclear Magnetic Resonance
Preparation of compounds
EXAMPLE 1
Preparation of N-(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide

Intermediate-1: Preparation of 9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Step 1: Preparation of 2-(4-methylbenzoyl) benzoic acid

To a stirring solution of phthalic anhydride (250 g, 1.68 mol) and toluene (197 ml, 1.85 mol) in dry DCM (2.5 lit) was added aluminum chloride (495 g, 3.71 mol) portion-wise over a period of 4 h at 0°C and the resulting mixture was stirred at room temperature for 24 h. After the complete conversion of starting material, the reaction mixture was diluted with cold water and the organic layer was separated. The organic layer was distilled out to get the title product ESI-MS (m/z): 241.08 (M+H)+

Step 2: Preparation of 2-methylanthracene-9,10-dione

The mixture of the product obtained from step 1 (100 g, 0.41 mol) in sulfuric acid (1 lit) was heated at 100°C for a period of 16 h. After the complete conversion of starting material, the reaction mixture was cooled to 0°C and poured into cold water. The solid obtained was filtered and washed with water to get title product. ESI-MS (m/z): 223.07 (M+H)+

Step 3: Preparation of 9, 10-dioxo-9, 10-dihydroanthracene-2-carboxylic acid

To a stirring solution of the product obtained from step 2 (60 g, 0.27 mol) in a mixture of acetic acid (2.5 lit) and water (50 mL) was added chromium trioxide (216 g, 2.16 mol) portion-wise over a period of 1 h and the resulting mixture was refluxed for 8 h. After the complete conversion of starting material, the reaction mixture was cooled to 0°C and poured into cold water. The solid obtained was filtered and washed with water to get title product. ESI-MS (m/z): 253.05(M+H)+

Preparation of N-(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide

To a stirring solution of product obtained from step 3 (1.0 g, 3.69 mmol) and thionyl chloride (1.0 ml) was refluxed for 1 hr. After complete conversion of starting material, solvent was evaporated under reduced pressure to get corresponding acid chloride, which was then added portion wise to a stirring solution of 2-aminoethan-1-ol hydrochloride and trimethylamine (1.0 ml, 7.39 mmol) in dry DCM (1.8 ml) at 0°C. The resulting mixture was stirred at room temperature for 4 hrs. After complete conversion of starting material, reaction mixture was quenched into water and extracted with DCM. Organic layer was concentrated to get crude product, which was trituration with ethanol and filter to get desired product. ESI-MS (m/z): 294.07 (M-H)
Using appropriate starting materials and suitable modifications of the process described in above example, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art; the following compound was prepared in an analogue’s manner
Ex. No Structure Name ESI-MS (m/z)
2
N-(2-hydroxyethyl)-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 310.10
3
N, N-bis(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 340.12
4
N-(benzyloxy)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 358.10
5
N-(2-(ethyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 372.06
6
N-(2-(methyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 358.02
7 N-hydroxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 282.07
8
N-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 282.07
9
N-((1-(methyl sulfonyl) cyclopropyl) methyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 384.00
10
1-(9,10-dioxo-9,10-dihydroanthracene-2-carbonyl) piperidine-4-carbonitrile 345.13
11
2-(4-methyl-1H-pyrazole-1-carbonyl) anthracene-9,10-dione 317.11
12
N-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 268.02
13
2-(morpholine-4-carbonyl) anthracene-9,10-dione 322.10
14
9,10-dioxo-9,10-dihydroanthracene-2-carboxamide 252.06

EXAMPLE 15
Preparation of 1-methoxy-6-(4-methylpiperazine-1-carbonyl) anthracene-9,10 dione

Intermediate-1: Preparation of 5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Step 1: Preparation of methoxy-2-(4-methylbenzoyl) benzoic acid

To a stirring solution of 4-methoxyisobenzofuran-1,3-dione (1 g, 5.61 mmol) in toluene (30 ml) was added aluminium trichloride (2.245 g, 16.84 mmol) portion wise over a period of 4 hrs at 0°C and the resulting mixture was stirred at room temperature for 24 hrs. After complete conversion of starting material, reaction mixture was diluted with cold water and extracted by DCM. Organic layer was separated, washed with water and evaporated under reduced pressure to get crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 269.08 (M-H)+

Step 2: 1-hydroxy-6-methylanthracene-9,10-dione

The mixture of the product obtained from step 1 (1 g, 3.70 mmol) in sulfuric acid (5 ml) was heated at 100°C for a period of 6 hrs. After complete conversion of starting material, reaction mixture was cooled to 0°C and poured in to cold water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 239.07(M+H)+

Step 3: 1-methoxy-6-methylanthracene-9,10-dione

To a stirring solution of product obtained from step 2 (13 g, 54.6 mmol) in DMF (150 ml) was added potassium carbonate (18.85 g, 136 mmol) followed by methyl iodide (8.53 ml, 136 mmol) at 0°C and reaction mixture was stirred at room temperature for 16 hrs. After complete conversion of starting material, reaction mixture was poured into water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 253.08 (M+H)+

Step 4: 5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of potassium permanganate (31.8 g, 201 mmol) in water (60 ml) was drop wise added solution of tetra butyl ammonium bromide (66.5 g, 206 mmol) in water (30 mL) and it was stirred at room temperature for 1h. The precipitated solid was filtered and wash with water. Purple solid was immediately dissolved in pyridine (250 ml) to this product obtained from step 3 (12.7 g, 50.3 mmol) was added and reaction mixture was stirred at 80°C for 16 hrs. After complete conversion of starting material, reaction mixture was poured into water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 383.05 (M+H)+

Preparation of 1-methoxy-6-(4-methylpiperazine-1-carbonyl) anthracene-9,10-dione

Mixture of 5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (0.16 g, 0.53 mmol) and thionyl chloride (5 ml) was refluxed for 1 hr. After complete conversion of starting material, solvent was evaporated under reduced pressure to get corresponding acid chloride which was then added portion wise to a stirring mixture of 1-methyl piperazine (0.053 g, 0.53 mmol) and trimethylamine (0.37 ml, 2.66 mmol) in dry acetonitrile (20 ml) at 0°C. The resulting mixture was stirred at room temperature for 24 hrs. After complete conversion of starting material, reaction mixture was poured into water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 365.15 (M+H)+
EXAMPLE 16
Preparation of 5-(methylsulfonyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Step 1: 2-(4-methylbenzoyl)-3-nitrobenzoic acid

To a stirring solution of 4-nitroisobenzofuran-1,3-dione (20 g, 104 mmol) in mixture of DCM (200 ml) and toluene (33.1 ml, 311 mmol) was added aluminum trichloride (34.5 g, 259 mmol) portion wise at 0°C.The reaction mixture was stirred for 2 hrs at room temperature. After complete conversion of starting material, reaction mixture was diluted with cold water (300 ml) and extracted by DCM (2 x 400 ml). Organic layer was separated, washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get the title product. ESI-MS (m/z): 286.20 (M+H)+

Step 2: 3-amino-2-(4-methylbenzoyl) benzoic acid

To a stirring solution of product obtained from step 1 (6 g, 21.03 mmol) in mixture of THF (30 ml) and MeOH (30 ml). was added ammonium format (13.26 g, 210 mmol) and Pd-C (0.895 g, 8.41 mmol) at room temperature and the reaction mixture was stirred at 80°C for 2 h. After complete conversion of starting material, reaction mixture was passed through the hyflo bed and excess solvent was removed under vacuum to get crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 254.1 (M-H).

Step 3: 1-amino-6-methylanthracene-9,10-dione

The mixture of product obtained from step 2 (4 g, 15.67 mmol) and sulfuric acid (20.88 ml, 392 mmol) was stirred at 120°C for 2 hrs. After complete conversion of starting material reaction mixture was diluted with cold water (100 ml) and extracted by DCM (2 X 40 ml). The organic layer was separated, washed with water, dried over Na2SO4 and evaporated under reduced pressure to get the crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 238.09 (M+H)+

Step 4: 1-chloro-6-methylanthracene-9,10-dione

To a stirring solution of product obtained from step 3 (0.6 g, 2.53 mmol) in acetonitrile (5 ml) was added isoamyl nitrate (0.511 ml, 3.79 mmol) followed by copper chloride (0.374 g, 2.78 mmol) at 0°C and the reaction mixture was heated at 50°C for 2 hrs. After complete conversion of starting material, reaction mixture was diluted with cold water (50 ml) and extracted by DCM (2 X 50 ml). Organic layer was separated, washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get the crude product which was purified by column chromatography to get desired product. ESI-MS (m/z): 256.9 (M+H)+
Step 5: 6-methyl-1-(methylthio) anthracene-9,10-dione

To a stirring solution of product obtained from step 4 (2 g, 7.79 mmol) in DMF (20 ml) was added sodium thiomethoxide (1.092 g, 15.58 mmol) at room temperature and reaction mixture was heated at 80°C for 2 hrs. After complete conversion of starting material, the reaction mixture was diluted with cold water (30 ml) and extracted by DCM (3 X 40 ml). Organic layer was separated, washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get crude product which was purified by column chromatography to get the desired product. ESI-MS (m/z): 269.06 (M+H)+

Step 6: 6-methyl-1-(methyl sulfonyl) anthracene-9,10-dione

To a stirring solution of product obtained from step 5 (2 g, 7.45 mmol) in DCM (10 ml), m-CPBA (3.86 g, 22.36 mmol) was added at 0°C and reaction mixture was stirred at room temperature for 16 hrs. After complete conversion of starting material, reaction mixture was diluted with cold water (30 ml) and extracted by DCM (3 X 40 ml). Organic layer was separated, washed with sodium bicarbonate solution, dried over Na2SO4 and evaporated under reduced pressure to get desired product. ESI-MS (m/z): 301.05 (M+H)+

Step 7: 5-(methylsulfonyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of product obtained from step 6 (0.5 g, 1.665 mmol) in acetic acid (5ml), chromium trioxide (0.166 g, 1.665 mmol) was added and reaction mixture was stirred 90°C for 2 hrs. After complete conversion of starting material, reaction mixture was quench with cold water (50 ml) and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 329 (M-H)
EXAMPLE 17
Preparation of 5-chloro-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of 1-chloro-6-methylanthracene-9,10-dione (4 g, 1.558 mmol, prepared in example 16) in acetic acid (5 ml) was added chromium trioxide (1.558 g, 15.58 mmol) at 0oC and reaction mixture was stirred at 90°C for 2 hrs. After complete conversion of starting material, reaction mixture was quench with cold water (30 ml) and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 285 (M-H).
EXAMPLE 18
Preparation of 4-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Step 1: Preparation of 1-hydroxy-3-methylanthracene-9,10-dione

Mixture of aluminium trichloride (13.50 g, 101 mmol) and sodium chloride (4.93 g, 84 mmol) was heated at 1200C to this was added isobenzofuran-1,3-dione (5 g, 33.8 mmol) followed by m-cresol (4.02 g, 37.1 mmol) at 1200C and reaction mixture was stirred for 2 hrs. After complete conversion of starting material, reaction mixture was diluted with cold water and extracted with DCM. Organic layer was separated, washed with water and evaporated under reduced pressure to get crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 239.07 [M+1].
Step 2: 1-methoxy-3-methylanthracene-9,10-dione

To a stirring solution of product obtained from step 1 (13 g, 54.6 mmol) in DMF (150 ml) was added potassium carbonate (18.85 g, 136 mmol) followed by methyl iodide (8.53 ml, 136 mmol) at 0°C and reaction mixture was stirred at room temperature for 16 hrs. After complete conversion of starting material, reaction mixture was poured into water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 253.08 (M+H)+

Preparation of 4-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of potassium permanganate (31.8 g, 201 mmol) in water (60 ml) was drop wise added solution of tetra butyl ammonium bromide (66.5 g, 206 mmol) in water (30 mL) and it was stirred at room temperature for 1h. the precipitated solid was filtered and wash with water. Purple solid was immediately dissolved in pyridine (250 ml) to this product obtained from step 2 (12.7 g, 50.3 mmol) was added and reaction mixture was stirred at 80°C for 16 hrs. After complete conversion of starting material, reaction mixture was poured into water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 383.05 (M+H)+
EXAMPLE 19
Preparation of N-(2-hydroxyethyl)-5-methoxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide

Intermediate-1: Preparation of 4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

Step 1: Preparation of 1-hydroxy-3-methylanthracene-9,10-dione

Mixture of aluminium trichloride (13.50 g, 101 mmol) and sodium chloride (4.93 g, 84 mmol) was heated at 1200C to this was added isobenzofuran-1,3-dione (5 g, 33.8 mmol) followed by m-cresol (4.02 g, 37.1 mmol) at 1200C and reaction mixture was stirred for 2 hrs. After complete conversion of starting material, reaction mixture was diluted with cold water and extracted with DCM. Organic layer was separated, washed with water and evaporated under reduced pressure to get crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 239.07 [M+1].

Step 2: 3-methyl-9,10-dioxo-9,10-dihydroanthracen-1-yl acetate

To a stirring solution of product obtained from step 1 (4.5 g, 18.89 mmol) in pyridine (45 ml) was added acetic anhydride (5.78 g, 56.7 mmol) and reaction mixture was refluxed for 2 hrs. After complete conversion of starting material, reaction mixture was quenched by cold water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 281.08 [M+1].

Step 3: 4-acetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of product obtained from step 2 (4.0 g, 14.27 mmol) in mixture of acetic acid (20 ml) and acetic anhydride (14.57 g, 143 mmol) was added chromium trioxide 2 (7.13 g, 71.35 mmol) and refluxed it for 6 hrs. After complete conversion of starting material, reaction mixture was quenched by cold water and the precipitated solid was filtered to get the title product. ESI-MS (m/z): 309.04.07 [M-1].

Step 4: 4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid

To a stirring solution of product obtained from step 3 (100 mg, 0.322 mmol) in water (5 ml) was added sodium carbonate (171 mg, 1.612 mmol) and stirred it for 6 hrs at room temperature. After complete conversion of starting material, reaction mixture was quenched by cold water the precipitated solid was filtered to get the title product. ESI-MS (m/z): 268.66 [M+1].

Preparation of N-(2-hydroxyethyl)-5-methoxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide

To a stirring solution of product obtained from step 4 (200 mg, 0.746 mmol) in ethylene glycol (5 ml) was added 1,3-dioxolan-2-one (65.7 mg, 0.746 mmol) and stirred it for 6 hrs at 1000C. After complete conversion of starting material, reaction mixture was quenched by cold water and the precipitated solid was filtered to get the crude product which was purified by column chromatography to get the title product. ESI-MS (m/z): 311.05 [M-1].

Activity Data
LPS-induced recruitment of peritoneal macrophages
Male Balb/c mice (8-12 weeks old) were treated with test compounds (100 mg/kg, orally, twice a day). After thirty minutes of test compounds administration, lipopolysaccharide (3 mg/kg, intraperitoneal route) was given to all animals. After 48 h of dosing (four doses of test compounds), all mice were anaesthetized with ketamine/xylazine (100/20 mg/kg, IP). The mice were injected 10.0 mL of phosphate buffered saline (PBS) by intraperitoneal route. Immediately after PBS administration, 8 mL of peritoneal fluid was collected. The total cells (macrophages) in the peritoneal fluid were counted in Neubauer chamber and expressed as % of cell decreased against vehicle control. The activity data of selected compounds are shown in Table 1. + = =20 %-= 30% reduction, ++ = =30% reduction.
Table 1:
Example No. % decreased against vehicle control
1 +
2 ++
3 ++
4 ++
5 +
6 +
8 ++
9 ++
10 ++
11 ++
12 ++
13 +
14 ++
15 +
16 +
17 ++
18 ++
19 +

Monosodium iodoacetate (MIA)-induced arthritic pain
Male Sprague Dawley rats (7-8 weeks old) were acclimatized for three days in the incapacitance meter for measuring weight bearing. The rats were given MIA (2 mg/50 µL/rat) by intraarticular route. Next day, rats were randomized based on their weight distribution ratio (% of weight in MIA-injected paw) and treated with test compounds (50 mg/kg, twice a day) for four days. The weight distribution ratio was measured daily for four days. The data expressed as % change in weight distribution ratio against vehicle control. The activity data of selected compounds are shown in Table 2. + = =20 %-= 30%, ++ = =30%.

Table 2:
Example No. % Change in weight distribution against vehicle control
2 +
12 +
14 ++

, Claims:
We claim:

1. Compounds of the general formula (I),

wherein,
R1 and R2 are selected from hydrogen, hydroxy, cyano, halo, nitro, haloalkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR5, -COOR5, -OR5, -OSO2CH3, -OCOR5, -S(O)pR5, -NR5R6, -CONR5R6, -N(R5)COR6, -N(R5)COOR6, -N(R5)CONR5R6, -SO2NR5R6, -N(R5)SO2R6;
R5 and R6 are selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aralkyl, heterocyclylalkyl and haloalkyl; R5 and R6 together with the N atom to which they are attached to form a 5-8 membered cyclic ring;
X is selected from hydroxyl, -NR3R4;
R3 and R4 are selected from hydrogen, an optionally substituted group selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, -OR5 and haloalkyl; R3 and R4 together with the N atom to which they are attached to form a 5-8 membered cyclic ring; wherein substitution on alkyl, cycloalkyl, haloalkyl selected from hydrogen, hydroxy, cyano, halo, nitro, oxo, imino, haloalkyl, optionally substituted groups selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C8)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl and heterocyclylalkyl, alkylsulfonyloxy, -COR5, -COOR5, -OR5, -NR5R6, -CONR5R6, -N(R5)COR6, -N(R5)COOR6, -OCH2COR5, -N(R5)CH2COR6, -N(R5)CONR5R6, -S(O)pR5 derivatives; wherein, R5 and R6 are as defined earlier;
p is 0-2.

2. Compounds of formula (I) as claimed in claim 1 are selected from:
N-(2-hydroxyethyl)-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N, N-bis(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(benzyloxy)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(2-(ethyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-(2-(methyl sulfonyl) ethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-hydroxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-((1-(methyl sulfonyl) cyclopropyl) methyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
1-(9,10-dioxo-9,10-dihydroanthracene-2-carbonyl) piperidine-4-carbonitrile;
9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
2-(4-methyl-1H-pyrazole-1-carbonyl) anthracene-9,10-dione;
1-methoxy-6-(4-methylpiperazine-1-carbonyl) anthracene-9,10-dione;
5-(methylsulfonyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
5-chloro-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
4-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
N-(2-hydroxyethyl)-5-methoxy-N-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide.

3. Pharmaceutical composition comprising compound of general formula (I) as claimed in claim 1, their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.

4. Use of the compounds as claimed in claim 1 for the treatment of cytokine related disorders, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
5. Method of treating osteoarthritis in a subject which comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 or its suitable pharmaceutical composition.

6. A compound having IUPAC name:
N-(2-hydroxyethyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
N-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
2-(morpholine-4-carbonyl) anthracene-9,10-dione;
9,10-dioxo-9,10-dihydroanthracene-2-carboxamide;
5-chloro-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid;
4-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid.

7. Pharmaceutical composition comprising compounds as claimed in claim 6, their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.

8. Use of the compounds as claimed in claim 6 for the treatment of cytokine related disorders, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.

9. Method of treating cytokine related disorder in a subject which comprising administering to a patient in need thereof an effective amount of compounds as claimed in claim 6 or its suitable pharmaceutical composition.

Dated this 9th day of May 2023.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS