ZA200206649B - Orally administrable acid stable anti-ulcer benzimidazole derivatives. - Google Patents

Description

TITLE OF THE INVENTION

Orally admunistrable acid stable antiulcer benzimidazole [ 4 derivatives.

Technical Field

The benzimidazole derivatives are polymeric benzimidazoles of the formula I: 0 [ x K._ x

A : r <c —_ 7 " - Rg y — cH CH -Y ci, TH 3 5

Formula] wherein R; = H or CH;, X = -OCOCH,CO0-, {0 or -

CONHCH,NHCO-, R; = H, CHs, C;Hsor CONH,, Y = OH or NH,,E = -

COO-, B 1s benzimidazole moiety of the formula IIA: 0 <a . R, N 4 | Rs Ny oR,

PO Parte ~x ~

R

=3 dan

Formula IIA wherein each of R;, R2, Rs, Ra, Rs = H, Cy.jz alkyl, Ce.1z (un)substituted aryl,

C,.s alkoxy, Ce.1; aryloxy, C.s alkoxy carbonyl, Cq.;; aryloxy carbonyl, Cs alkoxy alkyl, Cy.;; alkoxyaryl, C,.s haloalkyl, C,.s alkyl or Cs.) ;aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyanc, nitro. carboxylic acid or carbocyclic or O, N, S containing heterocyclic Tig systems or enantiomers thereof.

This invention also relates to pharmaceutically acceptable acid addition salts of the acid stable antiulcer polymeric benzimidazoles, process for the preparation thereof, formulation comprising the same and process foi the preparation of the formulation.

The compounds of the invention on oral administration inhib exogenously or endogenously stimulated gastric acid secretion and thus may be used in the treatment/prevention of peptic ulcers, gastro intestiiial inflammatory diseases like duodenal/gastric ulcer or gastritis or other gastro intestinal disorders. . Background Art

Antiulcer benzimidazoles of the formula II:

Ra

R N 3 OE R,

EES Cea

Re y

Formula Il wherein each of R;. R. Ra Rs, Rss as defined above, are known to be unstable at neutral or acidic pH of the gastric fluid and undergo decomposition in gastriointestinal fluid on oral administration resulting in loss of activity. Therefore, these compounds are not directly orally ingested. Instead, they are formulated for use by enteric coating or by N- subgtitution with non-polymeric substituents followed by entenc coating [US Patents Nos 4045563, 5039806 and 5948773, PCT Publications Nos Wo 95/32957. WO 94/27988 and WO 91/19711, EP Patents Nos 176308 and 0045200 and J. Med. Chem., 34,1049(1991) John Sih et al}.

Enteric coated formulations in the form of tablet compmnse an . initial barrier coating on the active with polymers such as hydroxy propyl methyl cellulose, polyvinyl pyrrolidone or the like, followed by acid resistaii coating with polymers such as cellulose acetate phthalate, hydroxy propyl methyl phthalate, polyvinyl acetate phthalate or copolymer of methacrylic acid and ethyl acrylate. The method of preparing enteric coated tablet involves provision of multiple coatings and numerous unit operations such as ‘ communition, blending, pelletisation, pan coating, drymg, spray coaung and/or fluid bed coating/drying because of which it is cumbersome, time consuming and expensive. Benzimidazole actives being sensitive to light, moisture and organic solvents such as dichloromethane, acetone or isopropyl alcohol, there are chances of decomposition of the actives during pelletisation thereof. The biologically active compound from such enteric coated formulation is directly released in neutral pH in the intestinal fluid bypassing contact with acidic gastric fluid, where a good percentage of the active is decomposed due to its instabihity in neutral pH. Thus the bioavailability of benzimidazole actives from enteric coated formulations thereof 1s low. Anti- ulcer benzimidazoles are not known or reported to have been formulated into other oral dosage forms such as syrup or suspension.

Bioactives other than benzimidazoles covalently conjugated with synthetic polymers directly or through a reactive functional group are known . and reported. For example, progesterone has been conjugated with aliphatic } polyesters such as poly-(e-Caprolactone). poly-[e-(+,-)-Calactonc], polypivalolactone and poly - (+.-) - dilactide through an ester linkage [(Biomed. Mater. Res, Pitt et al. 1979, 13, 491); (Polymer confuses with

Anticancer Activity, Advances in Polymer Science, D Putnam et al, 1995, Vol 122, page 55 - 123, Springer Verlag Berline)]. These polymer-conjugates are administered by subdermal route.

US Patent No 4587046 describes covalent conjugation of naturally occuring catecholamines and autocoid moieties with monodisperse amino acid polymers or peptides having an alkyl group through ester/amide linkages. These conjugates are administered parenterally.

US Patent No 5783178 describes conjugation of actives like vinca alkaloids, mitomycins, bleomycins, fluconazole, amphotericin B, paclitaxel derivatives, cytokines, erythroprotein or polynucleotides with block copolymer of ethyleneoxy monomer or a mixture of ethyleneoxy and the -

OCH(CH;)CH,- monomers through bifunctional linking group. This system is mainly used as targeted drug delivery system.

US Patent No 5510418 describes covalent conjugation of glycosaminoglycan with polyethylene glycol through an ether linkage and 1s useful for hard/soft tissue augmentation. These polymer-conjugates are . to be administered by parenteral route. . Biphenylamine derivatives have been conjugated with polymethacrylic acid. Release of the biphenyl amine derivative from the conjugate was reported only after intraperitoneal injection.

US Patent No 5889078 describes conjugates of biologically active compounds such as cytostatic fluoro uracil with homopolymer of acrylic acids through ester or amide linkages. These polymer conjugates are mainly used as drug delivery system by parenteral route wherein the polymeric backbone after release of the bioactives is difficult to be excreted from the biological system.

US Patent No 5037883 describes conjugate of active such as anticancer daunomycin with copolymer of N-( 2-hydroxypropyl) acrylamde,

N-methacrylamide, N-methacrylic acid and/or N-methacryloylated amino acid through peptide group. These polymer-conjugates are administered by parenteral route.

US Patent No 5976527 describes conjugates of proteins such as albumin, immunoglobulins, blood clotting factors and peptide hormones with polymethylmethacrylate or polymethacrylamide comprising reactive oxuanc groups, which after immobilisation are used for teraction with biological systems. These conjugate systems are mainly used for diagnostic purposes and as sorbents for pollutants. . Benzimidazole compounds substituted with polymer at the nitrogen thereof are not known or reported.

An object of the invention is to provide orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically ) acceptable salts thereof, having imereased bicavailabil, ty -

Another object of the invention isto provide orally admumstrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof. which are not enteric coated.

Another object of the invention is to provide orally admimstrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which have activity comparable to unsubstituted benzimidazoles.

Another object of the invention is to provide orally adminmistrable acid stable anti-ulcer benzimidazole denvatives and pharmaceutically acceptable salts thereof which are capable of being clinically used.

Another object of the invention is to provide a process for the preparation of orally admimstrable acid stable anti-ulcer benzimidazole denvatives and pharmaceutically acceptable salts thereof which results in products having increased bioavailability.

Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzinudazole derivatives and pharmaceutically acceptable salts thereof, which results in products that are not enteric coated and is therefore simple, less tune consuming, less expensive. easy and convenient to carry out.

Another object of the mvention is to provide a process for the preparation of orally admimistrable acid stable anti-ulcer benzimidazcle derivatives and pharmaceutically acceptable salts thereof, which results iin products having activity comparable to the unsubstituted benzamidazoles.

Another object of the invention is to provide a process for the preparation of orally administrable acid stable anti-ulcer benzimidazelc derivatives and pharmaceutically acceptable salts thereof, which results ii products capable of being used clinically.

Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, having increased bioavailability.

Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer polymeric benzimidazoles and : pharmaceutically acceptable salts thereof, which are not enteric coated.

Another object of the invention is to provide a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which have activity comparable to the unsubstituted benzimidazoles.

Another object of the mvention 1s to provide a formulation of orally admimstrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which are capable of being used chnically.

Another object of the invention is to provide a process for the preparation of a formulation of orally admumstrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products having increased bioavailability.

Another object of the mvention is to provide a process for the preparation of a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products that are not enteric coated and is theicfoic simple, less time consuming, less expensive, easy and convenient to carry out. } Another object of the invention is to provide a process for the preparation of a formulation of orally administrable acid stable anti-ulcer benzimidazole denvatives and pharmaceutically acceptable salts thereof,

which results in products having activity comparable to the unsubstituted benzimidazoles.

Another object of the invention is to provide a process for the preparation of a formulation of orally admimstrable acid stable anti-ulcer benzimidazole derivatives and pharmaceutically acceptable salts thereof, which results in products capable of being used clinically.

Disclosure of the Invention

According to the mvention there 1s provided orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I:

X Ry X

ANT

E E

Rp —¢H cH — Rg

Vv — I CH= Y

CH CH a 2

B 8 : Formula wherein Rg = H or CH;, X = -OCOCH,COO-, —o) or -

CONHCH,NHCO-. R, = H, CH;, C;Hs or CONH,, Y = OH or NH, E - -

COO-,B is benzimidazole moiety of the formula IA:

R, % N 5 oT Ri

POE “So S—— cn, ©

N

RZ ne

Formula IIA wherein each of R,, Ry, Rs, Ra. Re = H. Cy; alkyl, Cs. ; (un)substituted aiyi,

C,.z alkoxy, Cs.i; arvioxy, C,.s alkoxy carbonyl, Cs; aryloxy carbonyl, C,.s alkoxy alkyl, Cs.;; alkoxyaryl, C,.s haloalkyl, C,.s alkyl or Cs, Laryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic iiiig, systems or enantiomers thereof: and pharmaceutically acceptable acid addition salts thereof.

According to the invention there is also provided a process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I:

\ \ ~~

X R4 X

AEA

/

E E

R LT i" - Rg

Y — CH CH —Y i" ra 8 B

Formula 1 wherein Rg = Hor CH, X = -OCOCH,C00-, —{O)— or -

CONHCH,NHCO-. R, = H, CH;, C;Hsor CONH,, Y = OH or NH, E= -

COO-.B ic benzimidazole moiety of the formula IIA:

R lo R, =

Re nN 1 oT Ki

PO Wait. p N > N

Formula IIA . wherein each of Ry, R;. Rs. Ri. Rs =H, Cy; alkyl, C.j; (un)substituted aryl, . C,.3 alkoxy, Cs.i; aryloxy, C,.s alkoxy carbonyl, Cs.;; aryloxy carbonyl, Ci. alkoxy alkyl. Cs.;; alkoxvaryl, C,.c haloalkvl. C,.s alkyl or C;.j;aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano,

nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof. and pharmaceutically acceptable acid additioii salts thereof, the process comprising; a) condensing a benzimidazole of the formula 1{:

Ra © R, R,

R 4 EN 4 ®

Ss en, LG

SN

Rs

H

Formula 11 wherein each of R,, R;, Rs, Ry, Rs is as defined above, with a biocompatible partially orally biodegradable synthetic cross linked polymer of the formula x Rs x

R C Re

E E

R, —< H on - R Cc ] } 9 / H 9 +H ~ )

K ~cH "a * Formula III wherein Rg, R» and E each is as defined above and Y'=0 or N, in aqueous medium at 5-80°C and pH 4 - 11 under inert atmosphere and stirming; the weight percentage of the benzimidazole with respect to the conjugate being 1 - b) cooling, isolating and drying the resulting polymenc benzimidazole at 25 - 45°C; and ¢) if desired, converting the polymeric benzimidazole into pharmaceutically acceptable acid addition salts.

According to the invention. there is also provided a formulation of orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I:

NN

X R= x

AA J

E E

R, — cn cH— Rg

Y — cH cH-Y

Ch CHa 8 Formula I B : wherein Ry = Hor CH, X = -OCOCH;C00-, —{0)— or - : CONHCH,NHCO-. R= H, CH3, C;Hs or CONH,, Y = OH or NH, E — -

COO-, B is benzimidazole moiety of the formula IIA:

Ra 2 R

R, AN 1 CE

Ele s

Formula IIA wherein each of R,. R;, Rs, Ry, Rs = H. C,.y; alkyl. Cq.;; (un)substituted aryl,

C,.g alkoxy, Cs.i; arvioxy, C,.s alkoxy carbonyl, Ci.;; aryloxy carbonyl, Cc alkoxy alkyl, C;.;; alkoxyaryl, C,.s haloalkyl, Cs alkyl or Cs.;zaryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyanc, nitro. carboxylic acid or carbocyclic or O. N. S containing heterocyclic iii, svstems or enaniiomers thereof: and pharmaceutically acceptable acid addition salts thereof. in combination with pharmaceutically acceptable excipients.

According to the invention there is also provided a process for the preparation of a formulation of orally administrable acid stable anii- ulcer benzimidazole derivatives of the formula I:

X Ks x

AeA £ £

R c cH cH — Rg \ 7 — i CH —Y

RE 8

B® B

Formula wherein Rg = H or CH;, X = -OCOCH;COO-, —{o)- or -

CONHCH,;NHCO-. Ry = H, CH;, C;Hsor CONH;, Y = OH or NH, E= -

COOQO-.B is benzimidazole moiety of the formula IIA: o R2

R R

OE pa ror

S ——cty N

R N

5

Formula IIA : wherein each of R,, R;, Rs, Rs. Rs =H, C.;; alkyl, Cq.,; (un)substituted aryl,

Ci. alkoxy. Cs.; aryloxy, Cs alkoxy carbonyl, Ci.;; aryloxy carbonyl, C,. alkoxy alkyl, C;.;; alkoxvaryl, C,.s haloalkyl, C,.s alkyl or Cq.j;aryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano,

nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof, and pharmaceutically acceptable acid addition salts thereof, the process comprising mixing the polymeric benzimidazole or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients.

The compounds of the formula II may be racemic oi enantiomeric.

Preferably the compound of the formula II may be 5- methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)sulfinyl}- 1H-benzimidazole i.e. omeprazole, wherein R; = CHa, R; = OCH, R3 =CH3 Ry =OCH;, Rs =

H: or 5-(difluoro methoxy) -2-[[(3.4-dimethoxy-2-pyridinyl)methyl]sulfinylj- 1H-benzimidazole ie pantoprazole, wherein R; =H, R; =OCH; R;= O

CH;, R, = OCHF,, R; =H; or 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl}methyl]sulfinyl}- 1H-benzimidazole ie lansoprazole, wherein Ry =

H.R; =OCH,CF;,R: =CH;, Ry =H, Rs =H.

The polymers may be formed in known manner by polymeisation of monomers such as acrylic acid, substituted acrylic acids, acrylamide, substituted acrylamides, acrylonitrile, substituted acrylonitiiics, esters of acrylic or substituted acrylic acids, styrene, vinyl styrene, vinyl anhydride or derivatives thereof, preferably acrylic acid, methacrylic acid,

acrylamide, methacrylamide. acrylonitrile, ethyl acrylate, methyl acrylate, butyl acrylate. hydroxyethylmethyl acrylate or 2-hexylethylmethacrylate.

Preferably Y' in the polvmer of the formula III 1s oxygen aiom and Y mn the polymeric benzimidazole of the formula 1 is hydroxyl group.

Pharmaceutically acceptable acid addition salts of the conjugate may be hydrochloride. hydrobromide. hydroiodide, sulfate, phosphate, nitrate, perchlorate, formate. acetate. propionate, succinate, glycolate, lactate, tartarate, citrate, ascorbate, piruvate or alginate prepared m a known manner by treating the polymeric benzimidazole with acid such as hydrochloric acid, hydrobromic acid, hydroiodic. sulphuric acid, phosphoric acid, nitric acid, perchloric acid. formic acid. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, pyruvic acd, or alginic acid respectively.

The weight percentage of the benzimidazole of the formula ii may be preferably 20% with respect to the conjugate.

The condensation pH may be preferably 6 - 11. : The temperature for condensation may be preferably 10 - 40°C.

Isolation of the polymenc benzinmdazole may be by filtration, decantation or centrifugation, preferably filtration.

The polymeric benzimidazole may be dried in a tray dryer or vacuum tray drver, preferably tray dryer, preferably at 30 - 50°C.

The excipients may be lactose, magnesium stearate, methyl cellulose. distilled water. microcrystalline cellulose, maltodextrin, glvcenn, flavouring agents or other excipients known in the art.

The polymeric benzimidazoles of the invention are novel and are found to be acid stable due to the polymeric N-substitution. Therefore, they do not disintegrate in the gastrointestinal fluid and are suitable for oral administration without enteric coating. Since they do not disintegrate in thc gastrointestinal fluid, their bioavailability 1s increased as compared to enienc coated benzimidazoles and their activities are comparable to those of unsubstituted benzimidazoles. Because the process for the preparation of the compounds of the invention climinates enteric coating, it is simple, less timc consuming, less expensive. easy and convement to carry ouf. Upon ord administration. under the influence of enzymes/chemicals in the gastrointestinal fluid, the polymeric benzimidazole cleaves at the hydrolysable group (E) to release a N-substituted benzimidazole derivative (ie thc - benzimidazole along with a part of the polymer) having anti-ulcer activity.

The remaining part of the polymer is inert, non-toxic and non-absorbabie in the gastro intestinal fluid and is excreted from the body as such or as nonabsorbable metabolites thereof. Therefore the polymeric benzimidazole conjugates of the invention are safe for clinical use. The polymeiic benzimidazoles of the invention may be formulated into tablets or capsules besides other oral dosage forms such as syrup or suspension.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

EXAMPLE 1

The copolymer (5.0 g) prepared using acrylonitrile, glycidyl acrviate and glycol dimethacrviate was muxed with omeprazole [1.25 gj dissolved in aqueous medium at pH 9.5. The reaction mixture was stirred at 30°C for 18 hours. The product was filtered washed with water (100 ml x 5) and dried under vacuum ai 45°C for 12 hours to obtain 6.1 g of the polymer- substituted omeprazole.

Example 2

The copolymer (5.0 g) prepared using glycidyl methacrylate and acrvlamide was mixed with omeprazole (1.25 g) dissolved in aqueous medium at pH 9.8 The reaction mixture was stirred at 30°C for 18 hours. The product was filtered washed with water (100 ml x 5) and dried under vacuum at 45°C for 12 hours to obtain 5.92 g of the polymer-substituted omeprazole.

Example 3

The copolymer (5.0 g) prepared using glycidyl methacrylate and glycol dimethacrylate was mixed with omeprazole (1.25 g) dissolved in aqueous madium at pH 104. The reaction mixture was stirred at 30°C for i» hours. The product was filtered washed with water (100 ml x 5) and dried under vacuum at 45°C for 12 hours to obtain 6.05 g of the polymer- substituted omeprazole.

Example 4

The procedure of Example 2 was followed using omeprazole (2.5g) and pH 10.2 instead of omeprazole (1.25 g) and pH 9.8 to obtain 6.45 g of the polymer-substituted omeprazole.

Example $

The procedure of Example 3 was followed using omeprazole (25g) instead of omeprazole (1.25 g) to obtain 6.32 g of the polymer- substituted omeprazole.

Example 6

The procedure of Example 2 was followed using lansoprazole (3.0 g) instead of omeprazole (1.25 g) to obtain 58 g of the polymer- substituted lansoprazole.

Example 7

The procedure of Example 2 was followed using pantoprazole (3.0 g) instead of omeprazole (1.25 g) to obtain 5.9 g of the polymer- substituted pantoprazole.

Example 8

Tablets containing the following ingredients

Polymeric benzimidazole of Example 2 ; 1000g

Lactose : 700g

Magnesium stearate : 15g

Methyl cellulose ; 06g

Crosspovidone : 55g

Distilled water : q.s were prepared by mixing to form a wet mass and forcing the wet mass through a sieve, granulating and drying on an oven. ARer drying, the granulate was mixed with crosspovidone and magnesium stearate. The dry mixture was pressed into tablet (1000 tablets) Each tablet contaming 100 mg of active substance using 5 mm diameter punches.

Example 9

Suspension containing the following ingredients were prepared :

Polymeric benzimidazole of Example 2 : 20g

Glycenn : 550¢g

Pharma grade sugar : 3200¢g

Maltodextnn : 05g

Flavourning agent : 05g

Ethanol ; 5.0ml

Distilled water ; 100.0 mi

Example 10

Capsules containing :

Polymeric benzimidazole of Example 2 : 1000 g

Anhydrous lactose : 3000¢g

Microcrystalline cellulose : 200g

Magnesium sterate ; 05¢g were mixed in geometrical order using planatory mixer. The blend was sieved and filled into capsules.

Biological activity

Wistar albino rats of either sex, fed on standard rat chow diet were divided into the groups of 10 amimals each. The distribution of animals in groups, the sequence of trials and the treatment allotted to each group were randomized. Gastric ulceration was produced by pylorus ligation and absolute ethanol administration. In these methods, animals were fasted for 36 hrs before the experiment. Coprohagy was prevented by fasting the animals in cages with grating as the floor. Duodenal ulceration was produced by cysteamine and in this model fasting is not required and hence food and water were made available as libidum till the start of the experiment. The animals were sacrificed using anaesthetic ether after the completion of experiments, the stomachs were removed, opened along the greater curvature, washed with saline and examined with 6.4* (cm diameter) binocular magnifier. Lesions were assessed by two observers unaware of the experimental protocol.

DRUG TREATMENT SCHEDULE

Drugs used were polymeric benzimidazoles of Examples 1 to 7 (1.5 mg to 10 mg/kg, peroral ic p.o) and unsubstituted and unenteric coated omeprazole (manufactured by us, 0.40 mg/kg p.o). They were administered per orally, 30 minutes after the drug treatment the ammals were subjected to any ulcerogenic procedure.

PYLORUS LIGATED RATS

Rats were anaesthetized with anaesthetic ether and the portion of abdomen was opened by a small midline incision below the xiphoid process.

Pylorus portion of the stomach was lifted and ligated. During the process care was taken to avoid the traction of the pylorus or damage to its blood supply. The stomach was isolated from the body and its contents were collected, measured and centrifuged. The supernatant was used immediately for biochemical analysis for total acidity. Immediately after the removal of the contents from the stomach, they were examined for lesions m the stomach portion which was measured and expressed in terms of ulcer index calculated as the total ulcerated area divided by the total mucosal area.

ETHANOL INDUCED GASTRIC MUCOSAL DAMAGE

Rats were given 1.0 ml of 100% ethyl alcohol (p.o) by gavage needle, 30 minutes after the administration of test compound. Two hours after ethanol administration all rats were sacrificed. The area of the glandular portion of the stomach was measured in millimeters. Then the area of, the gastric mucosal damage was calculated in square millimeters and the severity of the gastric mucosal injury was expressed as percentage of the surface area of the glandular stomach.

CYSTEAMINE-HCI INDUCED DUODENAL ULCERS IN RATS

Wistar albino rats of either sex were used. Food and water were available and libidum; throughout the study. Duodenal ulcers were induced by two administrations of cysteamine hydrochloride 400 mg/ kg p.o,

in 10% aqueous solution at an interval of 4 hour. The drugs under study were administered 30 minutes before each dose of cysteamine hydrochloride. All the animals were sacrificed 24 hours after the first dose of cysteamine and duodenum were excised carefully and opened along the antimesenteric side. The mean ulcer area was obtained by measuring the dimensions of the duodenal ulcer(s) in square millimeters.

RESULTS

EFFECT ON ULCER INDEX AND TOTAL ACID OUTPUT

IN PYLORUS LIGATED RATS

Pylorus ligation for 19 hours produced accumulation of gastric secretory volume and increase in the total acid output of the gastric juice as shown in Table I.

TABLE-1

Effect of polymeric benzimidazoles of Examples 1 to 7 and omeprazole on total acid output and intensity of gastric lesions in pylorus ligated rats as calculated by fmean + Standard Error Mean 1e SEM] a

Polymeric mg/kg x days Total acid output Ulcer index benzimidazole of {p.o) mey/1./100 g

Control 0x0 186.41419.05 2.8810.18

Example 1 2x1 60.544.1 1.09+0.51 10x 1 71.3244.5 1.1540.34

Example 2 2x1 65.816.3 1.2840.32 0x1 61.1569 1.171042

Example 3 2x1 71.154+2.5 1.3520.37 10x 1 69.811+2.4 1.3310.39

Example 4 15x1 72.3616.81 1.1840.23 0x1 68.11146.53 1.2410.39

Example 5 1.5x1 55.1415.81 1.2110.51 10x 1 54.061+6.52 1.1540.67

Example 6 15x1 77.1516.3 1.2540.45 2s 16x1 68.5316.9 1.1540.32

Example 7 1.5x1 59.58+7.19 1.4140.32 10x1 52.6515.5 1.3740.51

Omeprazole 04x 1 72.9317.17 0.8310.10

The benzimidazole active content in the compounds of Examples 1to 7 was 20 - 30 %.

Conclusion :- The results of Table 1 showed that polymeric benzimidazoles of Examples 1to 7 (both the doses) produced decrease in ulcer index and total acid output. The activities of the polymenc benzimidazoles of Examples 1to 7 were comparable to those of omeprazole.

EFFECT ON ABSOLUTE ETHANOL INDUCED

GASTRIC MUCOSAL DAMAGE

Oral administration of absolute ethanol produced blackish clongated bands of haemorrhagic lesions in the corpus mucosa along the long axis of the stomach within 2 hours. Polymeric benzimidazoles of Examples 1 to 7 when administered in the doses 1.5 mg to 2mg / kg p.o decreased the area of gastric mucosal lesions when compared to ethanol treated rats in control, as shown in Table 2.

TABLE -2 : Effect of polymeric benzimidazoles of Examples 1-7 on gastric mucosal injury induced by absolute ethanol in 7 rats polvmeric (mg/kg x days) Area of gastric lesions (mm?) % of control benzimizole of (p.0) (% of the glandular stomach) of untreated rats

SE —

Control 0x0 34.6214 1.44 100

Example 1 (2x1) 3.8540.19 11.12

Example 2 (2x1) 4.51 10.22 12.99

Example 3 (2x1) 3.51 + 0.81 10.14

Example 4 {(1.5x1) 1.551 0.6 448

Example 5 {(1.5x1) 1.73 £0.32 4.99

Example 6 (1.5x1) 1.95 +048 S.63

Example 7 (1.5x1) 1.79+ 0.32 5.17

The benzimidazole active content in the compounds of

Examples 1 to 7 was 20 - 30 %.

The results of Table 2 were significantly different from those of control conditions as indicated by P<0.05.

EFFECT ON CYSTEAMINE INDUCED DUODENAL

ULCER MODEL

Administration of cysteamine caused some mortality in rats within 24 hour. The rats when died had perforated ulcers. Polymeric benzimidazoles of Examples 1-7 (1.5 mg and 2 mg/kg) decreased significantly the mean ulcer area when compared to those in rals in control. However mortality was reduced in the animals treated with polymeric benzimidazole of

Examples 1 to 7 as shown in Table 3.

TABLE - 3

Effect of polymeric benzimidazoles of Examples 1-7 on cysteamine induced duodenal ulcer 7 rats models : (mean + SEM)

Polymeric benzimidazole of (mg/kg x days) Mean Ulcer Area

P-9) (mm%)

J ——

Control (0x0) 13.94 £1.27

Example 1 (2x1) 6.55103

Example 2 (2x1) 7.13 £9043

Example 3 (2x1) 6.85 + 0.51

Example 4 {1.5x1) 6.34 +£0.62

Example 5 {(1.5x1) 6.13 20.35

Example 6 (1.5x1) 6.83 10.33

Example 7 (15x 1) 6.53 10.47

The benzimidazole active content in the compounds of

Examples 1 to 7 was 20 - 30 %.

The results of Table 3 were significantly different from those of control conditions as indicated by P<:0.05.

EXPRESSIONS OF RESULTS AND STATISTICS

The results were analyzed statistically using the unpaired students T test. The value of P less then 5% (P<0.05) was considered to be statistically significant.

IN-VITRO STUDIES

In-vitro digestion of polymeric benzimidazole of Examples 1 -

S using simulated gastric and intestinal fluids for 2 and 7 hrs respectively at 37°C, did not show the release of Omeprazole (tested by HPLC procedure given for omeprazole in USP - 23). Similarly, polymenc benzimidazole of

Examples 6 and 7 after digestion, did not show release of lansoprazole and pantoprazole (USP-23) respectively. Therefore it should be assumed that the drugs released were denvatives (modified forms) of omepraole, lansoprazole and pantoprazole respectively.

In-vivo screening of the polymeric benzimidazole of

Example 1-7 in rats by pylorus ligation, ethanol induced cytoprotective property and antiduodenal ulcer property reveals significant proton pump inhibiting property at 1.5 - 2 mg/kg body weight dose. } CONCLUSIONS

Polymeric benzimidazoles of Examples 1- 7 show significant antiulcer activity in rats in all the three experimental models, viz. pylorus ligated rats, ethanol induced gastric mucosal injury and cysteamine induced duodenal ulcer.

Activities were comparable with that of omeprazole in pvlorus ligated rats model.

Claims (5)

1. CLAIMS 1) Orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I: AeA : E R, — cH i —

   i. IA oH Rg Y — CH ot -Y J 5 B Formula I wherein Rg= Hor CHy, X = -OCOCH;COO-, —(o)- or - CONHCH,NHCO-. R, = H. CH;, C;Hsor CONH;, Y = OH or NH, E = - COO-, B is benzimidazole moiety of the formula IIA: 6) i Ry R i Nod Lor PO Gratien N Rg Formula ITA wherein each of R.. Rz, Rs, Re, Rs = H, C,.;; alkyl, Ce.i2 (un)substituted aryl,

   C,.3 alkoxy, Ce.i2 aryloxy, Cys alkoxy carbonyl, Ce.iz aryloxy carbonyl, C,.s alkoxy alkyl, Cs.,, alkoxyaryl, C,.s haloalkyl, C,.s alkyl or Cq.jqaryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring systems or enantiomers thereof, and pharmaceutically acceptable acid addition salts thereof.
2. 2) Polymeric benamidazoles as claimed in clam 1, wheremn the benzimidazole moiety is omeprazole.
3. 3) Polymeric benzimidazoles as claimed in claim 1, wherein the benzimidazole moiety is lansoprazole.
4. 4) Polymeric benzimidazoles as claimed in claim 1, wherein the benzimidazole moiety is pantoprazole.
5. 5) A process for the preparation of orally administrable acid stable anti-ulcer benzimidazole derivatives of the formula I:

   X R3 X E k ] R, — cw ™ — Re y —_— TH = ¥ T Hy T 2 B B Formula I wherein R; = H or CH;, X = -OCOCH,COO-, —(o)- or - CONHCH,NHCO-, R, = H, CH;, C;H; or CONH,;, Y = OH orNH, E= - COO-, B is benzimidazole moiety of the formula IIA: S Ra Se C5 = S — CH N BOW > Re Formula ITA wherem each of R;, R;, R;, Rs, Rs = H.

   Ci.iz alkyl, Ce.12 (un)substituted aryl, Cs alkoxy, Cs..; aryloxy, C,.s alkoxy carbonyl, Cs.;; aryloxy carbonyl, Cis : alkoxy alkyl, Cs.12 alkoxyaryl, Cys haloalkyl, C,.s alkyl or Cs. zaryl thioethers, (un) substituted amines or diamines, (un) substituted amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing heterocyclic ring system or enantiomers thereof, and pharmaceutically acceptable acid addition salts thereof, the process comprising; a) condensing a benzimidazole of the formula II: 0 0 Ry R IN 1 oT Ry 4 @ BS Ot = Ea R - H Formula II wherein each of R,, R;, Rs, Ry, Rs is as defined above, with a biocompatible partially orally biodegradable synthetic cross linked polymer of the formula X En LE E E R, —— cH cn — Rg : i} y' pd | | Ha y ’ ~~ cH, CH i Formula III wherein Rs, R, and E each is as defined above and Y?=0 orN, in aqueous medium at 5 - 80°C and pH 4 - 11 under inert atmosphere and stirring; the