SK698A3 - Use of allylamine derivatives such as terbinafine, in the manufacture of a medicament for the treatment of helicobacter pylori infection of associated diseases - Google Patents

Abstract

Use of compounds of formula (I), wherein R has various significances, in free base form or in pharmaceutically acceptable salt form, as agents against H. pylori infection and associated diseases.

Description

Technical field

The invention relates to the therapeutic use of certain allylamine compounds.

BACKGROUND OF THE INVENTION

Allylamines are known to be squalene epoxidase inhibitors and have antifungal activity. It has now unexpectedly been found that some compounds of this class are also active against Helicobacter pylori (Campylobacter pyloridis).

The members of the genus Helicobacter are gram-negative spiral bacteria that are usually found in the mucosal layer of the stomach of humans and animals. They are microaerophilic, contain flagella and produce a number of extracellular products including urease, proteases, and other compounds that allow them to survive in the hostile environment of the stomach. Worldwide, approximately half of the human population of H.pylori is positive. Without therapy leading to eradication, there appears to be a developed infection caused by Helicobacter pylori throughout life. H. pylori infection usually results in chronic active gastritis (type B gastritis), but rarely becomes clinically conclusive. Recently, a causal relationship between H.pylori infection and peptic ulcer disease has been shown.

Furthermore, based on previous epidemiological evidence, H.pylori was classified by the World Health Organization (WHO) as a category I human carcinogen (unambiguous). The difficulties to be considered in assessing the risk of gastric cancer in various susceptible populations have been identified and new data have been presented to support a model of chronic gastritis that leads to atrophy, followed by intestinal metaplasia and gastric cancer.

SUMMARY OF THE INVENTION

It has now been found that some compounds of the allylamine class of antimycotics exhibit excellent inhibitory activity against H.pylori. They are therefore useful in the treatment of the above diseases.

The invention relates to the use of a compound of formula I

(I) wherein either R is attached at the 1 or 2 position of the naphthyl ring and denotes -CH N (CH) CH CH <f'CHCsC-C (CH) 2 '3 * 2 * 3 * 3 or R is attached at the position 1 and means

-CH ₂ N (CH ₃ ) CH ₂ CH ⁽ = CH-phenyl or N - ((E) -3-phenyl-2-propenyl)) - 2-piperidinyl as a free base or as a pharmaceutically acceptable salt in the treatment of infection caused by Helicobacter pylori and concomitant diseases such as gastritis, peptic ulcer, duodenal ulcer, gastric mucosal atrophy, intestinal metaplasia, nonulcerative dyspepsia, MALT, lymphoma (lymphoma of lymphatic tissue associated with gastric mucosa, gastric mucosa, gastric mucosa) hereinafter called use of the invention.

It also relates to the use of the formula I in the form of a pharmaceutically acceptable salt in the treatment of an infection caused by the above defined free base compound or in the manufacture of a medicament for the use of Helicobacter pylori and the above defined concomitant diseases optionally in combination with one or more others active agents.

It further relates to a method of treating an infection caused by Helicobacter pylori and to the aforementioned concomitant diseases which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I as a free base or a pharmaceutically acceptable salt. This administration may advantageously be carried out in combination with one or more other, preferably orally active agents.

It further relates to an agent for use in the treatment of an infection caused by Helicobacter pylori and the above-mentioned concomitant diseases, comprising a compound of formula I in free base or pharmaceutically acceptable salt form, together with at least one pharmaceutically acceptable carrier or diluent, optionally in combination with one or a plurality of other, preferably orally active agents.

The invention further relates to a process for the preparation of a medicament for the use as defined above, which comprises mixing a compound of the formula I in free base or pharmaceutically acceptable salt form with one or more other, preferably orally active agents, together with at least one. a pharmaceutically acceptable carrier or diluent.

It also relates to a pharmaceutical composition adapted for the above-defined use, which consists of a compound of formula I in the form of the free base or in the form of a pharmaceutically acceptable salt, optionally in combination with one or more other active agents and adapted as an orally administrable capsule or drinking solution. for release and action in the gastrointestinal system.

Compounds of formula (I) in free base or salt form, methods for their preparation and their use as antifungal agents are known, for example, from EP 24587, USP 4,282,251, EP

00896, GB 2,051,799 and / or A.Stutz, Ann. N.Y. Acad. Sci. 544 (1988) 46-62.

The compound of formula (I) may be in the form of the free base or in the form of a salt, especially an acid addition salt. It is preferably in the form of a salt, for example the hydrochloride salt. When R includes a 2-piperidinyl group, it may also be in the form of an optically active, for example, the (R) (+) enantiomer.

Preferably, R is attached at the 1-position and contains a triple bond. When this compound is in the form of its hydrochloride salt, it is known as terbinafine (Lamisil®).

A subgroup of the compounds of formula I are those defined above with the exception of terbinafine.

The term "therapy" is to be understood as referring to both prophylaxis and treatment. Preferably, the patient suffering from an H. pylori infection is not affected or is not being treated for a fungal infection. In a subgroup, a patient affected by an H. pylori infection preferably is not affected or is not being treated for fungal, trychemia or yeast infection.

The efficacy of the compounds of formula I against Helicobacter pylori can be verified, for example, by determining the MIC (minimum inhibitory concentration) by the following test method using various clinical isolates of H.pylori:

Clinical isolates of H.pylori are stored at -70 ° C in Brucella broth with 20% glycerol. All isolates were subcultured on fresh blood agar (blood agar base # 2, Unipath, with 5% defibrinated horse blood) and confirmed as Helicobacter pylori Gram stain assays, catalase, oxidase assays and urease test. Initial incubation is carried out microaerobically in a variable-atmosphere incubator (6% O, 10% CO, 3% H, 81% N) at 37 ^e C. Subcultures and MIC tests are carried out in humidified air with 5% _CO2 at 37 C. Test compounds are incorporated into Mueller-Hinton agar (Unipath) with 7% defibrinated horse blood at pH 7.2. After growth for 72 hours on blood agar, the H.pylori suspension is treated in Brucella broth (Unipath) with equivalent McFarland standard no. 3. This represents 10 ^a cfu / ml H.pylori. The multipurpose inoculator provides 1 μΐ per drop (approximately 10 ® cfu). The strain type NCTC 11637 is used as a control in each experiment. Plates are incubated for 72 hours and the MIC is determined at the lowest concentration of test compound to completely suppress growth. The tests are performed in triplicate.

In the above test, compounds of Formula I have a MIC of from about 0.06 mg / L to about 30 mg / L. Thus, the compound of formula I in the R (+) - enantiomeric form and in the form of the hydrochloride salt and wherein R is the N- ((E) -3-phenyl-2-propenyl) -2-piperidinyl group attached at the 1-position has been found It has a MIC of 0.06 to 4 mg / L, the remaining three compounds of formula I in the form of the hydrochloride salt have MIC values of 8 to 32 mg / L.

Compounds of formula I in free base or pharmaceutically acceptable salt form are therefore useful as agents for the treatment of Helicobacter pylori infection and concomitant diseases such as gastritis, peptic ulcer, duodenal ulcer, atrophy, intestinal metaplasia, nonulcerative dispepsia, MALT lymphoma, non Hodgkin's lymphoma and gastric cancer. For this use, effective dosages will, of course, vary depending upon the particular agent employed, the mode of administration and the treatment desired. In general, however, satisfactory results are obtained when the agent is administered at a daily dosage of from about 0.02 mg / kg to about 50 mg / kg of animal body weight, conveniently administered in divided doses two to four times daily. For the largest mammals, the total daily dosage is from about 1 mg to about 3500 mg, preferably from about 10 mg to about 2000 mg, especially from about 500 mg to about 1500 mg, especially from about

550 mg to about 1200 mg, especially about 600 mg, administered once or twice daily. They can be applied in a similar manner to known standards for use in these indications. It is reported that for this use they can be administered to larger mammals, for example humans, by similar routes of administration at similar or lower dosages than those commonly used with known standards for these indications. The usefulness of the compounds of formula I in free base or pharmaceutically acceptable salt form for the above indications is also shown in standard climatic experiments. Typically, a clinical trial can be performed as follows:

The experiment is carried out using a group of volunteers (both male and female of moderate body weight) who have been found to be infected by H.pylori, for example by a suitable breath test (urease test) or antibody test, and then endoscopic examined. Selected individuals are primarily selected from the long-term ill and those who do not respond to conventional therapy. Each subject will receive a composition of the invention, for example a tablet. The compositions are administered orally in an amount of about 10 mg to about 1000 mg. Administration is performed one, two or three times daily. Treatment is continued for each subject for between 7 days and 10 weeks, preferably about 2 to 4 weeks. After a further treatment-free period of between 7 days and 6 weeks, preferably about 4 weeks, a second examination is carried out, for example by means of a respiratory test, to determine the condition of the individual H. pylori and a second endoscopic examination is performed. Alternative treatment is discontinued before and during treatment with the test compound. Each subject will undergo a complete gastric examination prior to initiation of treatment to determine the extent, location and severity of the lesion. Each individual is asked about subjective experience with the disease. These questions are repeated after stopping treatment and any changes are noted. At the end of treatment, each subject is again asked for subjective disease-related complaints. All changes in the individual's condition, in particular the extent, intensity of the lesion, as well as any side effects are noted with particular emphasis on determining the eradication of H.pylori.

The results obtained after administration of the composition of the invention are compared with those obtained in the placebo group not containing the test compound. The results obtained show an apparent reduction in gastritis in subjects receiving the disclosed compositions of the invention as compared to control groups receiving placebo. Test compositions of the invention have been found to be well tolerated.

The reagents are well tolerated. The acute toxicity in mice of representative compounds of formula I is as follows:

- compound of formula I in hydrochloride salt form and wherein R is attached at the 1 position and is _-CH2 N _{(CH3) 2} ^<=> CH-phenyl: LD _having to> 1000 mg / kg, ip LD _{= q} ~ 560 mg / kg

- a compound of formula I in the form of its hydrochloride salt and in which R is attached at the 1-position and represents -CH _and N (CH ₃ ) CH ₂ CH <5> CHC = CC (CH ₃ ) ₃ : LD _with > 1000 mg / kg,

LD _with ip = 790 mg / kg.

The tolerance of other compounds within the scope of the invention can be determined in a conventional manner and is shown to be of the same order as the tolerance of the above representative examples.

The agents of the invention are optionally administered in combination with one or more other, preferably orally active agents, such as an H ₂ receptor blocker, for example cimetidine, ranitidine or famotidine, an azole such as omeprazole or metronidazole, or a basic aluminum complex, such as sucralfate. The dosage of the components of these combinations is similar or lower than usual.

The compounds of formula (I) in free base or pharmaceutically acceptable salt form, optionally in combination with one or more, preferably orally active agents, may be admixed with conventional chemotherapeutically acceptable diluents and carriers and are administered, for example, parenterally or intravenously, preferably orally. , in the form of capsules or tablets. The concentration of the active ingredient will, of course, vary with, for example, the compound employed, the treatment desired and the nature of the form.

The pharmaceutical compositions for oral use are preferably formulated in unit dosage form, for example, filled into orally administrable capsule shells. The capsule shells may be soft or hard gelatin capsule shells. However, the pharmaceutical compositions may optionally be in the form of a drinkable solution and may contain water or other water system to provide emulsion or microemulsion systems suitable for drinking.

Claims (9)

PATENT CLAIMS ' Use of allylamines of the general formula I (I) in which either R is attached at the 1 or 2 position of the naphthyl ring and represents -CH N (CH) CH CH 2 CHC 5 C-C (CH), or R is attached at the 1 position and means CH _and N _{(CH3) and} CH ^{<? >} CH-phenyl or N - ((E) -3-phenyl-2-propenyl)) -2-piperidinyl in free base or pharmaceutically acceptable salt form for the manufacture of a medicament for use in the treatment of Helicobacter pylori infection and concomitant diseases such as gastritis, peptic ulcer, duodenal ulcer, gastric mucosal atrophy, intestinal metaplasia, nonulcerative dyspepsia, MALT lymphoma, non-Hodgkin's lymphoma, and gastric cancer, wherein the patient is suffering from an infection caused by H.pylori infection or it does not cure. Use of a compound of the formula I as defined in claim 1, wherein R is attached at the 1-position and represents -CH _and N (CH _a ) CH _and CH ^c > CHC = CC (CH ₃ ) ₃ in free base form or in the form of a pharmaceutically acceptable salt. Use according to claim 2, in the form of the hydrochloride salt. wherein the compound is in A method of treating Helicobacter pylori infection and concomitant diseases as defined in claim 1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1, wherein the patient suffering from an infection caused by H.pylori, does not suffer from or is not treated with a fungal infection. The use of a compound according to claim 1 in the treatment of Helicobacter pylori infection and concomitant diseases as defined in claim 1, wherein the patient suffering from H.pylori infection does not suffer from or is not being treated with a fungal infection. An agent for use in the treatment of Helicobacter pylori infection and concomitant diseases as defined in claim 1, wherein the patient suffering from H. pylori infection does not suffer from or is not being treated with a fungal infection, characterized in that it contains a compound of the formula I according to claim 1 in free base or pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent. A pharmaceutical composition adapted for use in the treatment of Helicobacter pylori infection and concomitant diseases according to claim 1, wherein the patient suffering from H.pylori infection does not suffer from or is not being treated with a fungal infection, characterized in that it comprises a compound of the formula I as defined in claim 1 in free base or pharmaceutically acceptable salt form, optionally in combination with one or more other active agents, and is provided as an orally administrable capsule or drinkable solution for release and efficacy in the gastrointestinal system. The use according to claim 1 or 5, the method according to claim 4, the agent according to claim 6 or the composition according to claim 7, wherein the compound of formula I as defined in claim 1 is in combination with one or more other orally active agents such as cimetidine, ranitidine, famotidine, omeprazole, metronidazole and sucralfate. A method of preparing a medicament for use in the treatment of Helicobacter pylori infection and concomitant diseases as defined in claim 1, wherein the patient suffering from H.pylori infection is not suffering from or not being treated with a fungal infection, characterized in that the compound is mixed. according to claim 1, optionally in combination with one or more other active agents, together with at least one pharmaceutically acceptable carrier or diluent.