U.S. patent application number 15/243365 was filed with the patent office on 2016-12-08 for pyridone derivatives as acid secretion inhibitors and process for preparation thereof.
The applicant listed for this patent is Emcure Pharmaceuticals Limited. Invention is credited to Ashok Tukaram Chaudhari, Mukund Keshav Gurjar, Vijay Keshav Kalhapure, Tushar Pandurang Khaladkar, Rajendra Dagesing Mahale, Golakchandra Sudarshan Maikap, Samit Satish Mehta, Sanjay Shankar Pawar, Narendra Kumar Tripathy.
Application Number | 20160355529 15/243365 |
Document ID | / |
Family ID | 50776641 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160355529 |
Kind Code |
A1 |
Gurjar; Mukund Keshav ; et
al. |
December 8, 2016 |
PYRIDONE DERIVATIVES AS ACID SECRETION INHIBITORS AND PROCESS FOR
PREPARATION THEREOF
Abstract
The present invention relates to the preparation of stable
pyridone disulphide derivatives having general formula (I) and its
stereoisomers, which are useful in the treatment of
gastrointestinal disorders. Pyridone disulphide derivatives (I)
wherein, R.sub.1, R.sub.2 and R.sub.3 are independently alkyl,
alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen
and could be the same or different and X is CH or N. R.sub.1 is
methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and
hydrogen, R.sub.2 is methyl, methoxy and hydrogen, and R.sub.3 is
methyl and hydrogen.
Inventors: |
Gurjar; Mukund Keshav;
(Bhosari, IN) ; Tripathy; Narendra Kumar;
(Bhosari, IN) ; Maikap; Golakchandra Sudarshan;
(Bhosari, IN) ; Mahale; Rajendra Dagesing;
(Bhosari, IN) ; Khaladkar; Tushar Pandurang;
(Bhosari, IN) ; Chaudhari; Ashok Tukaram;
(Bhosari, IN) ; Pawar; Sanjay Shankar; (Bhosari,
IN) ; Kalhapure; Vijay Keshav; (Bhosari, IN) ;
Mehta; Samit Satish; (Bhosari, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Emcure Pharmaceuticals Limited |
Bhosari |
|
IN |
|
|
Family ID: |
50776641 |
Appl. No.: |
15/243365 |
Filed: |
August 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14703515 |
May 4, 2015 |
9447094 |
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15243365 |
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PCT/IN2013/000699 |
Nov 18, 2013 |
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14703515 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 471/04 20130101; A61P 1/04 20180101; C07D 519/00 20130101;
A61P 43/00 20180101; C07D 401/14 20130101 |
International
Class: |
C07D 519/00 20060101
C07D519/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 26, 2012 |
IN |
3360/MUM/2012 |
Claims
1.-16. (canceled)
17. Pyridone disulfide derivative of formula (I) ##STR00008##
wherein, R.sub.1, R.sub.2 and R.sub.3 are independently alkyl,
alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen
and could be same or different, and X is N.
18. Pyridone disulfide derivative of formula (I) according to claim
17, wherein R.sub.1 is selected from the group consisting of
methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and
hydrogen.
19. Pyridone disulfide derivative of formula (I) according to claim
17, wherein R.sub.2 is selected from the group consisting of
methyl, methoxy and hydrogen.
20. Pyridone disulfide derivative of formula (I) according to claim
17, wherein R.sub.3 is selected from the group consisting of methyl
and hydrogen.
21. The process for preparation of pyridone disulfide derivative of
formula (I) according to claim 17 comprising treating compound (IV)
##STR00009## wherein R.sub.1, R.sub.2 and R.sub.3 are as previously
defined, with a dealkylating agent to give compound of formula (V),
##STR00010## wherein R.sub.1, R.sub.2 and R.sub.3 are as previously
defined, oxidizing the compound of formula (V) with an oxidizing
agent to give compound of formula (VI), ##STR00011## wherein
R.sub.1, R.sub.2 and R.sub.3 are as previously defined, and
treating the compound of formula (VI) with an acid in presence of a
solvent, in the pH range of 4.5 to 8.5, to give the pyridone
disulfide derivative of formula (I).
22. The process according to claim 21, wherein the dealkylating
agent is selected from the group consisting of sodium sulfide,
hydrobromic acid and aluminium chloride.
23. The process according to claim 21, wherein the oxidizing agent
is selected from 10-camphorsulfonyl oxaziridine and sodium
hypochlorite.
24. The process according to claim 21, wherein the pyridone
disulfide derivative of formula (I) is obtained by treating
compound (VI) with an acid selected from the group consisting of an
organic acid selected from the group consisting of acetic acid,
citric acid, propionic acid, lactic acid, and mixtures thereof a
mineral acid selected from the group consisting of hydrochloric
acid, sulfuric acid, nitric acid, and mixtures thereof; and a
solvent selected from the group consisting of esters, alcohols,
ketones, hydrocarbons, halogenated hydrocarbons, water and mixtures
thereof.
25. A method for treatment of peptic ulcers, gastroesophageal
reflux, or heartburns arising out of excessive secretion of acidic
gastric fluids in a subject in need thereof, comprising
administering to the subject a pharmaceutical composition of
pyridone disulfide derivative of formula (I) according to claim
17.
26. Pyridone disulfide derivative of formula (I) according to claim
17 wherein the pyridone disulfide derivative is a compound selected
from the group consisting of:
2-((2-((1,4-dihydro-1-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3,5-dimet-
hyl-4-oxopyridin-2-yl)methyl)disulfinyl)methyl)-1-(5-methoxy-1H-imidazo[4,-
5-b]pyridin-2-yl)-3,5-dimethylpyridin-4(1H)-one (compound I-B-3);
2-((2-((1,4-dihydro-3-methoxy-1-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-
-4-oxopyridin-2-yl)methyl)disulfinyl)methyl)-3-methoxy-1-(5-methoxy-1H-imi-
dazo[4,5-b]pyridin-2-yl)pyridin-4(1H)-one (compound I-B-2);
2-((2-((1,4-dihydro-1-(1H-imidazo[4,5-b]pyridin-2-yl)-3,5-dimethyl-4-oxop-
yridin-2-yl)methyl)disulfinyl)methyl)-1-(1H-imidazo[4,5-b]pyridin-2-yl)-3,-
5-dimethylpyridin-4(1H)-one (compound I-B-1); and pharmaceutically
acceptable salts thereof.
27. A pharmaceutical formulation comprising a pyridone disulfide
derivative of formula (I) according to claim 17 and a
pharmaceutically acceptable carrier.
28. A pharmaceutical formulation comprising a pyridone disulfide
derivative of claim 26 and a pharmaceutically acceptable
carrier.
29. The pharmaceutical formulation of claim 27, wherein the
pharmaceutical formulation is administered in the form of a tablet,
coated tablet, granule, powder or capsule.
30. The pharmaceutical formulation of claim 28, wherein the
pharmaceutical formulation is administered in the form of a tablet,
coated tablet, granule, powder or capsule.
31. The pharmaceutical formulation of claim 27, wherein the
pharmaceutical formulation is administered in the form of a
subcutaneous, intramuscular or intravenous injection.
32. The pharmaceutical formulation of claim 28, wherein the
pharmaceutical formulation is administered in the form of a
subcutaneous, intramuscular or intravenous injection.
Description
[0001] This application is a continuation-in-part of International
Application No. PCT/IN2013/000699, filed Nov. 18, 2013, which in
turn claims priority to Indian Patent Application No.
3360/MUM/2012, filed Nov. 26, 2012.
FIELD OF THE INVENTION
[0002] 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.
##STR00001##
[0003] Wherein, R.sub.1, R.sub.2 and R.sub.3 are alkyl, alkoxy,
halogen, halogenated alkoxy, halogenated alkyl, hydrogen and could
be same or different and X is CH or N.
[0004] R.sub.1 is methyl, methoxy, fluorine, trifluoromethyl,
difluoromethoxy and hydrogen,
[0005] R.sub.2 is methyl, methoxy and hydrogen, R.sub.3 is methyl
and hydrogen.
BACKGROUND OF THE INVENTION
[0006] 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-H.sub.2-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.
[0007] 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 [--CH.sub.2S(O)--] group. The
mode of action involves inhibition of gastric acid secretion in the
lumen of the stomach by blockage of (H.sup.+/K.sup.+)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.
[0008] 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 (P1). 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)
##STR00002##
[0009] 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).
##STR00003##
[0010] 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).
##STR00004##
[0011] It has also been reported that sulfenamides characterized by
structures similar to compound (P1) are difficult to isolate and
are usually isolated as acid addition salts.
[0012] U.S. Pat. No. 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 HPF.sub.6,
HBF.sub.4 or HAuCl.sub.4. 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.
[0013] U.S. Pat. No. 4,769,456, U.S. Pat. No. 5,162,317 also
discloses 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.
[0014] 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.
##STR00005##
wherein, R.sub.1, R.sub.2 and R.sub.3 are independently alkyl,
alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen
and could be the same or different and X is CH or N, R.sub.1 is
methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and
hydrogen, R.sub.2 is methyl, methoxy and hydrogen, R.sub.3 is
methyl and hydrogen.
[0015] 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.
[0016] 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.
[0017] 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
[0018] 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.
[0019] 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
[0020] An aspect of the present invention is to provide stable
pyridone disulfide compounds of formula (I).
##STR00006##
wherein, R.sub.1, R.sub.2 and R.sub.3 are independently alkyl,
alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen
and could either be the same or different and X is CH or N R.sub.1
is methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and
hydrogen, R.sub.2 is methyl, methoxy and hydrogen, R.sub.3 is
methyl and hydrogen.
[0021] 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
[0022] In an embodiment, the present invention provides novel
pyridone disulfide derivatives of formula (I), a 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 stereoisomeric isomers of stable pyridone disulfide
derivatives.
##STR00007##
[0023] 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.
[0024] 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.
[0025] Step 1 involves reaction of substituted benzimidazo-2-thiol
or substituted imidazo-pyridine-2-thiol (compound II) with
substituted-2-chloromethyl-4-methoxy-pyridine derivative (compound
III) in presence of a base and solvent to give substituted
methoxy-2-pyridinyl-methylsulfidyl benzimidazole or the
corresponding imidazo-pyridine derivative (compound IV).
[0026] The base was selected from the group comprising of sodium
hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide
etc. The solvent was selected from the group comprising of water,
methanol, ethanol, isopropanol, butanol etc. and mixtures
thereof.
[0027] The reaction was carried out at 20-40.degree. 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.
[0028] Step 2 involved regioselective dealkylation of substituted
methoxy-2-pyridinyl-methylsulfidyl benzimidazole or
imidazo-pyridine derivative (compound IV) in presence of a
dealkylating agent and a solvent to give compound of formula
(V).
[0029] 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.degree. 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.
[0030] 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-pyridinyl-methylsulfidyl-benzimidazole or
imidazo-pyridine derivative (compound V) having desired purity.
[0031] 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.degree. C., depending upon the type of the dealkylating
reagent used.
[0032] 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).
[0033] Step 3 comprised treatment of substituted
hydroxy-2-pyridinyl-methylsulfidyl-benzimidazole or
imidazo-pyridine derivative (compound V) with an oxidizing agent to
give compound of formula (VI).
[0034] This step involved treatment of compound of formula (V) with
an oxidizing agent such as (10)-camphorsulfonyl oxaziridine (CSO)
and its stereoisomers 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.degree. C. in
presence of a base and organic solvent like isopropanol.
[0035] 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.
[0036] 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.
[0037] 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.degree. 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).
[0038] Alternatively, after completion of oxidation reaction, 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 using acid and
the mass was stirred at 20-35.degree. 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).
[0039] 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).
[0040] The solvent was selected from the 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,
dimethoxyethane, methyl-tertiary butyl ether etc. The solvents were
selected from the group comprising of ethyl acetate, acetone,
methanol, toluene, xylene, dichloromethane etc.
[0041] 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.
[0042] In this step, the acid was slowly added with stirring to the
mixture of compound (VI) and solvent(s) at 20-35.degree. 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 between 6.5 and 8.0. After completion of
the reaction, the desired compound of formula (I) separated out
from the reaction mixture, 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.
[0043] The desired compounds were obtained as stable, crystalline
or amorphous solids and were characterized by .sup.1H NMR, .sup.13C
NMR and MS.
[0044] The different compounds obtained by varying the substituent
in the general formula (I) are provided in Tables 1A and 1B.
TABLE-US-00001 TABLE 1A Pyridone Disulphide Derivatives of formula
(I-A), X = CH Name of the Substituents Compound R.sub.1 R.sub.2
R.sub.3 I-A-1 H H H I-A-2 H CH.sub.3 CH.sub.3 I-A-3 H OCH3 H I-A-4
CH.sub.3 CH.sub.3 CH.sub.3 I-A-5 CH.sub.3 OCH.sub.3 H I-A-6
OCH.sub.3 CH.sub.3 CH.sub.3 I-A-7 OCH3 OCH3 H I-A-8 F CH.sub.3
CH.sub.3 I-A-9 CF.sub.3 OCH.sub.3 H I-A-10 OCHF.sub.2 CH.sub.3
CH.sub.3 I-A-11 OCHF.sub.2 OCH.sub.3 H I-A-12 H or CH.sub.3
CH.sub.3 CH.sub.3 I-A-13 CH.sub.3 or OCHF.sub.2 CH.sub.3 CH.sub.3
I-A-14 H or OCHF.sub.2 CH.sub.3 CH.sub.3
TABLE-US-00002 TABLE 1B Pyridone Disulphide Derivatives of formula
(I-B), X = N Name of the Substituents Compound R.sub.1 R.sub.2
R.sub.3 I-B-1 H CH.sub.3 CH.sub.3 I-B-2 OCH.sub.3 OCH.sub.3 H I-B-3
OCH.sub.3 CH.sub.3 CH.sub.3
[0045] For clinical use, the compounds of the invention were
utilized for pharmaceutical formulations for oral, rectal,
parenteral or other modes 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.
[0046] 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.
[0047] 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.
[0048] Examples of fillers include lactose, corn starch, white
sugar, glucose, sorbitol, crystalline cellulose and silicon
dioxide. Examples of binder include polyvinyl alcohol, polyvinyl
ether, methylcellulose, gum arabic, tragacanth, gelatin, shellac,
hydroxypropyl-cellulose, hydroxypropyl starch and
polyvinylpyrrolidone. Example of disintegrating agent includes
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.
[0049] 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.
[0050] The principles, preferred embodiments and modes of operation
of the present invention have been described in the foregoing
examples. 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.
GENERAL PROCEDURE
[0051] General procedures for preparation of compound IV, compound
V and compound VI are given below.
A. Preparation of Compound IV (Scheme-3)
[0052] The reaction of substituted benzimidazothiol derivatives or
substituted imidazopyridine-thiol derivatives (compound II) with
substituted methoxypyridinium hydrochloride derivatives (compound
III) was carried out at 25-30.degree. C., in presence of aqueous
solution of base such as sodium hydroxide and an organic solvent
like methanol. The reaction was monitored by TLC and after
completion of the reaction, the mixture was filtered, the solid was
separated and dried to give the respective substituted
methoxy-pyridinylmethylsulfidyl imidazole or imidazopyridine
derivatives (compound IV).
B. Preparation of Compound V
B.1--(Using Sodium Sulfide):
[0053] The solution of compound IV in N-methyl pyrrolidone was
treated with sodium sulfide at 80-110.degree. C. The reaction was
continued till completion of the reaction, as monitored by TLC. The
reaction mass was cooled and pH was adjusted in the range of 6 to 7
using aqueous solution of acetic acid. Filtration of the obtained
solid and drying gave compound V having desired purity.
B.2--(Using HBr/Acetic Acid):
[0054] A stirred mixture of compound IV, acetic acid and aqueous
HBr was heated to 100-110.degree. C. till the reaction was
complete, as monitored by TLC. After completion, the reaction mass
was cooled and concentrated under reduced pressure. The residue was
diluted with water and washed with dichloromethane. The aqueous
layer was neutralized by addition of sodium carbonate solution,
which was followed by addition of methanol and filtered. The
residue thus obtained was optionally washed with aqueous methanol
and dried to give compound V.
B.3--(Using AlCl.sub.3):
[0055] A mixture of compound IV, aluminium chloride were stirred in
a solvent like chloroform and heated to 50-70.degree. C. till the
reaction was complete, as monitored by TLC. The reaction mass was
cooled, quenched with water and concentrated. Hydrochloric acid was
added to the residue and the aqueous layer was neutralized using
aqueous sodium carbonate solution. The precipitated solid was
filtered, dried, and optionally purified to give compound V.
C. Preparation of Compound VI
[0056] C.1: Oxidation with Camphorsulfonyl Oxaziridine:
[0057] (10-Camphorsulfonyl) oxaziridine was gradually added to a
solution of compound V and sodium hydroxide in isopropyl alcohol at
25 to 30.degree. C. and stirred at same temperature. After
completion of the reaction, as monitored by TLC, the reaction mass
was filtered, and the filtrate was concentrated under vacuum to
obtain compound VI, which was directly used for further reaction.
In some cases, the residue obtained after concentration was
dissolved in methanol, concentrated and further treated with
toluene and dried to obtain compound VI
C.2: Oxidation with Sodium Hypochlorite:
[0058] Compound V was added to a stirred mixture of aqueous sodium
hydroxide and methanol, followed by gradual addition of sodium
hypochlorite solution at 25-30.degree. C. The reaction mixture was
stirred at the same temperature till completion of the reaction and
then extracted with an organic solvent. The organic layer was
concentrated to give the desired product. Alternatively, the
reaction mass containing compound VI was carried forward for the
next reaction, without isolating the product.
D--Preparation of Compound I
[0059] A solution of compound VI dissolved in water or an organic
solvent or mixtures thereof was treated with acid, which was
gradually added to it at 25-30.degree. C., till the pH of the
reaction mixture was in the range of 4.5 to 8.5, preferably 6.5 to
8. The mass was stirred till completion of the reaction as
monitored by TLC. The suspension thus obtained was filtered and
solid was dried to get compound I, which was optionally purified
using suitable methods.
EXAMPLES
Example 1
Preparation of
1-(5-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-2-((2-((1-(5-(difluorome-
thoxy)-1H-benzo[d]imidazol-2-yl)-1,4-dihydro-3-methoxy-4-oxopyridin-2-yl)m-
ethyl)disulfinyl)methyl)-3-methoxypyridin-4(1H)-one [I-A-11]
Example 1A
Preparation of IV-A-11
[0060] Methanol (270 ml) was added to a solution of NaOH (41.5 gms)
in water (180 ml), followed by addition of
5-difluoromethoxy-2-mercapto-1H-benzimidazole (105.2 gms). A
solution of 2-chloromethyl-3,4-dimethoxy-pyridine.hydrochloride
(100.3 gm in water (150 ml)) was gradually added to the reaction
mixture and stirred at 25-30.degree. 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.
[0061] Yield: 140.6 gm (83%).
[0062] 1H NMR (400 MHz, CDCl3): .delta. 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).
[0063] ESI-MS: 368.9 (M+1).
Example 1B
Preparation of V-A-11
[0064] The solution of compound IV-A-11 (50.7 gms) and sodium
sulfide (38.6 gm, assay 55%) in N-methyl pyrrolidone (700 ml) were
heated to 90 to 100.degree. 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 dried to get compound V-A-11.
[0065] Yield: 29.5 gm (61%).
[0066] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 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+1).
Example 1C
Preparation of
2-(5-difluoromethoxy-1H-benzoimidazole-2-sulfinylmethyl)-3-methoxy-pyridi-
n-4-ol-disodium [VI-A-11]
[0067] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (33.7 gm) was
gradually added to a solution of V-A-11 (50.1 gm), and sodium
hydroxide (12.4 gm) in isopropyl alcohol (350 ml) at 25 to
30.degree. C. The reaction mixture was stirred at 25 to 30.degree.
C. The reaction mass was filtered and the filtrate was concentrated
under vacuum to obtain VI-A-11 (60.1 gm) and carried forward for
next reaction.
Example 1D
Preparation of [I-A-11]
[0068] 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.degree. 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-11.
[0069] Yield: 14.1 gm (11%).
[0070] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 13.35 (br. s,
2H), 7.94 (d, J=7.6 Hz, 2H), 7.59 (br.s, 2H), 7.40 ((s, 6H br.s,
2H), 7.22 (t, J=74 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.33 (d, J=7.6
Hz, 2H), 4.17 (s, 4H), 3.76 (s, 6H).
[0071] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 173.0, 147.9,
146.9, 146.3, 139.4, 137.5, 119.4, 116.8, 116.6, 115.7, 114.2,
59.6, 32.7.
[0072] ESI-MS: 705 (M+1).
Example 2
Preparation of
2-((2-((1-(1H-benzo[d]imidazol-2-yl)-1,4-dihydro-4-oxopyridin-2-yl)methyl-
)disulfinyl)methyl)-1-(1H-benzo[d]imidazol-2-yl)pyridin-4(1H)-one
[I-A-1]
Example 2A
Preparation of
2-(-1H-benzoimidazole-2-sulfinylmethyl)-pyridin-4-ol-disodium
[VI-A-1]
[0073] The experimental procedure that was followed was same as
that described for synthesis of (VI-A-11) wherein compound (V-A-1,
72.8 g), sodium hydroxide (22.4 g), isopropyl alcohol (500 ml) and
(1R)-(-)-(10-camphorsulfonyl) oxaziridine (67.9 g) were used to
obtain compound (VI-A-1) which was used for further reactions.
[0074] Yield: 112.6 g
Example 2B
Preparation of [I-A-1]
[0075] The experimental procedure that was followed was same as
that described for synthesis of (I-A-11) wherein compound (110.4
g), ethyl acetate (1100 ml), water (660 ml) and aqueous acetic acid
(50%) were used to obtain (I-A-1).
[0076] Yield: 13.0 g
[0077] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.25 (br.s, 2H,
D.sub.2O exchangable), 7.98 (d, J=8.0 Hz, 2H), 7.57 (s, 4H),
7.29-7.25 (m, 4H), 6.30 (d, J=2.4 Hz, 2H), 6.21 (dd, J=2.8, 8.0 Hz,
2H), 4.06 (s, 4H).
[0078] .sup.13C NMR (100 MHz, DMSO): .delta. 177.7, 145.7, 145.3,
141.7, 122.9, 120.4, 116.7, 38.3. ESI-MS: 612.9 (M+1).
Example 3
Preparation of
2-((2-((1-(1H-benzo[d]imidazol-2-yl)-1,4-dihydro-3,5-dimethyl-4-oxopyridi-
n-2-yl)methyl)disulfinyl)methyl)-1-(1H-benzo[d]imidazol-2-yl)-3,5-dimethyl-
pyridin-4(1H)-one [I-A-2]
Example 3A
Preparation of
2-(1H-benzoimidazole-2-sulfinylmethyl)-3,5-dimethyl-pyridin-4-ol-disodium
[VI-A-2]
[0079] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (167.5 g) was
gradually added to a mixture of (V-A-2) (200.7 g), and sodium
hydroxide (57.2 g), in isopropyl alcohol (1400 ml) under stirring
at room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-2),
which was used for further reactions.
[0080] Yield: 235.6 g
Example 3B
Preparation of [I-A-2]
[0081] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-A-2), (130.4 g), in ethyl acetate (1300 ml)
and water (780 ml) till the pH of the reaction mass was between 6.5
and 7.5. Reaction mass was stirred at room temperature till
completion of the reaction as monitored by TLC. The reaction mass
was filtered and the obtained solid was dried to give compound
(I-A-2).
[0082] Yield: 21.5 g
[0083] .sup.1H NMR (400 MHz, CD3OD): .delta. 7.84 (s, 2H),
7.58-7.56 (m, 4H), 7.36-7.33 (m, 4H), 3.99 (s, 4H), 2.01 (s, 6H),
2.00 (s, 6H).
[0084] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 177.3, 146.0,
141.6, 137.5, 124.2, 122.9, 122.3, 115.5, 36.7, 13.3, 11.4.
[0085] ESI-MS: 569.1 (M+1).
Example 4
Preparation of
2-((2-((1-(1H-benzo[d]imidazol-2-yl)-1,4-dihydro-3-methoxy-4-oxopyridin-2-
-yl)methyl)disulfinyl)methyl)-1-(1H-benzo[d]imidazol-2-yl)-3-methoxypyridi-
n-4(1H)-one [I-A-3]
Example 4A
Preparation of
2-(1H-benzoimidazole-2-sulfinylmethyl)-3-methoxy-pyridin-4-ol-disodium
[VI-A-3]
[0086] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (83.2 gms) was
gradually added to a mixture of (V-A-3); (100.4 g) and sodium
hydroxide (29.6 gms) in isopropyl alcohol (700 ml) under stirring
at room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-3),
which was used for further reactions.
[0087] Yield: 137.8 g
Example 4B
Preparation of [I-A-3]
[0088] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-A-3); (120.3 g), in ethyl acetate (1200 ml)
and water (720 ml), till the pH of the reaction mass was between
6.5 and 7.5. Reaction mass was stirred at room temperature till
completion of the reaction as monitored by TLC. The reaction mass
was filtered and the obtained solid was dried to give compound
(I-A-3).
[0089] Yield: 26.6 g
[0090] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 13.15 (br.s,
2H, D.sub.2O exchangable), 7.94 (d, J=7.6 Hz, 2H), 7.56 (br.s, 4H),
7.28-7.26 (m, 4H), 6.32 (d, J=7.6 Hz, 2H), 4.17 (s, 4H), 3.75 (s,
6H).
[0091] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 172.9, 147.9,
145.3, 139.5, 137.7, 122.9, 116.5, 59.6, 32.7.
[0092] ESI-MS: 573.1 (M+1).
Example 5
Preparation of
2-((2-((1,4-dihydro-3,5-dimethyl-1-(5-methyl-1H-benzo[d]imidazol-2-yl)-4--
oxopyridin-2-yl)methyl)disulfinyl)methyl)-3,5-dimethyl-1-(5-methyl-1H-benz-
o[d]imidazol-2-yl)pyridin-4(1H)-one [I-A-4]
Example 5A
Preparation of
2-(5-methyl-1H-benzoimidazole-2-sulfinylmethyl)-3,5-dimethyl-pyridin-4-ol-
-disodium [VI-A-4]
[0093] The experimental procedure that was followed was same as
that described for synthesis of (VI-A-3) wherein compound (V-A-4,
(150.6 g), sodium hydroxide (41.9 g) isopropyl alcohol (1050 ml)
and (1R)-(-)-(10-camphorsulfonyl) oxaziridine (119.3 g) were used
to obtain compound (VI-A-4) which was used for further
reactions.
[0094] Yield: 218.3 g.
Example 5B
Preparation of [I-A-4]
[0095] The experimental procedure that was followed was same as
that described for synthesis of (I-A-3) wherein compound (VI-A-4),
(200.3 g), ethyl acetate (2000 ml), water (1200 ml) and aqueous
acetic acid (50%) were used to obtain (I-A-4).
[0096] Yield: 15.8 g
[0097] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.05 (br.s, 2H,
D.sub.2O exchangable), 7.89 (s, 2H), 7.6-7.2 (br.m, 4H), 7.09 (d,
J=7.6 Hz, 2H), 4.10 (s, 4H), 2.42 (s, 6H), 1.90 (s, 6H), 1.88 (s,
6H)
[0098] .sup.13C NMR (100 MHz, DMSO): .delta. 177.2, 145.4, 141.6,
137.4, 133.4, 133.0, 131.4, 124.1, 122.2, 118.8, 111.4, 36.7, 21.3,
13.3, 11.4.
[0099] ESI-MS: 597.0 (M+1).
Example 6
Preparation of
2-((2-((1,4-dihydro-3-methoxy-1-(5-methyl-1H-benzo[d]imidazol-2-yl)-4-oxo-
pyridin-2-yl)methyl)disulfinyl)methyl)-3-methoxy-1-(5-methyl-1H-benzo[d]im-
idazol-2-yl)pyridin-4(1H)-one [I-A-5]
Example 6A
Preparation of
2-(5-methyl-1H-benzoimidazole-2-sulfinylmethyl)-3-methoxy-pyridin-4-ol-di-
sodium [VI-A-5]
[0100] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (87.2 gms) was
gradually added to a mixture of (V-A-5) and sodium hydroxide (30.3
gms), in isopropyl alcohol (770 ml) under stirring at room
temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-5),
which was used for further reactions.
[0101] Yield: 155.4 g
Example 6B
Preparation of [I-A-5]
[0102] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-A-5), (150.8 g), in ethyl acetate (1200 ml)
and water (720 ml), till the pH of the reaction mass was between
6.5 and 7.5. Reaction mass was stirred at room temperature till
completion of the reaction as monitored by TLC. The reaction mass
was filtered and the obtained solid was dried to give compound
(I-A-5).
[0103] Yield: 24.0 g
[0104] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 12.99 (br.s,
2H), 7.92 (d, J=7.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 2H), 7.33 (s, 2H),
7.08 (d, J=8.0 Hz, 2H), 6.32 (d, J=7.6 Hz, 2H), 4.16 (s, 4H), 3.75
(s, 6H), 2.41 (s, 6H).
[0105] .sup.13C NMR (100 MHz, DMSO): .delta. 172.8, 147.8, 144.9,
139.4, 137.7, 132.3, 124.3, 116.5, 59.6, 32.8, 21.2.
[0106] ESI-MS: 600.9 (M+1).
Example 7
Preparation of
2-((2-((1,4-dihydro-1-(5-methoxy-1H-benzo[d]imidazol-2-yl)-3,5-dimethyl-4-
-oxopyridin-2-yl)methyl)disulfinyl)methyl)-1-(5-methoxy-1H-benzo[d]imidazo-
l-2-yl)-3,5-dimethylpyridin-4(1H)-one [I-A-6]
Example 7A
2-(5-Methoxy-1H-benzoimidazole-2-sulfinylmethyl)-3,5-dimethyl-pyridin-4-ol-
-disodium [VI-A-6]
[0107] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (74.4 g) was
gradually added to a mixture of (V-A-6, 100.1 gms) and sodium
hydroxide (25.4 g) in isopropyl alcohol (700 ml) under stirring at
room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-6) as
pale yellow powder.
[0108] Yield: 60.6 g
[0109] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 7.54 (s, 1H),
7.32 (d, J=8.8 Hz, 1H), 6.98 (d, J=2.4 Hz 1H), 6.53 (dd, J=2.4, 8.8
Hz 1H), 4.23-4.12 (ABq, J=12.8 Hz, 2H), 3.71 (s, 3H), 1.96 (s, 3H),
1.84 (s, 3H).
[0110] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 174.1, 161.9,
154.2, 146.9, 145.9, 141.4, 121.8, 121.3, 117.7, 109.7, 99.8, 61.9,
55.7, 15.2, 12.3.
[0111] ESI-MS: 331.8 (M+1).
Example 7B
Preparation of [I-A-6]
[0112] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-A-6; 15.3 gms) in ethyl acetate (150 ml)
and water (90 ml) till the pH of the reaction mass was between 6.5
and 7.5. Reaction mass was stirred at room temperature till
completion of the reaction as monitored by TLC. The reaction mass
was filtered and the obtained solid was dried to give compound
(I-A-6).
[0113] Yield: 4.5 g
[0114] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 13.0 (s, 2H,
D.sub.2O exchangable), 7.88 (s, 2H), 7.47 (br.s, 2H), 7.03 (br.s,
2H), 6.88 (dd, J=2.0, 8.8 Hz, 2H), 4.09 (s, 4H), 3.79 (s, 6H), 1.90
(s, 6H), 1.88 (s, 6H).
[0115] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 177.2, 156.3,
145.2, 141.7, 137.5, 124.0, 122.2, 112.6, 56.5, 36.8, 13.3,
11.4.
[0116] ESI-MS: 627 in negative ion mode.
Example 8
Preparation of
2-((2-((1,4-dihydro-3-methoxy-1-(5-methoxy-1H-benzo[d]imidazol-2-yl)-4-ox-
opyridin-2-yl)methyl)disulfinyl)methyl)-3-methoxy-1-(5-methoxy-1H-benzo[d]-
imidazol-2-yl)pyridin-4(1H)-one [I-A-7]
Example 8A
Preparation of
2-(5-methoxy-1H-benzoimidazole-2-sulfinylmethyl)-3-methoxy-pyridin-4-ol-d-
isodium [VI-A-7]
[0117] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (150.3 g) was
gradually added to a mixture of (V-A-7) (200.2 g), and sodium
hydroxide (52.1 g) in isopropyl alcohol (1400 ml) under stirring at
room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-7),
which was used for further reaction.
[0118] Yield: 282.4 g
Example 8B
Preparation of [I-A-7]
[0119] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-A-7), (280.2 g) in ethyl acetate (2800 ml)
and water (1680 ml) till the pH of the reaction mass was between
6.5 and 7.5. Reaction mass was stirred at room temperature till
completion of the reaction as monitored by TLC. The reaction mass
was filtered and the obtained solid was dried to give compound
(I-A-7).
[0120] Yield: 63.8 g
[0121] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 12.99 (br.s,
2H, D.sub.2O exchangable), 7.91 (d, J=7.6 Hz, 2H), 7.51-6.87 (m,
6H), 6.32 (d, J=7.6 Hz, 2H), 4.13 (s, 4H), 3.79 (s, 6H), 3.76 (s,
6H).
[0122] ESI-MS: 633.0 (M+1).
Example 9
Preparation of
1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-((2-((1-(5-fluoro-1H-benzo[d]imid-
azol-2-yl)-1,4-dihydro-3,5-dimethyl-4-oxopyridin-2-yl)methyl)disulfinyl)me-
thyl)-3,5-dimethylpyridin-4(1H)-one [I-A-8]
Example 9A
Preparation of
2-(5-fluoro-1H-benzoimidazole-2-sulfinylmethyl)-3,5-dimethyl-pyridin-4-ol-
-disodium [VI-A-8]
[0123] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (157.1 gms) was
gradually added to a mixture of (V-A-8), (200.5 g) and sodium
hydroxide (54.3 g) in isopropyl alcohol (1400 ml) under stirring at
room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-8),
which was used for further reaction.
[0124] Yield: 300.1 g
Example 9B
Preparation of [I-A-8]
[0125] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of (VI-A-8) (200.2 g) in ethyl acetate (2000 ml) and water
(1200 ml) till the pH of the reaction mass was between 6.5 and 7.5.
Reaction mass was stirred at room temperature till completion of
the reaction as monitored by TLC. The reaction mass was filtered
and the obtained solid was dried to give compound (I-A-8).
[0126] Yield: 12.2 g
[0127] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 13.36 (br. s,
2H, D.sub.2O exchangable), 7.92 (s, 2H), 7.63-7.51 (br.m, 2H),
7.45-7.33 (br.m, 2H), 7.16-7.12 (m, 2H), 4.10 (s, 4H), 1.90 (s,
6H), 1.88 (s, 6H).
[0128] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 177.2, 160.0,
157.7, 146.9, 141.4, 137.3, 124.1, 122.3, 111.3, 36.7, 13.2,
11.4.
[0129] ESI-MS: 604.9 (M+1).
Example 10
Preparation of
1-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2-((2-((1-(5-(trifluorom-
ethyl)-1H-benzo[d]imidazol-2-yl)-1,4-dihydro-3-methoxy-4-oxopyridin-2-yl)m-
ethyl)disulfinyl methyl)-3-methoxypyridin-4(1H)-one [I-A-9]
Example 10A
Preparation of
2-(5-trifluoromethyl-1H-benzoimidazole-2-sulfinylmethyl)-3-methoxy-pyridi-
n-4-ol-disodium [VI-A-9]
[0130] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (52.5 g) was
gradually added to a mixture of (V-A-9), (77.6 g) and sodium
hydroxide (18.0 g) in isopropyl alcohol (540 ml) under stirring at
room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-9),
which was used for further reaction.
[0131] Yield: 101.1 g
Example 10B
Preparation of [I-A-9]
[0132] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of (VI-A-9), (100.6 g) in ethyl acetate (1000 ml) and water
(600 ml) till the pH of the reaction mass was between 6.5 and 7.5.
Reaction mass was stirred at room temperature till completion of
the reaction as monitored by TLC. The reaction mass was filtered
and the obtained solid was dried to give compound (I-A-9).
[0133] Yield: 10.1 g
[0134] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 7.98 (d, J=7.6
Hz, 7.92 (s, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),
6.35 (d, J=7.6 Hz, 2H), 4.20 (s, 4H), 3.77 (s, 6H).
[0135] .sup.13C NMR (100 MHz, DMSO): .delta. 172.9, 147.9, 147.8,
139.3, 137.4, 124.8 (q, J=270 Hz, CF.sub.3), 123.5 (q, J=31 Hz),
119.5, 116.6, 115.8, 113.6, 59.6, 32.8.
[0136] ESI-MS: 708.8 (M+1).
Example 11
Preparation of
1-(5-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)-2-((2-((1-(5-(difluorome-
thoxy)-1H-benzo[d]imidazol-2-yl)-1,4-dihydro-3,5-dimethyl-4-oxopyridin-2-y-
l)methyl)disulfinyl)methyl)-3,5-dimethylpyridin-4(1H)-one
[I-A-10]
Example 11A
Preparation of
2-(5-difluoromethoxy-1H-benzoimidazole-2-sulfinylmethyl)-3,5-dimethyl-pyr-
idin-4-ol-disodium [VI-A-10]
[0137] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (123.4 gms) was
gradually added to a mixture of (V-A-10), (182.3 gms), and sodium
hydroxide (42.2 gms) in isopropyl alcohol (1270 ml) under stirring
at room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC and
filtered. The filtrate was concentrated under reduced pressure to
provide a residue, which was dissolved in methanol, concentrated
and further treated with toluene and dried to obtain (VI-A-10),
which was used for further reaction.
[0138] Yield: 220.1 g
Example 11B
Preparation of [I-A-10]
[0139] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of (VI-A-10) (220.1 g) in ethyl acetate (2200 ml) and water
(1320 ml) till the pH of the reaction mass was between 6.5 and 7.5.
Reaction mass was stirred at room temperature till completion of
the reaction as monitored by TLC. The reaction mass was filtered
and the obtained solid was dried to give compound (I-A-10).
[0140] Yield: 9.1 g
[0141] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.85 (s, 2H),
7.59 (d, J=8.8 Hz, 2H), 7.37 (s, 2H), 7.17 (d, J=8.8 Hz, 2H), 6.83
(t, J=74.4 Hz, 2H), 4.04 (s, 4H), 2.03 (s, 6H), 2.01 (s, 6H).
[0142] .sup.13C NMR (100 MHz, CD.sub.3OD): .delta. 180.5, 149.5,
147.8, 144.5, 139.2, 138.6, 126.6, 125.2, 120.7, 118.1, 118.0,
115.6, 107.6, 38.4, 13.7, 12.1.
[0143] ESI-MS: 701.0 (M+1).
Example 12
Preparation of
2-((2-((1,4-dihydro-1-(1H-imidazo[4,5-b]pyridin-2-yl)-3,5-dimethyl-4-oxop-
yridin-2-yl)methyl)disulfinyl)methyl)-1-(1H-imidazo[4,5-b]pyridin-2-yl)-3,-
5-dimethylpyridin-4(1H)-one [I-B-1]
Example 12A
Preparation of
2-(1H-imidazo-[6,7-c]pyridine-2-sulfinylmethyl)-3,5-dimethyl-pyridin-4-ol-
-disodium [VI-B-1]
[0144] The experimental procedure followed was same as that
described for synthesis of (VI-A-11) wherein compound (V-B-I;
(120.5 g), sodium hydroxide (34.6 g), isopropyl alcohol (840 ml)
and (1R)-(-)-(10-camphorsulfonyl) oxaziridine (99.8 g) were used to
obtain crude (VI-B-1) which was used for further reactions.
[0145] Yield: 200.3 g
Example 12B
Preparation of [I-B-1]
[0146] The experimental procedure followed was same as that
described for synthesis of (I-A-11) wherein compound (VI-B-1);
(200.6 g), ethyl acetate (2000 ml), water (1200 ml) and aqueous
acetic acid (50%) were used to obtain (I-B-1).
[0147] Yield: 19.7 g
[0148] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.25 (d, J=4.8 Hz,
2H), 8.03 (s, 2H), 7.92 (d, J=7.6 Hz, 2H), 7.14 (dd, J=4.8, 8.0 Hz,
2H), 4.32 (s, 4H), 1.90 (s, 6H), 1.86 (s, 6H)
[0149] .sup.13C NMR (100 MHz, DMSO): .delta. 177.2, 153.2, 152.8,
142.0, 141.3, 137.6, 133.9, 124.2, 123.8, 121.9, 116.7, 37.4, 13.4,
11.5.
[0150] ESI-MS: 570.9 (M+1).
Example 13
Preparation of
2-((2-((1,4-dihydro-3-methoxy-1-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-
-4-oxopyridin-2-yl)methyl)disulfinyl)methyl)-3-methoxy-1-(5-methoxy-1H-imi-
dazo[4,5-b]pyridin-2-yl)pyridin-4(1H)-one [I-B-2]
Example 13A
Preparation of
2-(5-methoxy-1H-imidazo-[6,7-c]pyridine-2-sulfinylmethyl)-3-methoxy-pyrid-
in-4-ol-disodium [VI-B-2]
[0151] The experimental procedure that was followed was same as
that described for synthesis of (VI-B-1), wherein compound (V-B-2)
(77.7 g), sodium hydroxide (19.1 g), isopropyl alcohol (540 ml) and
(1R)-(-)-(10-camphorsulfonyl) oxaziridine (58.7 g) were used to
obtain compound (VI-B-2) which was used for further reactions.
[0152] Yield: 147.2 gms.
Example 13B
Preparation of [I-B-2]
[0153] The experimental procedure that was followed was same as
that described for synthesis of (I-B-1) wherein compound (VI-B-2),
(140.3 g), ethyl acetate (1400 ml), water (840 ml) and aqueous
acetic acid (50%) were used to obtain (I-B-2).
[0154] Yield: 25.6 g
[0155] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 13.58 (br.s, 2H.
D.sub.2O exchangable), 7.93-7.90 (m, 4H), 6.74 (d, J=8.8 Hz, 2H),
6.31 (d, J=8.0 Hz, 2H), 4.16 (s, 4H), 3.88 (s, 6H), 3.77 (s,
6H).
[0156] .sup.13C NMR (100 MHz, DMSO): .delta. 172.8, 161.1, 147.9,
144.3, 139.4, 137.5, 126.2, 116.5, 106.9, 59.6, 53.4, 32.7.
[0157] ESI-MS: 634.9 (M+1).
Example 14
Preparation of
2-((2-((1,4-dihydro-1-(5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3,5-dimet-
hyl-4-oxopyridin-2-yl)methyl)disulfinyl)methyl)-1-(5-methoxy-1H-imidazo[4,-
5-b]pyridin-2-yl)-3,5-dimethylpyridin-4(1H)-one [I-B-3]
Example 14A
Preparation of
2-(5-Methoxy-3H-imidazo[6,7-c]pyridine-2-sulfinylmethyl)-3,5-dimethyl-pyr-
idin-4-ol-disodium [VI-B-3]
[0158] (1R)-(-)-(10-camphorsulfonyl) oxaziridine (88.4 g) was
gradually added to a mixture of (V-B-3; 80.2 gms) and sodium
hydroxide (23.3 gms) in isopropyl alcohol (700 ml) under stirring
at room temperature. The reaction mixture was stirred at the same
temperature till completion of the reaction as monitored by TLC.
When the reaction was complete, the solid was filtered off and the
filtrate was concentrated under reduced pressure to obtain compound
(VI-B-3) as a solid, which was used for further reaction.
[0159] Yield: 180.5 g
Example 14B
Preparation of [I-B-3]
[0160] Aqueous acetic acid (50%) was gradually added to the stirred
mixture of compound (VI-B-3; 180.1 gms), dissolved in a mixture of
ethyl acetate (1050 ml) and water (1500 ml) till the pH of reaction
mass was 7.3. The reaction mass was stirred at room temperature
till completion of the reaction as monitored by TLC. After
completion, the reaction mass was filtered and the obtained solid
was stirred in hydrochloric acid, filtered, washed with water and
dried to give compound (I-B-3).
[0161] Yield: 63.8 g
[0162] .sup.1H NMR (400 MHz, DMSO d.sub.6): .delta. 7.94-7.91 (m,
4H), 6.76 (d, J=8.8 Hz, 2H), 4.12 (s, 4H), 3.89 (s, 6H), 1.91 (s,
6H), 1.88 (s, 6H).
[0163] .sup.13C NMR (100 MHz, DMSO d.sub.6): .delta. 177.4, 161.4,
144.8, 142.0, 137.8, 124.5, 122.6, 107.2, 53.5, 37.0, 13.4,
11.5.
[0164] ESI-MS: 631.1 (M+1).
[0165] Spectral characterization of the aforementioned compounds
was carried out as given below. The magnetic resonance spectra
(.sup.1H NMR and .sup.13C NMR) were recorded on VARIAN 400-MR,
while mass spectra were recorded on Applied Biosystems API2000
LC/MS/MS and SHIMADZU LC/MS 8030.
Example 15
Solid Oral Formulation (Tablets) Containing the Active
Ingredient
[0166] A tablet containing compound (I) was prepared from the
following ingredients:
TABLE-US-00003 Ingredients % w/w 1. Active compound 20 2. Lactose
73 3. Methyl cellulose 0.5 4. Polyvinylpyrrolidone 5.0 5. Magnesium
stearate 1.5
[0167] The active ingredient was mixed with lactose, and granulated
with a water solution of methyl cellulose. The wet mass was forced
through a sieve and the granulate was dried in an oven. After
drying, the granulate was mixed with polyvinylpyrrolidone and
magnesium stearate. The dry mixture was pressed into tablet cores
(10 000 tablets), each tablet containing 20% by weight of the
active substance in a tableting machine using 6 mm diameter
punches.
[0168] Details of evaluation of the activity of the aforementioned
compounds are given below.
In Vitro Pharmacology
[0169] H+K+-ATPase assay Protocol Description:
Purpose
[0170] Evaluation of the effects of compounds on the activity of
the H.sup.+/K.sup.+ ATPase activity was quantified by measuring the
formation of para-nitrophenol (p-NP) from para-nitrophenol
phosphate (p-NPP) using an enzyme isolated from the rabbit or
porcine (pig) fundus.
Experimental Protocol
[0171] The test compound, reference compound or water (control) are
pre-incubated for 30 min at 37.degree. C. with the enzyme (5 .mu.g)
in a buffer containing 40 mM Hepes/Tris (pH 6.0), 20 mM KCl, 5 mM
MgCl.sub.2 and 1 mM ouabain. The enzymatic reaction was then
initiated by the addition of 2 mM p-NPP.
[0172] The absorbance was measured immediately at .lamda.=405 nm
using a microplate reader (EnVision, Perkin Elmer). This
measurement at t=0 was also used to verify any compound
interference with the spectrophotometric detection at the selected
wavelength.
[0173] Thereafter, the mixture was incubated for 15 min at
37.degree. C., after which time the reaction is stopped by addition
of 0.5 M NaOH and a second measurement is made at the same
wavelength (t=15). The enzyme activity is determined by subtracting
the signal measured at t=0 from that measured at t=15. The results
are expressed as a percent inhibition of the control enzyme
activity.
[0174] The standard inhibitory reference compound is
omeprazole,
BIBLIOGRAPHIC REFERENCE
[0175] Dantzig, H., Minor, P. L. Garrigus, J. L., Fukuda, D. S. and
Mynderse, J. S., Studies of the mechanism of action of A80915A, a
semi-naphtolquinone natural product, as an inhibitor of gastric
(H+/K+)-ATPase, Biochem. Pharmacol. (1991), 42: 2019.
General Information
[0176] Assay volume and format: 250 .mu.l in 96-well plate Compound
addition: [100.times.] solution in solvent, then [10.times.]
solution in water Maximum tolerable DMSO concentration: 1%
TABLE-US-00004 TABLE C IC.sub.50 values (rabbit, pig-porcine) of
the compounds embodied in the present invention Serial Name of the
IC.sub.50 (Rabbit) IC.sub.50 (Pig - Porcine) No compound uM uM 1
I-A-1 1.0 1.8 2 I-A-2 1.0 1.3 3 I-A-3 1.1 2.0 4 I-A-4 1.6 2.9 5
I-A-5 1.3 2.3 6 I-A-6 1.3 4.1 7 I-A-7 1.2 4.7 8 I-A-8 1.2 1.3 9
I-A-9 1.1 1.7 10 I-A-10 -- -- 11 I-A-11 1.5 3.3 12 I-A-12 -- -- 13
I-A-13 -- -- 14 I-A-14 -- -- 15 I-B-1 2.8 14.0 16 I-B-2 2.0 8.4 17
I-B-3 -- 45% @ 3-30 uM 18 Omeprazole 4.0* 3.9** *Literature
reference: C. K Scott and E. Sundell, Inhibition of H + K + ATPase
activity by SCH 28080 and SCH 32651, Eur. J Pharmacol, June 7,
(1985); 112(2): 268-70. **Literature reference - D. J. Keeling, C
Fallowfield, K. J. Milliner, S. K. Tingley, R. J. Ife, and A. H.
Underwood, "Studies on the mechanism of action of omeprazole",
Biochem Pharmacol, August 15, (1985); 34(16): 2967-73.
In Vivo Pharmacology
[0177] The anti-ulcer efficacy of various test compounds (I-A-1 to
I-A-11, I-B-1 to I-B-3) was assessed in Indomethacin-induced
gastric ulceration model in female albino Wistar rats (Bhattacharya
S., Banerjee D., Bauri A. K., Chattopadhyay S., Bandyopadhyay S. K.
Healing property of the piper betelphenol, allylpyrocatechol
against indomethacin-induced stomach ulceration and mechanism of
action. World J Gastroenterol., 13(27): 3705-13, 2007; Lee A.
Animal models of gastroduodenal ulcer disease. Bailliere's Best
Pract. Res. Clinic Gastroenterol., 14(1): 75-96, 2000). The test
compounds were administered orally at various doses (0.2, 0.4, 0.8
and 1.6 mg/kg) in comparison to Omeprazole (10 mg/kg) as standard
comparator.
[0178] Experiments were conducted in overnight fasted healthy
female albino Wistar rats maintained at controlled environmental
conditions of temperature and humidity with water given ad libitum.
Non-steroidal anti-inflammatory drug (NSAID), Indomethacin (30
mg/kg, p.o.) was used to induce gastric ulcer (treatment groups)
with a comparative group without indomethacin treatment (negative
group). Indomethacin was administered to treatment groups 1 hour
after oral treatment with Vehicle (1% CMC), various doses of test
compounds (EPPIs) and Omeprazole (10 mg/kg). After 4-6 hours after
indomethacin administration, the animals were sacrificed by
cervical dislocation and their stomach was dissected out. Various
parameters like macroscopic ulcer index, gastric mucus content and
gastric acid pH measurements were undertaken. The rat stomachs were
cut opened along the greater curvature for macroscopic
determination of ulcer index.
[0179] All the tested compounds at higher doses (1.6/0.8 mg/kg)
produced very significant and equivalent anti-ulcerogenic effect in
comparison to Omeprazole (10 mg/kg) in this Indomethacin-induced
ulcer model in rats (Table D).
TABLE-US-00005 TABLE D Anti-ulcer activity (indomethacin-induced
ulcer model in rats) of the compounds embodied in the present
invention Serial Name of the Indomethacin-induced ulcer model (dose
@ which No. compound effect is similar to 10mpk of omeprazole)
mg/kg 1 I-A-1 1.6 2 I-A-2 1.6 3 I-A-3 1.6 4 I-A-4 0.8/1.6 5 I-A-5
1.6 6 I-A-6 -- 7 I-A-7 1.6 8 I-A-8 1.6 9 I-A-9 1.6 10 I-A-10
0.8/1.6 11 I-A-11 1.6 12 I-A-12 -- 13 I-A-13 -- 14 I-A-14 -- 15
I-B-1 1.6 16 I-B-2 1.6 17 I-B-3 1.6 18 Omeprazole 10
* * * * *