Medicines containing derivatives of imidazol-1 - yl

 

(57) Abstract:

The invention relates to pharmacology and describes a new tool for the treatment of irritable bowel syndrome. Such proposed antagonists NT-receptor - compound of General formula (I)

< / BR>
in which R' denotes a lower alkyl or hydrogen; m = 3; n = 2 or 3. Analgesic effect means superior to the previously known compounds. 3 C. p. F.-ly, 4 tab., 1 Il.

The invention relates to the use of derivatives of imidazol-1-yl for the treatment of functional gastrointestinal disorders in the lower part of the intestine and to receive suitable treatment medicines.

The basis of the invention is the creation of new pharmaceutical compositions for the treatment of functional symptoms in the lower part of the intestine.

According to the invention to obtain pharmaceutical compositions for the treatment associated with increased sensitivity to pain and/or abnormal passage of feces in the field of colon cancer, functional disorders in the lower part of the intestine in large mammals and people used connection imidazol-1-yl General formula (I):

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g is">

and their physiologically acceptable salts accession acids.

Used according to the invention compounds "m" preferably denotes 2 and "n" preferably denotes 3. R1preferably denotes a lower alkyl residue, which can be linear or branched and can contain 1 to 4, in particular 1 to 2 carbon atoms and preferably denotes methyl.

The compounds of formula (I) at the junction of the tetracyclic skeleton imidazol-1-yl-methyl side chain contain a chiral center, which, depending on the circumstances, may be R - or S-configuration. According to the invention, it is possible to apply the individual stereoisomeric forms of the compounds of formula (I) or mixtures thereof.

Particularly suitable are 5,6,9,10-tetrahydro-10-//2 - methyl-1H-imidazol-1-yl/-methyl/-4H-pyrido/3,2,2-jk/-carbazole-11/8H/- ons, in particular, /S/-5,6,9,10-tetrahydro-10-//2-methyl-1H-imidazol - 1-yl/-methyl/-4H-pyrido/3,2,1-jk/carbazole-11/8H/he, and their physiologically acceptable salts accession acids.

As physiologically acceptable salts accession acid compounds of the formula (I) suitable salts with inorganic acids, such as halogen acids, in particular hydrochloric acid acid as acetic acid, fumaric acid, tartaric acid, lactic acid, maleic acid or citric acid, or aromatic carboxylic acids, such as salicylic acid, dibenzoyltartaric acid or dItalia acid, or sulfonic acids, such as, for example, (lower alkyl) sulfonic acids, as methanesulfonate, or if necessary substituted in the benzene ring by halogen or lower alkyl of benzosulfimide as p-toluensulfonate.

Used according to the invention for the treatment of functional disorders in the lower part of the intestine compounds fall under the scope described in European patent application N 0297651 containing bellrowan indole skeleton compounds with 5-HT-antagonistic properties and are known from this patent application. The compounds of formula (I) can be obtained in itself known manner as described in the above European patent application methods or analogously to this method.

Now unexpectedly found that the applied according to the invention the group of compounds of formula (I) suitable not only as specified in wyrezyserowany European patent application for the treatment of diseases in gastroc the same these compounds can be used for the treatment of diseases and functional disorders in the lower part of the intestine.

Thus, unexpectedly opened opportunities for the treatment of totally different, not associated with diarrhoeal disease States.

Violations in the area of the distal small intestine, and increased pain sensitivity at physiological caused by digestion of the stretching of the colon can lead to disorders of motility, as observed in the case of the so-called "irritable intestinal syndrome" ( = IBS). To appear the symptoms, along with visceral pain and impaired motility in the lower area of the intestine can also apply disorders of defecation, especially abnormally accelerated passage of feces in the colon.

Now found that compounds of the formula (I) reduces visceral pain sensitivity and because of this can impede called hypersensitive response to distension of the colon inhibition of the motility of the colon. Additional compounds have a prolonging effect on the passage of feces through the colon, and thus to normalize abnormally accelerated passage of the colon.

The pharmacological activity of the compounds of formula (I) is"ptx2">

Description of pharmacological research methods

I. studying the activity of the compounds on the passage of feces through the colon in rats.

As measures, resulting in release of feces motility of the colon, is determined by the average duration of stay in the colon entered into the radioactively labeled material until its release in Calais.

For testing use, depending on the circumstances, groups of 8 male Wistar rats. Under anesthesia by ketamine animals injected a small polyethylene catheter from the nape of the neck into the abdominal cavity and from there into the lumen of the proximal colon at a distance of 2 cm from the mouth of the caecum - proximal colon.

Through the catheter animals injected 0.1 ml of the labeled radioactive 51Cr solution of sodium chromate (=10 C/ml). Then from waste stool in intervals of 1 h take samples until, until Kale is no longer detected no radioactivity. Contained in the samples of the fecal radioactivity was measured using a count of gamma radiation. These measurements calculate the average residence time of radioactively labeled material in the colon. This is the average residence time can serve ka is prebyvania 51Cr - labeled material in the colon is 7.1 hours Subcutaneous administration /S/-5,6,9,10-tetrahydro-10-//2-methyl - 1H-imidazol-1-yl/-methyl/-4H-pyrido/3,2,1-jk/-carbazole-11/8H/he - hydrochloride at a dose of 1 mg/kg 15 min before injection of radioactive labeled chromate sodium causes the prolongation of the allocation of the colon and leads to a lengthening of the average time of radioactively labeled material in the colon to 9.8 hours It shows the substance being tested reduces leading to the excretion of the feces activity of the colon.

II. The radiation effect of the compounds on visceral sensitivity in rats

Male Wistar rats weighing 250 - 350 g prepared by surgery for electromyography those that impose them the electrodes them chronicleby wire in the wall of the proximal colon. Electromyographic recordings of the movements of the large intestine begins after 5 days after surgery. For the implementation experience animals rectally into the colon enter inflate the balloon, so that the end of the cylinder was remote at 1 cm from the rectum, and the bladder is fixed in position on the tail. During the experience of animals kept in a tunnel-shaped cage, to reduce the motility of the colon. This reduces the number of series compression in 5 min in the case of a group of control animals to 43% of the initial value. After intraperitoneal the introduction of /S/-5,6,9,10-tetrahydro-10-//2-methyl-1H-imidazol-1-yl/- methyl/-4H-pyrido/3,2,1-jk/carbazole-11-/8H/he-hydrochloride at a dose of 1 mg/kg before the start of the experiment to reduce the sensitivity to stretching and the number of series of reductions in 5 min is reduced to only 85% of the initial value.

The above pharmacological test results show that the compounds of formula (I) can be prevented caused by stimulation of afferent nerves motility disorders of the colon and therefore suitable for the treatment of IBS. The applied dose can be individually different and of course can vary depending on the kind treatable condition and the substance used. In General, for administration to humans and large mammals, however, suitable dosage form with the content of biologically active substances of 0.1 to 80, in particular 1 to 10 mg of biologically active substances in a single dose.

Compounds according to the invention can be in solid or liquid pharmaceutical compositions together with conventional pharmaceutical excipients and/or EDI, pills, capsules, powders or granules, or candles. These preparations may contain conventional pharmaceutically inorganic and/or organic carriers, such as talc, lactose or starches, along with pharmaceutically customary excipients, for example, as giving to the slipperiness of the substance or excipients for tablets. Liquid preparations, as a suspension or emulsion of biologically active compounds, may contain the usual diluents, such as water, oil and/or suspendresume means as glycols, etc. Optionally, you can add other excipients, such as preservatives, improves the taste of substances, etc.

Biologically active substance by itself in a known manner can be mixed with pharmaceutical excipients and/or carriers and get the preparative form. For solid dosage forms of the biologically active substance can be mixed in the usual way, for example, excipients and/or carriers and subjected to wet or dry granulation. Granular or powder can be directly added to the capsule or the usual way to extrude into core tablets. The last in a desirable scenario, you know who to formula (I) pharmaceutical compositions however, without limiting the scope of protection of the invention.

Example 1. Tablets.

The composition,including:

/S/-5,6,9,10-Tetrahydro-10-//2-methyl-1H-imidazol-1-yl/-methyl/- 4H-pyrido/3,2,1-jk/-carbazole-11/8H/he-chloride - 5

Corn starch - 30

Lactose - 70

Kollidon 25 - 5

Magnesium stearate - 2

Talc - 3

In General - 115

The method of obtaining

The biologically active material in the mixer is mixed with corn starch and melkoporistoj lactose. The resulting mixture is moistened with a 20% aqueous solution of polyvinylpyrrolidone (kollidon 25 firm BASF) in demineralized water. If necessary, add an additional amount of demineralized water. The wet granulate is forced through two sieve, dried at 40oC on the grill and then forced through onemillimeter sieve (Frewitt machine). After mixing the granules with magnesium stearate and talc from the mixture is pressed to tablets weighing 115 mg, so that each tablet contains 5 ml of biologically active substances.

Example 2. The capsule.

The composition,including:

/S/-5,6,9,10-Tetrahydro-10-//2-methyl-1H-imidazol-1-yl/- methyl/-4H-pyrido/3,2,1-jk/-carbazole-11/8H/he-chloride - 5

Corn starch - 20

Lactose - 60

Kollidon 25 - 3

Stesta in the mixer is mixed with corn starch and melkoporistoj lactose. The resulting mixture is moistened with a 20% aqueous solution of polyvinylpyrrolidone (kollidon 25 firm BASF) in demineralized water. If necessary, add demineralized water. The wet granulate is forced through a 1.6 mm sieve (Frewitt machine), dried on the grid at 40oC and then forced through onemillimeter sieve (Frewitt). After mixing the granules with magnesium stearate and highly dispersed silicic acid (Aerosil 200, firm DEGUSSA), if desired 90 mg of this mixture by means of an automatic machine for filling capsules bring in hard gelatin capsules of size 4, so that each capsule contains 5 mg of biologically active substances.

1. The use of 5HT-receptor-antagonistically active compounds imidazol-1-yl General formula I

< / BR>
in which R1is lower alkyl or hydrogen;

m = 2 or 3;

n = 2 or 3,

and their physiologically acceptable acid additive salts as biologically active substances for the treatment of functional disorders of the lower part of the intestine in higher mammals and humans in the form of increased visceral pain sensitivity and/or anomalies of the passage of feces in the area of the colon.

2. Application under item (1, [(2-methyl-1H-imidazol-1-yl)-methyl] -4H-pyrido(3,2,1-ik)-carbazole-11(8H)-he and its physiologically acceptable acid additive salt.

4. Application under item 3, where the compound of General formula I is (S)-5,6-9,10 - tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-pyrido(3,2,1-ik)-carbazole-11(8H)-he and its physiologically acceptable acid salt additive.

 

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< / BR>
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