WO2003092692A1

WO2003092692A1 - Therapeutic agent comprising lafutidine

Info

Publication number: WO2003092692A1
Application number: PCT/EP2003/004415
Authority: WO
Inventors: Koji Takeuchi; Shinichi Kato
Original assignee: Ucb, S.A.
Priority date: 2002-04-30
Filing date: 2003-04-28
Publication date: 2003-11-13
Also published as: CN1649590A; KR20040104658A; JP2003321366A; AU2003229741A1

Abstract

The present invention provides a safer therapeutic agent for anti-inflammatory bowel disease that has minimal adverse side-effects.The present invention discloses a therapeutic agent for inflammatory bowel disease that contains as its active ingredient lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof.

Description

THERAPEUTIC AGENT COMPRISING LAFUTIDINE

The present invention relates to a therapeutic agent for the treatment of inflammatory bowel disease, ulcerative enteropathogenesis, ulcerative colitis and Crohn's disease.

Inflammatory bowel disease (IBD) is the generic term for a disease of unknown cause that causes chronic inflammation or ulceration of the mucosas of the large and small intestine. This inflammatory bowel disease includes such diseases as ulcerative colitis and Crohn's disease. Among these, ulcerative colitis is a disease that causes a diffuse inflammation of unknown cause in the mucosa of the large intestine, and its main symptoms consist of diarrhea, bloody stool (that frequently also contains mucous) and abdominal pain. There are various theories to be possible causes of ulcerative colitis, which include familial/genetic, immunological, and infection factors. In ulcerative colitis, the extend of inflammed areas vary in degree, the symptomatology is also varying ranging from presenting with fever and other systemic symptoms to only mild symptoms, the colitis type is known to have a high cancer complication rate.

In the past, the treatment of ulcerative colitis has consisted of the use of sulfasalazine, 5-aminosalicylic acid itself referred to as mesalazine, or its derivatives. Among these, since 5-aminosalicylic acid is nearly completely absorbed in the upper digestive tract when directly administered orally, it has a tendency to not reach the effective concentration at the affected site.

However, the pharmacological action of 5-aminosalicylic acid (5ASA) in this disease (ulcerative colitis) is that of anti-inflammatory action, and inhibition of the production of leucotriene B4, radical scavenging, an immunological mechanism have been proposed for its mechanism. Although the drugs containing 5ASA inhibit inflammation, they do not intensively promote healing.

Aside from the above, in the treatment of inflammatory bowel disease, although immunosuppressants and steroids are also used for the purpose of suppressing inflammation, these immunosuppressants and steroids have problems with adverse side effects.

Thus, there is a strong need to develop a drug for inflammatory bowel disease having minimal adverse side effects.

The object of the present invention is to provide a prophylactic or therapeutic agent for inflammatory bowel disease that eliminates the above problems of the prior art.

Another object of the present invention is to provide a safer prophylactic or therapeutic agent for inflammatory bowel disease having minimal adverse side effects.

Still another object of the present invention is to provide a drug capable of acting not only on inflammation localized in the large intestine, but also throughout the entire lower digestive tract. The therapeutic agent for inflammatory bowel disease of the present invention contains as its active ingredient lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof.

In a first embodiment, the invention concerns a therapeutic agent for ulcerative enteropathogenesis and /or inflammatory bowel disease comprising as an active ingredient, lafutidine, its optical isomer or pharmaceutically acceptable salt thereof.

In a second embodiment, the invention concerns the use of lafutidine, its optical isomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating inflammatory bowel disorder, ulcerative enteropathogenesis, ulcerative colitis, and/or Crohn's disease. In another embodiment, the invention concerns a method of treating patients with ulcerative enteropathogenesis and /or inflammatory bowel disease by administering an effective dose of an active compound selected among the group consisting of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable derivative thereof. In another embodiment, the invention concerns a method of treating patients with ulcerative colitis, and/or Crohn's disease by administering an effective dose of an active compound selected among the group consisting of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof. In another embodiment, the invention concerns a pharmaceutical composition for treating an ulcerative enteropathogenesis, inflammatory bowel disease, ulcerative colitis, and/or Crohn's disease comprising a therapeutically effective amount of an active compound selected among the group consisting of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier.

The terms "parts" and "%" used to represent weight ratios in the following description are based on weight unless specifically indicated otherwise.

By inflammatory bowel disease we understand chronic functional (of unknown etiology) bowel disorder characterised by recurrent crampy abdominal pain, bloating and diarrhea, or constipation or alternating diarrhea and constipation with secretion and passage of large amount of mucus (without blood). By ulcerative enteropathogenesis we understand the production of ulcerative disorder or disease of the intestines such as ulcerative colitis and Crohn's disease.

By Ulcerative colitis we understand nonspecific inflammation of the colon and rectum of unknown etiology, characterised by diarrhea with discharge of mucus and blood, cramping abdominal pain and inflammation and oedema of the mucus membrane with patches of ulceration.

By Crohn's Disease we understand chronic inflammatory autoimmune disease of not well-understood etiology (involves both genetic and environmental causes), involving anypart of the gastro-intestinal tract, but commonly the terminal ileum with scarring and thickening of the bowel wall. It frequently leads to intestinal obstruction and fistula and abscess formulation and has a high rate of recurrence after treatment. The inflammation extends deep and cause cramping abdominal pain and diarrhea with rectal bleeding accompanied with loss of appetite and weight.

By treatment, we understand also treatment of the acute attacks and maintenance of remissions. It also includes treatment of patients at risk, before the start of the disease.

The lafutidine used in the present invention, namely (±)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl]acetoamide, is a compound having the structural formula (formula Vindicated below.

Formula 1

This lafutidine is a known compound, and there are no particular restrictions on its production method. Lafutidine can be produced according to, for example, the method disclosed in European patent EP 0 282 077 or in European patent EP 0 582 304. In the present invention, although the (±) form (namely, the racemate) can be used, the content of one optical isomer may be increased and/ or one optical isomer may be isolated by optical resolution or other ordinary methods.

More precisely, it means that the active substance comprises at least 90% by weight, preferably at least 95% by weight, of one individual optical isomer of lafutidine and at most 10% by weight, preferably at most 5% by weight, of the other individual optical isomer of lafutidine. Each individual optical isomer may be obtained by conventional means, i.e., resolution from the corresponding racemic mixture or by asymmetric synthesis. Each individual optical isomer may be obtained from its racemic mixture by using conventional means.

The term "pharmaceutically acceptable salts" as used herein refers not only to addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids.

Lafutidine has conventionally been sold in Japan as a therapeutic pharmaceutical having as its indications digestive ulcers (gastric ulcers, duodenal ulcers) and gastritis.

In the present invention, although lafutidine can be used in the free state, it may also be used in the form of a pharmaceutically acceptable salt thereof as necessary. Although there are no particular restrictions on the methods for forming such salts, a pharmaceutically acceptable salt can be obtained by, for example, treating with a suitable acid in a suitable solvent. Examples of solvents that can be used at this time include water, methanol, ethanol, diethylether, tetrahydrofuran (THF) and dioxane. Examples of acids that can be used during salt formation include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 10-camphorsulfonic acid.

There are no particular restrictions on derivatives of lafutidine that can be used in the present invention provided they are pharmaceutically acceptable derivatives. Specific examples of such derivatives include compounds 6, 7, 8, 9, 11, 12, 14, 16, 19, 20, 21 and 22 among the compounds described in Table 1 of the Chemical & Pharmaceutical Bulletin Vol. 46 (1998), pp. 610-615; compound 15 described in Table 2 of the Chemical & Pharmaceutical Bulletin Vol. 46 (1998), pp. 616-622, and the compounds described in Examples 1, 2, 3, 12 and 21 contained in Table 3 described in European Patent

Publication No. 0282 077 Bl (Pyridyloxy derivatives) (the compound of Example 2 is lafutidine itself). Preferred compound as lafutidine derivatives, is 2-furfurylthio-N-[4-[4- (piperizinomethyl) -2-pyridyloxy] - (Z) -2-butenyl] acetamide.

In the present invention, lafutidine, its optical isomer, its derivative, or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent for inflammatory bowel disease as will be described later.

Lafutidine, its derivatives, or pharmaceutically acceptable salts thereof are known to have protective action against artificially induced gastric lesions (ulceration).

The mechanism of the above protective action of lafutidine has been reported to be mediated by the stimulation of neurons referred to as capsaicin-sensitive neurons among the sensory neurons present in the mucosa of the digestive tract. It is known from pharmacological experiments on lafutidine that said protective action is at least partially mediates through the action of accelerating repair of damaged tissue, and this action differs from the anti-inflammatory action observed in steroids and 5-aminosalicylic acid. Capsaicin-sensitlve neurons are known to be distributed not only in the stomach, but throughout the whole digestive tract.

Lafutidine exhibits suppression of the occurrence of mucosa damage in the small intestine, or promotion of its healing, induced by non-steroid analgesic antiphlogistlcs, and since this action of capsaicin is mediated by capsaicin-sensitive neurons, and capsaicin-sensitlve neurons are also distributed in the large intestine, the inventors of the present invention investigated the effects of lafutidine against colitis induced by inflammation-inducing substances, and confirmed lafutidine acts to suppress inflammation of the large intestine or to promote healing, thereby leading to completion of the present invention.

Crohn's disease is a condition that is mainly observed in young adults which results in the formation of ulcers that begins and extends throughout the digestive tract extending to the anus, and is accompanied by the occurrence of abdominal pain, diarrhea and bloody stools. Environmental factors and dietary habits have a significant effect on its occurrence, with its incidence being higher the greater the intake levels of animal protein and fat and the higher the standard of living. The clinical symptoms of Crohn's disease are extremely varied depending on the patient, and although they also differ according to the affected site of invasion (small intestine type, large intestine type or small/large intestine type), particularly characteristic symptoms of abdominal pain and diarrhea are observed in the majority of patients. Moreover, other frequently observed symptoms include fever, rectal bleeding, abdominal tumors, weight loss caused by absorption disorders, general malaise and anemia. In addition, during the course of Crohn's disease complications may occur locally including fistulation, constriction, abscesses, anal lesions, as well as extra-enteric complications such as arthritis, iritis, erythema nodosum, and, and presents with various symptoms according to the presence or absence of these complications. A therapeutic agent for inflammatory bowel disease containing as its active ingredient lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof of the present invention is also effective against Crohn's disease.

A therapeutic agent for inflammatory bowel disease containing as its active ingredient lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof of the present invention may be used orally or parenterally, and may be used by, for example, inhalation, rectal insertion or local administration. There are no particular restrictions on the drug form of the lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof of the present invention. The lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof of the present invention may be used in the form of, for example, a pharmaceutical composition or preparation (such as powder, granules, tablets, pills, capsules, injection, syrup, emulsion, elixir, suspension or solution). In consideration of distribution to the affected site, one or more drug forms selected from the group consisting of oral preparations, suppositories and transintestlnal preparations are preferable. These compositions or preparations can be obtained by formulating the lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof of the present invention either alone or after mixing with a pharmaceutically acceptable carrier as necessary (such as an adjuvant, vehicle, carrier and/or diluent) in accordance with ordinary methods. In the present invention, parenteral administration includes, for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or intravenous drip.

Injection preparations, such as aqueous suspensions or oily suspensions for sterile injection, can be prepared using a suitable dispersant or moisturizer in accordance with known methods in the relevant field. Preparations for sterile injection may be solutions or suspensions that can be injected aseptically in a pharmaceutically acceptable diluent or solvent capable of being administered parenterally such as an aqueous solution. Examples of usable vehicles and acceptable solvents include water, Ringer's solution and isotonic saline. Moreover, sterile non-volatile oils may also be used as ordinary solvents or suspension solvents. These non-volatile oils include arbitrary non-volatile oils, fatty acids, natural, synthetic or semi-synthetic fatty oils or fatty acids, as well as natural, synthetic or semi-synthetic mono-, di- or triglycerides.

Suppositories for rectal administration can be produced by mixing the drug with a suitable lowly irritating carrier such as cocoa butter or polyethylene glycol that is a solid at room temperature, but is a liquid at the temperature of the intestinal tract and which melts and releases the drug inside the rectum.

Examples of solid admiriistratlon drug forms for oral administration include powders, granules, tablets, pills and capsules. In such solid administration drug forms, the active ingredient compound may be mixed with at least one additive. Examples of additives that may be used at this time include sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi- synthetic polymers and glycerides.

Similar to ordinary drug forms, the above solid administration drug forms may also contain still other additives. Examples of these other additives include inert diluents, magnesium stearate and other lubricants, parabenzenes, sorbic acid and other preservatives, ascorbic acid, α-tocopherol, cysteine and other antioxidants, disintegration agents, binders, thickeners, buffers, sweeteners, flavorings and perfumes. Tablets and pills may also be enteric coated. Examples of liquids for oral administration include pharmaceutically acceptable syrups, emulsions, elixirs, suspensions and solutions. These may also contain inert diluents (such as water) ordinarily used in the relevant field.

The dosage form of the therapeutic agent of the invention is at least one form selected from the group consisting of oral dosage, suppository, and intestinal dosage. The patient dosage of the drug of the present invention may be decided corresponding to the patient's age, body weight, general physical condition, sex, diet, administration time, administration method, excretion rate, drug combinations, and the degree of the disease state for which the patient is being treated at that time, as well as in consideration of those and other factors. Since lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof has low toxicity, it can be used safely.

Although there are cases in which the dally dosage of said compound varies according to the patient's status, body weight, administration route and so forth, in the case of, for example, administration as a therapeutic agent for ulcerative colitis in an adult, the daily dosage for oral administration is about 10-60 mg, and preferably 10-40 mg (and particularly preferably 10-20 mg), while that for intravenous injection is about 0.1-3 mg, and preferably 0.1-1.5 mg (and particularly preferably 0.1-1 mg), preferably administered in a single administration or by dividing among two or three administrations . In addition, in the case of administering as a therapeutic agent for Crohn's disease in an adult, the daily dosage for oral administration is about 10-60 mg, and preferably 10-40 mg (and particularly preferably 10-20 mg), while that for intravenous injection is about 0.1-3 mg, and preferably 0.1-1.5 mg (and particularly preferably 0.1-1 mg), preferably administered in a single administration or by dividing among two or three administrations.

Although the effects of the present invention are clarified by the following test examples, these are merely examples, and the present invention is not limited by these in any way. Example 1

Lafutidine (racemate) was produced according to the method disclosed in European Patent EP 0 282 077.

Moreover, optical isomers were prepared by separation of the racemate to respectively obtain the (+) and (-) forms of lafutidine.

The respective gastric mucosal protective actions were compared using the lafutidine (racemate) and its (+) and (-) forms produced in this manner. Six-week-old, S.D. male rats (160-190 g, Japan Charles River) were used in the experiment after preliminarily housing the animals for 1 week prior to the start of the experiment.

The lafutidine (racemate), (+) -lafutidine and (-) -lafutidine produced as described above were used in the experiment after suspending in 5% aqueous gum arabic solution. 10 mg/kg of each drug was orally administered to the animals (N per group to be specified) after fasting for 18 hours, followed 30 minutes later by oral administration of 1% aqueous ammonia at 5 ml/kg. add information on the control group One hour after administration of aqueous ammonia, the animals were sacrificed by dislocation of the cervical vertebra followed by excision of the stomach. After expanding and immobilizing the excised stomachs by injecting 10 ml of aqueous formalin solution (approx. 2%), an incision was made along the curvatura ventriculi major. The surface area of damage to the gastric mucosa was measured using a stereoscopic microscope, and this value was used as an ulcer coefficient.

During measurement of the surface area of damage to the gastric mucosa, the portion that exhibited damage to the gastric mucosa was distinguished from normal portions depending on the presence or absence of hemorrhagic spots.

All results were expressed as the mean ± standard error, those results were judged to be significant in the case of P < 0.05 using Dunnett's test (reference: Dunnett, C.W. (1955), "A Multiple Comparisons Procedure for Comparing Several Treatments with a Control", Journal of the American Statistical Association, 50, 1096-1121) (SAS Institute,

Tokyo).

As shown in the following Table 1 and Fig. 1, the racemic form, (+) form and (-) form of lafutidine all exhibited equal inhibitory action against damage to gastric mucosa caused by ammonia.

**: Significant difference as compared with control (Dunnett's t-test, P<0.01).

Example 2

Seven-week-old, normally housed male F144 rats (body weights: 160-200 g) were used awake and without fasting unless specifically stated otherwise. In addition, the animals were housed normally under the day before the start of the experiment, were transferred to stainless steel cages on the day before the start of the study, and then used in the experiment starting on the following day in groups of 4-8 animals each.

Dextran sodium sulfate (DSS), lafutidine, cimetidine and capsaicin were used in the experiment.

The above DSS was prepared as a 3% solution with distilled water, filled into suction water dispensers and given to the animals ad libitum during the time the animals were housed.

Lafutidine, cimetidine and capsaicin were suspended in 0.5% sodium carboxymethyl cellulose (CMC), while SOD (superoxide dismutase) and Evan's blue were dissolved in physiological saline to a concentration of 1%. Each drug was prepared immediately prior to use, and administered orally at a volume of 0.5 ml per 100 g of body weight. The respective solvents were administered to the control group in the same volume and by the same administration route.

Colitis was induced by allowing the animals free access to a 3% dextran sodium sulfate solution (DSS, molecular weight: 5,000, sulfur content: 15.0-20.0%) for 7 days, and the animals were also allowed free access to food. In addition, animals of the control group were similarly allowed free access to distilled water.

Lafutidine (3-30 mg/kg) was administered orally at a dose volume of 5 ml/kg for 6 days twice a day from the start of the experiment, add info on cimetidine

CMC and physiological saline were administered at the same volume and by the same administration route to animals of the control group. Denervation of sensory neurons was carried out by subcutaneous administration of a total of 100 mg/kg of capsaicin for three consecutive days in separate doses two weeks before the start of the experiment.

Rats were intravenously injected with 1% Evan's blue solution under ether anesthesia 7 days after the start of treatment with DSS solution, and after sacrificing by systemic perfusion of physiological saline from the heart under ether anesthesia 1 hour later, the large intestine was excised. The large intestine was fixed from both the mucosa side and serous membrane side by injecting 2% formalin solution into the large intestine and additionally immersing the large intestine in the same solution for 10 minutes. After making an incision in the large intestine along the mesenterium, the surface area of damage in the colon and rectum as well as the length from the colon to the rectum were measured using NIH Image 1.61 (free software; downloaded from http://rsb.irnO.nm.gov/nih-image/download.html).

Myeloperoxidase (MPO) activity in the large intestine mucosal membrane was measured according to the procedure below based on a modification of the method of Krawisz et al. (reference: Gastroenterology 1984, Dec: 87(6): 1344-50).

The animals were sacrificed by systemic perfusion of physiological saline from the heart under ether anesthesia 7 days after the start of treatment with 3% DSS and each of the drugs, followed by excision of the large intestine. An incision was made in the excised large intestine along the mesenterium, and after washing with cold physiological saline, about 100 mg of the site of the lesion in the distal colon was sampled.

Extraction buffer (pH 6.0, 0.50 mM phosphoric acid + 0.5% cetyltiirnethylamrαonium bromide (HTAB) was added at the ratio of 1 ml per 50 mg of tissue weight, and after homogenizing with a glass homogenizer (Iuchi), freezing and thawing were repeated three times followed by centrifugal separation for 10 minutes at 2000 rpm while cooling (0-4°C).

0.1 ml of the centrifuged supernatant obtained above and 1.9 ml of phosphate buffer (pH 6.0, 10 mM phosphoric acid) were added to a 3.0-4.0 ml glass cuvette followed by mixing well. After adding 1 ml of hydrogen peroxLde-dianisidine reaction solution

(0.88 mM hydrogen peroxide : 20 mM o-dianisidine = 1:200), the change in absorbance at a wavelength of 450 nm was measured with a spectrophotometer.

The protein content of each specimen was measured using the BCA Protein Assay Kit (Pease). A standard curve was prepared by measuring the change in absorbance during addition of 1 ml various concentrations of hydrogen peroxide-dianisidine reaction solution (0.88 mM hydrogen peroxide:20 mM o-dianisidine = 1: 100, 1:200, 1:400, 1:800 and 1: 1600) to 0.1 ml of 5 μg/ml peroxidase standard, and MPO activity was then calculated using the formula shown below.

Specific activity (μmol H2θ2/min/protein) = (OD/min)/(OD/l μmol H2O2 x mg protein) . All data was expressed as the mean ± standard error of the values obtained from

4-8 animals per group. Statistical significance was tested in compliance with Student's t- test or Dunnett's multiple comparison test, and results were judged to be significant in the case of a level of significance of P<0.05.

Lafutidine dose-dependently reduced the surface area of large intestine damage induced by DSS. Cimetidine did not exhibit reductive action.

Although capsaicin was observed to exhibit damaged surface area reductive action similar to lafutidine, as was previously mentioned, this action disappears at high doses (10 mg/kg).

Although there is indication of action on MPO activity, an indicator of phagocyte invasion, an increase in MPO activity was observed following induction of inflammation by DSS. In contrast, lafutidine at 30 mg/kg and capsaicin at 3 mg/kg, which have damaged area reductive action, caused a decrease in MPO activity, and clearly inhibited inflammation.

The effect on length of the large intestine (colon-rectum) is another indicator of large intestine damage. DSS caused a reduction in large intestine length, lafutidine exhibited a dose-dependent reduction in length, while cimetidine did not exhibit such action. Although the action of lafutidine disappeared following sensory neuron denervation, this indicates that the action of lafutidine is mediated by capsaicin-sensitive sensory neurons. The action of these drugs on large intestine length yielded similar results as their action on damaged surface area.

As has been described above, according to the present invention, a safer therapeutic agent for inflammatory bowel disease is provided that has minimal adverse side-effects.

Claims

1 - A therapeutic agent for ulcerative enteropathogenesis or inflammatory bowel disease comprising as an active ingredient, lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof.

2 - A therapeutic agent according to claim 1, wherein the ulcerative enteropathogenesis comprises at least one disease selected from the group consisting of ulcerative colitis and Crohn's disease.

3 - A therapeutic agent according to claim 1 or 2, wherein the dosage form is at least one form selected from the group consisting of oral dosage, suppository, and intestinal dosage.

4 - Use of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof for the manufacture of a medicament for treating inflammatory bowel disorder.

5 - Use of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof for the manufacture of a medicament for treating ulcerative enteropathogenesis.

6 - Use of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof for the manufacture of a medicament for treating ulcerative colitis.

7 - Use of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof for the manufacture of a medicament for treating Crohn's disease.

8 - Method of treating in a patient ulcerative enteropathogenesis or inflammatory bowel disease by administering an effective dose of an active compound selected among a group consisting of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable derivative thereof. 9 - A pharmaceutical composition for treating an ulcerative enteropathogenesis or inflammatory bowel disease comprising a therapeutically effective amount of an active compound selected from the group consisting of lafutidine, its optical isomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier.