FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"PYRIDONE DERIVATIVES AS ACID SECRETION INHIBITORS AND PROCESS FOR PREPARATION THEREOF"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN
WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to stable pyridone disulphide derivatives of general formula (I), their preparation and utilization for the treatment of ailments related to the stomach and intestine.

\J \ //
R1 R1
Pyridone disulphide derivatives (I)

Wherein, R1, R2 and R3 are alkyl, alkoxy, halogen, halogenated alkoxy, halogenated
alkyl, hydrogen and could be same or different and X is CH or N.
Ri is methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and hydrogen,
R2 is methyl, methoxy and hydrogen,
R3 is methyl and hydrogen.
BACKGROUND OF THE INVENTION
Gastrointestinal disorders such as peptic ulcers, gastroesophageal reflux and heartburns arising out of excessive secretion of acidic gastric fluids are amongst the widely encountered diseases in modern age. These diseases, if not controlled, have a tendency to aggravate and ultimately result in gastric cancer. The initial treatment for this indication involved use of histamine-H2-receptor antagonists such as cimetidine as acid secretion inhibitors, which was later followed by introduction of the proton-pump inhibitors (PPIs), collectively known as the prazoles.
The vast majority of the proton-pump inhibitors belonging to prazole group of compounds are benzimidazole derivatives comprising of two heterocyclic moieties, imidazole and pyridine which are linked through a methylene sulfinyl [-CH2S(0)-] group. The mode of action involves inhibition of gastric acid secretion in the lumen of

the stomach by blockage of (H+/K+)ATPase enzyme of the parietal cell, which is responsible for gastric acid production and is located in the secretory membranes of the parietal cells. Incidentally, the prazole group of compounds are by themselves, not active inhibitors of this enzyme but are transformed within the acid compartments of the parietal cells into the active inhibitors.
Portugaliae Electrochimica Acta (2008), 433-448 discloses that in case of omeprazole, the inactive drug is converted to its active form by a probable mechanism which involves protonation and removal of a water molecule to form a sulfenamide intermediate of formula (PI). This intermediate reversibly reacts with the sulfenic acid from which it has been generated and leads to the molecule (P2), which possesses a disulfide linkage between the benzimidazo pyridine fragments. (Scheme-1)

Scheme-1: Mechanism for formation of sulfenamide intermediate and the disulfide
The intermediate (P1), as discussed in Acta Chemica Scandinavica (1989), 43,536-548, also undergoes aryl oxygen cleavage on treatment with hydrochloric acid to provide a pyridone derivative (P3) (Scheme-2).


OMe
N
■? | hydrochloric acid I I


w //
MeO MeO
sulphenamide intermediate (P1) pyridone derivative (P3>
Scheme-2: Reaction of sulfenamide (PI) to pyridone derivative (P3)
The pyridone derivative (P3) gets further converted to compound (P4), similar to the disulfide compound (P2). Herein, it is pertinent to note that the pyridone derivative (P3) is known to be an unstable intermediate in the reactions of prazoles occurring in the acidic environment and readily converts to the disulfoxide derivative (P4).

Disulfoxide derivative - (P4)
It has also been reported that sulfenamides characterized by structures similar to compound (PI) are difficult to isolate and are usually isolated as acid addition salts.
US 4,636,499 discloses methods for the preparation of the sulfenamides which can be employed for providing gastrointestinal cytoprotective effects during the treatment of gastrointestinal inflammatory diseases in mammals. The process comprises treatment of the respective prazole having a sulfoxide functional group with prohibitively expensive acids like HPF6, HBF4 or HAuCl4. Hence, the resulting sulfenamide is in the form of an acid addition salt with the said acids, which unfortunately cannot be administered as such and needs to be converted to its free base followed by optional treatment with pharmaceutically acceptable acids.

US 4,769,456, US 5,162,317 also disclose methods for preparing sulphenamides, which apparently due to difficulty in isolation of the product are isolated as their salts with costly acids like fluoroboric acid, tetrafluoroboric acid or hexafluorophosphoric acid and not suitable for therapeutic use.
The present inventors, while carrying out research for identifying compounds that are themselves active inhibitors of gastric acid secretion in the stomach through serendipity were successful in isolating compounds of formula (I) in a stable form. These compounds were found to exhibit instant therapeutic action against gastrointestinal disorders, without being converted further into any other active form.

Pyridone disulphide derivatives (I)
wherein, Ri, R2 and R3 are independently alkyl, alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen and could be the same or different and X is CH or N, Ri is methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and hydrogen, R2 is methyl, methoxy and hydrogen, R3 is methyl and hydrogen.
After an extensive study of the literature reports relating to the active compounds for gastrointestinal secretion inhibitory activity of prazoles, it was found that compounds of the invention having formula (I) were novel. Earlier, it was not possible to synthesize or isolate these compounds due to their unstable nature. Further, it was also found that the invented compounds having the pyridone moiety and the disulfide linkage were different from similar disulfide compounds (compound P2) disclosed in International Journal of Pharmaceutics (2006), 323, p.110-116.
Another noteworthy finding about compounds of formula (I) was that they were found to be at least six times more potent than the prazole compounds. This would

significantly lower the dosage of the active ingredient and also minimize any untoward side effects that are associated with higher dosage as compared to prior art compounds having similar therapeutic action.
The compounds of the embodied invention were prepared and isolated as stable, crystalline or amorphous solids, depending upon the structure of the compound and the method employed for their isolation.
OBJECT OF THE INVENTION
An object of present invention is to provide stable, crystalline or amorphous pyridone disulfide compounds of formula (I) and its stereoisomers, useful as proton pump inhibitors for exhibiting gastric acid secretion inhibitory activity.
A further object of the invention is to obtain pyridone disulfide derivatives of formula (I) having desired purity and with associated impurities conforming to regulatory limits.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide stable pyridone disulfide compounds of formula (I).

Pyridone disulphide derivatives (I)
wherein, Ri, R2 and R3 are independently alkyl, alkoxy, halogen, halogenated alkoxy,
halogenated alkyl, hydrogen and could either be the same or different and X is CH or N
Ri is methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and hydrogen,
R2 is methyl, methoxy and hydrogen,
R3 is methyl and hydrogen.
Yet another aspect of the present invention is to provide a process for the preparation
and isolation of stable pyridone disulfide derivatives of formula (I) comprising

treatment of compound (IV) with a dealkylating agent to give compound of formula (V) followed by oxidation to give compound of formula (VI) and further treatment with an acid in presence of a solvent in the pH range of 4.5 to 8.5 to provide a compound of formula (I) conforming to regulatory specifications.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides novel pyridone disulfide derivatives of formula (I), process for their preparation and isolation of stable compounds of formula (I) in the pH range of 4.5 to 8.5. The invention also includes the preparation of stereoisomers of stable pyridone disulfide derivatives.



(">


oxidizing agent 20-35 °C
(IV)

^NH

ii) acid 20 - 30 °C

(I)

(VI)

Scheme-3: Method embodied in the present invention for preparation of pyridine disulphide derivatives of formula (I)
The meaning of term 'stable' used herein indicates that the compound of formula (I) is obtained in a stable form, crystalline or amorphous, not easily prone to degradation.

In yet another embodiment, the present invention provides a process for preparation and isolation of novel pyridone disulfide derivatives of formula (I), comprising of the following steps.
Step 1 involves reaction of substituted benzimidazo-2-thioI or substituted imidazo-pyridine-2-thiol (compound II) with substituted-2-chloromethyl-4-methoxy-pyridine derivative (compound HI) in presence of a base and solvent to give substituted methoxy-2-pyridinyl-methylsulfidyl benzimidazole or the corresponding imidazo-pyridine derivative (compound IV).
The base was selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide etc. An aqueous solution of the base was used for the reaction. The solvent was selected from the group comprising of water, methanol, ethanol, isopropanol, butanol etc. and mixtures thereof.
The reaction was carried out at 20-40°C. After completion of the reaction as monitored by TLC, the mixture was filtered to give the respective substituted methoxy-2-pyridinyl-methylsulfidyl benzimidazole derivative or imidazo-pyridine derivative (compound IV) having desired purity.
Step 2 involved regioselective dealkylation of substituted methoxy-2-pyridinyl methyl-sulfidyl benzimidazole or imidazo-pyridine derivative (compound IV) in presence of a dealkylating agent and a solvent to give compound of formula (V).
Various dealkylating agents such as sodium sulfide, hydrobromic acid, aluminium chloride etc. were used. In case of sodium sulfide, the reaction was carried out in the temperature range of 80 to 110°C, in presence of a solvent. The solvent was selected from the group comprising of nitriles, alcohols, polar aprotic solvents such as N-methyl pyrrolidone, dimethyl formamide, dimethyl acetamide water or mixtures thereof.
After completion of the reaction based on TLC, the reaction mass was cooled and neutralized with an acid such as acetic acid. Filtration of the obtained solid and drying gave the respective substituted hydroxy-2-pyridmyl-methylsulfidyl-benzirnidazole or imidazo-pyridine derivative (compound V) having desired purity.

Alternatively, the dealkylation was also carried out by employing aqueous hydrobromic acid or using Lewis acid halides such as aluminium chloride, zinc chloride, optionally in presence of decanethiol. The reaction was carried out at a temperature ranging from 50-110°C, depending upon the type of the dealkylating reagent used.
After completion of the reaction as monitored by TLC, the product was isolated by concentrating the mixture and adding water followed by addition of an organic solvent like methanol to the aqueous layer at around neutral pH to obtain the desired product of formula (V).
Step 3 comprised treatment of substituted hydroxy-2-pyridinyl-methyl-sulfidyl-benzimidazole or imidazo-pyridine derivative (compound V) with an oxidizing agent to give compound of formula (VI)
This step involved treatment of compound of formula (V) with an oxidizing agent such as (10-camphorsulfonyI) oxaziridine (CSO) or an alkali metal hypochlorite to provide the sulfoxide derivative of formula (VI).
The sulfide derivative (V) was treated with the oxidizing agent at 20-35°C in presence of a base and organic solvent like isopropanol.
The base was selected from inorganic or organic bases. The inorganic base was selected from the group comprising of alkali metal hydroxides, carbonate and bicarbonates etc while the organic base was selected from DBU, triethyl amine, diisopropyl ethyl amine etc.
The solvent was selected from the group comprising of alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol etc. or mixtures thereof. After completion of reaction, as monitored by TLC, the reaction mass was filtered and the filtrate concentrated to get the desired compound (VI) which was optionally treated with organic solvents such as methanol, methyl tertiary butyl ether, toluene etc. or used as such for further reaction.
When oxidation was carried out using hypochlorite, compound (V) was added to a mixture of sodium hydroxide, water and methanol, followed by addition of sodium hypochlorite solution and the reaction was carried out at 20-35°C. The reaction was monitored by TLC and after completion, the reaction mass was extracted with an

organic solvent and the organic layer was then concentrated to give the desired compound (VI).
Alternatively, after reaction completion, the mass was carried forward for the next reaction. The pH of the reaction mass was adjusted in range of 4.5 to 8.5 with an acid and the mass was stirred at 20-35°C. Optionally an organic solvent such as methanol or ethyl acetate or solvent mixture was added during stirring and resulting solid was filtered after completion of the reaction as monitored by TLC, to give compound of formula (I).
Step 4 comprised treatment of compound (VI) with an acid in a solvent to obtain pH between 4.5 and 8.5, preferably 6.5 to 8, which was then stirred and filtered to obtain the desired compound (I)
The solvent was selected from a group comprising of water and organic solvents or mixtures thereof. The organic solvent was selected from the group comprising of ethers, esters, alcohols, ketones, hydrocarbons and halogenated hydrocarbons. The ethers were selected from the group comprising of dimethyl ether, diethyl ether, methyl-tertiary butyl ether etc. The solvents were selected from the group comprising of ethyl acetate, acetone, methanol, toluene, xylene, dichloromethane etc..
The acid employed was selected from an organic or mineral acid or a mixture thereof. The mineral acid was selected from the group comprising of hydrochloric acid, sulfuric acid and nitric acid. The organic acid was selected from the group comprising of acetic acid, citric acid, propionic acid, lactic acid etc., but preferably acetic acid.
In this step, the acid was slowly added with stirring to the mixture of compound (VI) and solvent(s) at 20-35°C till the desired pH was obtained. The desired pH range varied for different substrates in the class of compound (VI) and ranged from 4.5 to 8.5 but preferably 6.5 to 8. After completion of the reaction, the desired compound of formula (I) separating out from the reaction mixture was filtered and dried. Optionally, the compound of formula (I) was subjected to purification procedures such as crystallization, solvent treatment, treatment with acid, column chromatography etc. to obtain the desired purity.
The desired compounds were obtained as stable, crystalline or amorphous solids and were characterized by *H NMR, i3C NMR and MS.

The different compounds obtained by varying the substituent in the general formula (I)
are provided in Tables 1A and IB.
Table 1A: Pyridone Disulphide Derivatives of formula (I-A), X=CH

Name of the Compound Substituents

Ri R2 R3
I-A-l H H H
I-A-2 H CH3 CH3
I-A-3 H OCH3 H
I-A-4 CH3 CH3 CH3
I-A-5 CH3 OCH3 H
I-A-6 OCH3 CH3 CH3
I-A-7 OCH3 OCH3 H
I-A-8 F CH3 CH3
TA-9 CF3 OCH3 H
I-A-10 OCHF2 CH3 CH3
I-A-l 1 OCHF2 OCH3 H
I-A-12 HorCH3 CH3 CH3
I-A-13 CH3orOCHF2 CH3 CH3
I-A-14 HorOCHF2 CH3 CH3
Table IB: Pyridone Disulphide Derivatives of formula (I-B), X=N

Name of the Compound Substituents

Ri R2 R3
I-B-l H CH3 CH3
I-B-2 OCH3 OCH3 H
I-B-3 OCH3 CH3 CH3
For clinical use, the compounds of the invention were utilized for pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid,

semisolid or liquid diluent, or a capsule. Usually the amount of active compound is between 0.1 and 95.0 % by weight of the preparation.
When the compound of the present invention is to be administered as a therapeutic or preventive agent for peptic ulcer, it may be orally administered as powder, granule, capsule or syrup. Alternately, it may be parenterally administered in the form of suppositories, injections, external preparations or intravenous drips. The dose may vary depending on the condition, age and ulcer type of the patient. It may be administered in a dose of approximately 0.01 to 200 mg/kg/day, preferably 0.05 to 50 mg/kg/day and still preferably 0.1 to 10 mg/kg/day in one to several portions.
It may be formulated in a conventional manner by using conventional pharmacological carriers. When a solid preparation for oral administration is to be produced, for example, the active component is mixed with filler as well as a binder, a disintegrating agent, a lubricant, a colorant and/or a corrigent, if required. The obtained mixture is then formulated into tablets, coated tablets, granules, powders or capsules in a conventional manner.
Examples of the filler include lactose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose and silicon dioxide. Examples of the binder include polyvinyl alcohol, polyvinyl ether, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl-cellulose, hydroxypropylstarch and polyvinylpyrrolidone. Examples of the disintegrating agent include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. As the colorant, pharmacologically acceptable ones may be employed. Examples of the corrigent include cocoa powder, mentha herb, aromatic powder, mentha oil, borneol and cinnamon powder. Needless to say, these tablets or granules may be coated with, for example, sugar or gelatin.
When an injection is to be produced, the active component is mixed with various additives such as a pH modifier, a buffer, a stabilizer or a solubilizing agent, if required. Thus a subcutaneous, intramuscular or intravenous injection is obtained. The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative, rather than restrictive. Variations

and changes may be made by those skilled in the art, without departing from the spirit
of the invention.
The invention is further explained with the help of following illustrative examples,
however, in no way these examples should be construed as limiting the scope of the
invention.
EXAMPLES:
EXAMPLE 1 Preparation of l-(5-(difluoromethoxy)4H-benzo[d]imidazol-2-yI)-2-
((2-((l-(5-(difluoromethoxy)-lH-benzo[d]imidazol-2-yl)-l,4-dihydro-3-methoxy-4-
oxopyridin-2-yI)methyl)disulfinyl)methyl)-3-methoxypyridiii-4(lH)-one)
(Compound I-A-ll)
l(i) Preparation of IV-A-11: Methanol (270 ml) was added to a solution of NaOH
(41.5gms) in water (180 ml), followed by addition of 5-difluoromethoxy-2-mercapto-
lH-benzimidazole (105.2gms). A solution of 2-chloromethyl-3,4-dimethoxy-
pyridine.hydrochloride (100.3 gm in water (150ml) was gradually added to the reaction
mixture and stirred at 25-30°C till completion of the reaction.. After completion, as
monitored by TLC, the reaction mixture was filtered and the obtained solid was dried to
give compound IV-A-11.
Yield: 140.6 gm (83%).
1H NMR (400 MHz, CDC13): 5 8.27 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 6.87 (d, J = 5.6 Hz, 1H), 6.50 (t, J = 74.8 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), ESI-MS: 368.9 (M+l).
l(ii) Preparation of V-A-ll: The solution of compound IV-A-ll(50.7gms) and
sodium sulfide (38.6 gm, assay 55%) in N-methyl pyrrolidone (700ml) were heated to
90 to 100°C and stirred at the same temperature. After completion of the reaction, as
monitored by TLC, the reaction mass was quenched with water and pH was adjusted to
6.7 using aqueous acetic acid (50%). The obtained suspension was filtered and solid
was dried to get compound V-A-l 1.
Yield: 29.5 gm (61%).
*H NMR (400 MHz, DMSO df>): 5 7.66 (br.s, 1H), 7.48 (br.s, 1H), 7.30 (br.s, 1H), 7.16 (t, J = 74.4 Hz, 1H), 6.98 (dd, J = 2.0, 8.0 Hz, 1H), 6.25 (br.s, 1H), 4.54 (s, 2H), 3.76 (s, 3H), ESI-MS: 353.7 (M+l).
l(iii) Preparation of VI-A-11: QRH-HlQ-camphorsulfonyl) oxaziridine (33.7gm) was gradually added to a solution of V-A-ll (50.1 gm), and sodium hydroxide (12.4 gm) in isopropyl alcohol (350 ml) at 25 to 30°C. The reaction mixture was stirred at 25

to 30°C. The reaction mass was filtered and the filtrate was concentrated under vacuum to obtain VI-A-1 l(60.1gm), and carried forward for next reaction.
l(iv) Preparation of I-A-ll: Aqueous acetic acid (50%) was gradually added to a
solution of VI-A-11 (190.5 gm) in ethyl acetate (1900 ml) and water (1140 ml) at 25 to
30°C till the reaction mass attained pH 7.3. The mass was stirred till completion of the
reaction as monitored by TLC. The suspension thus obtained was filtered and solid was
dried to give compound I-A-ll.
Yield: 14.1 gm (11%).
!H NMR (400 MHz, DMSO da): 5 13.0 (s, 1H, D20 exchangable), 7.88 (s, 1H), 7.47 (br.s, 1H), 7.03 (br.s, 1H), 6.88 (dd, J = 2.0, 8.8 Hz 1H), 4.09 (s, 2H), 3.79 (s, 3H), 1.90 (s, 3H), 1.88 (s, 3H). 13C NMR (100 MHz, DMSO d