CN1649590A - Therapeutic agent comprising lafutidine - Google Patents

Abstract

The present invention provides safer therapeutic agents against inflammatory bowel disease with minimal adverse side effects. The invention discloses a therapeutic agent for inflammatory bowel disease, which contains lafutidine, its optical isomer, lafutidine derivative or pharmaceutically acceptable salt thereof as its active component.

Description

Therapeutics comprising lafutidine

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

Inflammatory bowel disease (IBD) is a general term for diseases of unknown cause that cause chronic inflammation or ulceration of the mucosa of the large and small intestines. The inflammatory bowel disease includes diseases such as ulcerative colitis and Crohn's disease.

Among these diseases, ulcerative colitis is a disease of unknown cause that causes diffuse inflammation in the mucosa of the large intestine, and its main symptoms include diarrhea, bloody stool (which often also contains mucus), and abdominal pain. Various theories exist regarding the possible cause of ulcerative colitis, including familial/genetic, immune and infectious factors. In ulcerative colitis, where the extent of spread of the inflamed area varies, and the symptomology also ranges from the presence of fever and other systemic symptoms to only mild symptoms, colitis is known to have a high rate of cancer complications.

In the past, management of ulcerative colitis has included the use of sulfasalazine, 5-aminosalicylic acid (which itself is known as mesalazine), or derivatives thereof.

Of these drugs, 5-aminosalicylic acid tends not to reach effective concentrations at the site of infection when it is taken orally directly, since it is almost completely absorbed in the upper gastrointestinal tract.

However, the pharmacological effects of 5-aminosalicylic acid (5ASA) in this disease (ulcerative colitis) are anti-inflammatory, as well as inhibition of production of leukotriene B4, free radical scavenging, and mechanisms have been proposed for it immune mechanism. Although 5ASA-containing drugs suppress inflammation, they do not strongly promote healing.

In addition to the above, in the treatment of inflammatory bowel disease, although immunosuppressants and steroids are also used to suppress inflammation, these immunosuppressants and steroids have problems in terms of adverse side effects.

Therefore, there is a strong need to develop drugs for inflammatory bowel disease with minimal adverse side effects.

An object of the present invention is to provide a preventive or therapeutic agent for inflammatory bowel disease which eliminates the above-mentioned problems of the prior art.

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

Another object of the present invention is to provide a drug that can not only act on the inflammation limited in the large intestine, but also act on the entire lower digestive tract.

The therapeutic agent for inflammatory bowel disease of the present invention contains lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof as its active ingredient.

In a first embodiment, the present invention relates to a therapeutic agent for ulcerative bowel disease and/or inflammatory bowel disease, which comprises lafutidine, its optical isomer or Its pharmaceutically acceptable salts.

In a second embodiment, the present invention relates to the use of lafutidine, its optical isomers, or pharmaceutically acceptable salts thereof in the manufacture of inflammatory bowel disease, ulcerative bowel disease, ulcerative colitis And/or the application in the medicament of Crohn's disease.

In another embodiment, the present invention relates to a method of treating a patient suffering from ulcerative bowel disease and/or inflammatory bowel disease by administering an effective dose of an active compound selected from the group consisting of: Lafur Tidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivative.

In another embodiment, the present invention relates to a method of treating a patient suffering from ulcerative colitis and/or Crohn's disease by administering an effective dose of an active compound selected from the group consisting of lafuratide D, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivative.

In another embodiment, the present invention relates to a pharmaceutical composition for treating ulcerative bowel disease, inflammatory bowel disease, ulcerative colitis and/or Crohn's disease, comprising a therapeutically effective amount of selected An active compound consisting of lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier.

The terms "part" and "%" used to represent weight ratios in the following description are based on weight, otherwise stated otherwise.

We understand inflammatory bowel disease as a chronic functional (of unknown etiology) bowel disorder characterized by recurrent cramping abdominal pain, bloating and diarrhea, or constipation or accompanied by the secretion and discharge of profuse mucus (without blood) Alternating diarrhea and constipation.

We understand ulcerative enteropathy to be the development of ulcerative disorders or diseases of the bowel, such as ulcerative colitis and Crohn's disease.

We understand ulcerative colitis as nonspecific inflammation of the colon and rectum of unknown etiology, characterized by diarrhea with discharge of mucus and blood, cramping abdominal pain and inflammation and edema of the mucosa with ulcerated plaques.

We understand Crohn's disease as a chronic inflammatory autoimmune disease of poorly understood etiology (both genetic and thick. It often results in intestinal obstruction and the formation of fistulas and abscesses, and has a high recurrence rate after treatment. The inflammation spreads deep and causes cramping abdominal pain and diarrhea with rectal bleeding, accompanied by loss of appetite and weight.

We also understand management to mean management of acute attacks and maintenance of remission. It also includes the management of at-risk patients prior to disease onset.

Lafutidine used in the present invention, namely (±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl)oxy- (Z)-2-butenyl]acetamide is a compound having the following structural formula (Formula 1).

Formula 1

The lafutidine is a known compound, and its production method is not particularly limited. Lafutidine can be produced for example according to the methods disclosed in European patent EP 0 282 077 or European patent EP 0 582 304.

In the present invention, although the (±) form (i.e., racemate) can be used, the content of one optical isomer can be increased and/or one optical isomer can be separated by optical resolution or other conventional methods. Construct.

More specifically, it means that the active substance comprises at least 90 wt%, preferably at least 95 wt% of one optical isomer of lafutidine and at most 10 wt%, preferably at most 5 wt% of the other lafutidine optical isomers. Each optical isomer can be obtained by a conventional method, ie, resolved from the corresponding racemic mixture or obtained by asymmetric synthesis. Each optical isomer can be obtained from its racemic mixture by a conventional method.

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

Lafutidine has been generally sold as a therapeutic drug in Japan, having peptic ulcer (gastric ulcer, duodenal ulcer) and gastritis as its indications.

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

There is no particular limitation on the lafutidine derivatives that can be used in the present invention as long as 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; the Chemical & Pharmaceutical Bulletin Vol.46 (1998), the compound 15 described in Table 2 of pp.616～622, and the compound 15 described in Table 3 described in European Patent Publication No.0282 077 B1 containing the compounds described in Examples 1, 2, 3, 12 and 21 (pyridyloxy derivatives) (the compound of Example 2 is lafutidine itself). A preferred compound as a lafutidine derivative is 2-furfurylthio-N-[4-[4-(piperidinomethyl)-2-pyridyloxy]-(Z)-2- Butenyl]acetamide.

In the present invention, lafutidine, its optical isomers, its derivatives or pharmaceutically acceptable salts thereof are suitable as a therapeutic agent for inflammatory bowel disease, as will be described below.

Lafutidine, its derivatives or pharmaceutically acceptable salts thereof are known to have a protective effect against artificially induced gastric damage (ulcer formation).

It has been reported that the mechanism of the above-mentioned protective effect of lafutidine is mediated by neuronal stimulation called capsaicin-sensitive neurons among the sensory neurons present in the mucosa of the digestive tract. From the pharmacological tests carried out on lafutidine, it is known that the protective effect is at least partly mediated by the effect of accelerating the repair of damaged tissue, and this effect is different from that in steroids and 5-aminosalicylic acid Anti-inflammatory effects observed.

Capsaicin-sensitive neurons are known to be distributed not only in the stomach but throughout the digestive tract.

Lafutidine has been shown to inhibit mucosal damage occurring in the small intestine or to promote its healing induced by non-steroidal analgesic anti-inflammatory drugs, and since this effect of capsaicin is mediated by capsaicin-sensitive neurons, And capsaicin-sensitive neurons are also distributed in the large intestine, the inventors of the present invention have studied the effect of lafutidine against the colitis induced by substances that cause inflammation, thereby confirming that lafutidine acts to suppress the inflammation of the large intestine Or promote healing, thus leading to the completion of the present invention.

Crohn's disease is a condition observed mainly in young adults that causes ulceration that begins in the digestive tract and spreads from the digestive tract to the anus, accompanied by abdominal pain, diarrhea, and bloody stools. Environmental factors and eating habits have a significant impact on its occurrence, the greater the intake of animal protein and fat and the higher the standard of living, the higher its incidence.

The clinical symptoms of Crohn's disease vary drastically depending on the patient, and, although they also differ according to the site of lesion involved (small bowel type, large bowel type, or small/large bowel type), abdominal pain and diarrhea are observed in most patients special characteristic symptoms. In addition, other commonly observed symptoms include fever, rectal bleeding, abdominal tumors, weight loss due to malabsorption, general malaise, and anemia. In addition, during the course of Crohn's disease, complications may arise locally, including fistulas, strictures, abscesses, anal lesions, and extraintestinal complications, such as arthritis, iritis, erythema nodosum, and according to The presence or absence of these complications and the performance of various symptoms.

The therapeutic agent for inflammatory bowel disease of the present invention comprising lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof as its active ingredient is also effective Anti Crohn's disease.

The therapeutic agent for inflammatory bowel disease of the present invention comprising lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof as its active ingredient can be orally or parenteral application, and can be used, for example, by inhalation, rectal insertion or topical administration. There is no particular limitation on the pharmaceutical form of lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof of the present invention. Lafutidine of the present invention, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof can be in the form of, for example, pharmaceutical compositions or preparations (such as powders, granules, tablets, pills, etc.) , capsules, injections, syrups, emulsions, elixirs, suspensions or solutions) applications. One or more pharmaceutical forms selected from oral formulations, suppositories, and enteral formulations are preferable in view of distribution to the lesion site.

These compositions or preparations can be formulated separately by lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof according to conventional methods or mixed with pharmaceutically acceptable The carrier (such as adjuvant, medium, carrier and/or diluent) is mixed and prepared.

In the present invention, parenteral administration includes, for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or intravenous drip.

Injectable preparations, such as aqueous or oily suspensions for sterile injections, can be prepared using suitable dispersing agents or wetting agents according to methods known in the related art. Preparations for sterile injection may be solutions or suspensions, which may be sterile injected in a pharmaceutically acceptable diluent or solvent (eg, aqueous solution) capable of parenteral administration. Examples of suitable vehicles and acceptable solvents include water, Ringer's solution and isotonic saline.

In addition, sterile, fixed oils can also be employed as conventional solvents or suspending solvents. Such fixed oils include any fixed oil, fatty acid, natural, synthetic or semi-synthetic fatty oil or fatty acid, and natural, synthetic or semi-synthetic mono-, diglyceride or triglyceride.

Suppositories for rectal administration can be prepared by mixing the drug with a suitable low-irritant carrier such as cocoa butter or polyethylene glycol, which is solid at room temperature but liquid at intestinal temperature And it melts in the rectum to release the drug.

Examples of solid administration forms for oral administration include powders, granules, tablets, pills and capsules. In such solid administration forms, the active ingredient compound can be mixed with at least one additive. Examples of additives applicable at this time include sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, Gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers and glycerides.

Similar to conventional pharmaceutical forms, the above-mentioned solid administration forms may also contain other additives. Examples of these other additives include inert diluents, magnesium stearate and other lubricants, parabens, sorbic acid and other preservatives, ascorbic acid, alpha-tocopherol, cysteine and other Oxidizing agents, disintegrants, binders, thickeners, buffers, sweeteners, flavorings and fragrances. Tablets and pills may also be enteric-coated.

Examples of oral fluids include pharmaceutically acceptable syrups, emulsions, elixirs, suspensions and solutions. These liquids may also contain inert diluents (such as water) commonly used in related fields.

The dosage form of the therapeutic agent of the present invention is at least one form selected from oral dosage forms, suppositories and enteral dosage forms.

The patient dose of the drug of the present invention can be determined according to the patient's age, body weight, general physical condition, sex, diet, administration time, administration method, excretion rate, drug combination and the degree of the patient's condition being treated at that time, and taking into account those and other factors to decide. Since lafutidine, its optical isomers, lafutidine derivatives or pharmaceutically acceptable salts thereof have low toxicity, they can be safely used.

Although there are cases in which the daily dose of the compound varies depending on the patient's condition, body weight, administration route, etc., for example, in the case of administration as a therapeutic agent for ulcerative colitis in adults, the oral daily dose is About 10-60 mg, preferably 10-40 mg (and particularly preferably 10-20 mg), while the daily dose for intravenous injection is about 0.1-3 mg, preferably 0.1-1.5 mg (and particularly preferably 0.1-1 mg), preferably in the form of A single dose or divided into two or three doses.

Furthermore, in the case of administration as a therapeutic agent for Crohn's disease in adults, the daily dose for oral administration is about 10 to 60 mg, preferably 10 to 40 mg (and particularly preferably 10 to 20 mg), and the daily dose for intravenous injection is about 0.1 to 3 mg, preferably 0.1 to 1.5 mg (and particularly preferably 0.1 to 1 mg), preferably administered as a single dose or divided into two or three doses.

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

Example 1

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

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

Lafutidine (racemate) produced in this way and its (+) and (-) forms were compared for their respective gastric mucosal protection.

Six-week-old S.D. male rats (160-190 g, Japan Charles River) were used for the test, and the animals were previously housed indoors for 1 week before starting the test.

Lafutidine (racemate), (+)-lafutidine and (-)-lafutidine produced as above were suspended in a 5% gum arabic aqueous solution and used for the test.

After fasting for 18 hours, animals (N animals per group) were orally administered 10 mg/kg of each drug, and then 1% ammonia water was orally administered at 5 ml/kg 30 minutes later. Added information for the control group. One hour after the administration of ammonia, the animals were sacrificed by cervical dislocation, followed by gastrectomy. After the resected stomach was distended and fixed by injecting 10 ml of formalin aqueous solution (about 2%), it was incised along the greater curvature of the stomach. The surface area of the gastric mucosal lesion was measured using a stereomicroscope, and this value was used as the ulcer coefficient.

During the measurement of the surface area of the damage to the gastric mucosa, the portion exhibiting damage to the gastric mucosa was distinguished from the normal portion based on the presence or absence of bleeding points.

All results are expressed as mean ± standard error, 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) those results were judged to be significant at P<0.05.

As shown in Table 1 and Figure 1 below, the racemic form, (+) form and (-) form of lafutidine all exhibited equal inhibitory effects on ammonia-induced gastric mucosal damage.

Table 1 drug Dose (mg/kg) Damage surface area (mm ² ) inhibition(%) control -- 42.2±5.4 -- (±)-Lafutidine 10 14.0±3.4 ^** 66.8 (+)-Lafutidine 10 16.3±5.2 ^** 61.4 (-)-Lafutidine 10 16.5±2.4 ^** 60.9

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

Example 2

Seven-week-old, sober and non-fasting male F144 rats (body weight: 160-200 g) in normal housekeeping were used, otherwise specified otherwise. In addition, before the day before the start of the experiment, the animals were normally housed, and the animals were transferred to stainless steel cages on the day before the start of the study, and then the animals were divided into several groups of 4 to 8 in the experiment starting the next day. group use.

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

The above-mentioned DSS was prepared as a 3% solution in distilled water, filled into a suction feeder and given ad libitum to the animals during their confinement period.

Suspend lafutidine, cimetidine and capsaicin in 0.5% sodium carboxymethylcellulose (CMC), and dissolve SOD (superoxide dismutase) and Evan's blue in physiological brine to a concentration of 1%.

Each drug was prepared just before application, and was orally administered in an amount of 0.5 ml per 100 g of body weight. The respective solvents were administered to the control group in the same amount and by the same administration route.

Colitis was induced by allowing animals to freely receive 3% dextran sulfate sodium solution (DSS, molecular weight: 5,000, sulfur content: 15.0-20.0%) for 7 days, and animals were also allowed to receive food freely. In addition, control animals were similarly given distilled water ad libitum.

Lafutidine (3-30 mg/kg) was orally administered twice a day at a dose of 5 ml/kg for 6 days from the beginning of the experiment. Added information on cimetidine.

CMC and normal saline were administered to control animals in the same amount and through the same route of administration.

Denervation of sensory neurons was performed by subcutaneous administration of capsaicin in a total of 100 mg/kg in separate doses on three consecutive days two weeks before the start of the experiment.

Seven days after starting the treatment with the DSS solution, the rats were intravenously injected with 1% Evans blue solution under ether anesthesia, and after the rats were killed 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 the mucosal side and the serosal side by injecting a 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 mesentery, the surface area of the lesion in the colon and rectum was determined using NIH Image 1.61 (freeware, downloaded from http://rsb.info.nih.gov/nih-image/download.html) and length from colon to rectum.

Myeloperoxidase (MPO) in the mucosa of the large intestine was determined according to the following procedure based on a modification of the method of Krawisz et al. (Reference: Gastroenterology 1984, Dec. 87(6):1344-50) active.

Seven days after the start of treatment with 3% DSS and each drug, the animals were sacrificed by systemic perfusion of physiological saline from the heart under ether anesthesia, followed by resection of the large intestine.

In the resected large intestine, an incision along the mesentery was made, and after washing with cold saline, about 100 mg was sampled at the site of injury in the distal colon.

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

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 thorough mixing. After adding 1 ml of hydrogen peroxide-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 sample was determined using the BCA protein assay kit (Pease). Add 1ml of various concentrations of hydrogen peroxide-dianisidine reaction solution (0.88mM hydrogen peroxide: 20mM o-dianisidine=1:100, 1:200, 1:400, 1:800 and 1:1600) during the change of absorbance to make a standard curve, and then use the following formula to calculate the MPO activity.

Specific activity (μmol H ₂ O ₂ /min/protein)=(OD/min)/(OD/1 μmol H ₂ O ₂ ×mg protein).

All data are presented as mean ± standard error of values obtained from 4-8 animals per group. Statistical significance was tested according to Student's t-test or Dunnett's multiple comparison test, and results were judged significant at a significance level of P<0.05.

Lafutidine dose-dependently reduced the surface area of large bowel damage induced by DSS. Cimetidine showed no reduction effect.

Although capsaicin was observed to exhibit a lesion surface area reduction effect similar to that of lafutidine (as mentioned earlier), this effect was abolished at high doses (10 mg/kg).

Although there were signs of an effect on MPO activity, an indicator of phagocyte invasion, an increase in MPO activity was observed following induction of inflammation by DSS. In contrast, 30 mg/kg of lafutidine and 3 mg/kg of capsaicin, which have a lesion area reducing effect, caused a decrease in MPO activity and markedly suppressed inflammation.

Effects on the length of the large intestine (colon-rectum) are another indication of damage to the large intestine. DSS caused a decrease in the length of the large intestine. Lafutidine showed a dose-dependent reduction in length, whereas cimetidine did not. Although the effects of lafutidine were lost after sensory neuron denervation, this suggests that the effects of lafutidine are mediated by capsaicin-sensitive sensory neurons. The effects of these drugs on the length of the large intestine produced similar results to their effects on the damaged surface area.

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

Claims (9)

1. one kind is used for that the ulcer enteropathy takes place or the therapeutic agent of inflammatory bowel, and it comprises the lafutidine as active component, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.

2. the therapeutic agent of claim 1, wherein, described ulcer enteropathy comprises at least a disease that is selected from down group: ulcerative colitis and segmental enteritis.

3. claim 1 or 2 therapeutic agent, wherein, dosage form is at least a form that is selected from down group: peroral dosage form, suppository and parenteral dosage forms.

4. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of inflammatory bowel in production.

5. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the enteropathogenic medicament of ulcer in production.

6. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of ulcerative colitis in production.

7. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of segmental enteritis in production.

8. handle that ulcer enteropathy among the patient takes place or the method for inflammatory bowel, this method is the reactive compound of organizing by being selected from that gives effective dose under: lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.

9. handle that the ulcer enteropathy takes place or the pharmaceutical composition of inflammatory bowel for one kind, what it comprised that treatment goes up effective dose is selected from lafutidine, its reactive compound and a kind of pharmaceutically acceptable carrier of optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.