Derivative of 1,8-acridinone, the pharmaceutical composition for relaxation of the bladder, substance, relaxing the bladder, methods of obtaining (options)

 

(57) Abstract:

The inventive 9-/3-cyanophenyl/-3,4,6,7,9,10-hexahydro-1,8-/2H, 5H/-acridinium produced by interaction of 3-cyanobenzaldehyde ammonium salt and 1,3-cyclohexandione or interaction of 3-amino-2-cyclohexen-1-one with 3-cyanobenzaldehyde or its reactive derivative. The proposed connection has a relaxing effect on the bladder and can be used as an active ingredient of the pharmaceutical composition. 4 C. and 1 C.p. f-crystals, 1 Il.

The invention relates to a new compound intended for use as an extender potassium ducts (channels) in mammals, for example humans. In particular, the invention relates to a particular connection 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H, 5H)-acridinone (represented by formula I and hereinafter referred to as the Union), its use for the treatment of urinary incontinence in mammals (including humans) and to pharmaceutical compositions containing the specified connection.

In DE 2003148 revealed a number of derivatives of 1,4-dihydropyridines, which have a wide and versatile range of pharmacological actions. Set in the article, is the surrounding area on the smooth muscles of the gastrointestinal tract, urinary tract, and respiratory systems of the body. Another important field of action of these compounds is the cardiovascular system, where these connections to discover "cardio-calming" effect and the effect of reducing blood pressure in mammals with normal and high blood pressure, which allows their use as antihypertensive drugs.

It has been unexpectedly discovered that a new connection has the ability to relaxation tissue smooth muscle of the bladder. In addition, the connection has the ability to selectively effect on the muscle of the bladder, without significant action on the cardiovascular system, which was established by measurements of heart rate and blood pressure. So the connection can be advantageously used for the treatment of urinary incontinence in patients, particularly the elderly, who are contraindicated drugs affecting the cardiovascular system, in particular drugs with hypotensive action.

As mentioned above, the present invention relates to 9-(3-cyanophenyl)-3,4,6,7,9,10-GE is seokatalog connection obtained with relatively strong acids carrying a physiologically acceptable anion.

The present invention also relates to pharmaceutical compositions containing 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinium in combination with a pharmaceutically acceptable diluent or carrier.

In addition, the present invention relates to a method of treating urinary incontinence without any noticeable or significant effects on blood pressure or heart rate, which is that the mammal in need of such treatment is administered an effective amount of 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinone.

The compound of the present invention can be obtained by known methods commonly used to obtain compounds with similar structure. These methods for obtaining compounds are another distinctive feature of the present invention and illustrated by the following procedures. The necessary starting materials (if they are not available commercially) for the implementation of the methods described below can be obtained using standard techniques of organic synthesis of chemical compounds, Cataratas technique, or using the technique described in the example. This method is mainly carried out by:

(a) by reaction of the benzaldehyde of the formula II or its acetal or polyacetale with ammonia or ammonium salt (such as ammonium acetate) and 1,3-cyclohexandione. This synthesis can be carried out by the method described Abou-Ghazbia in "Heterocycles", 1986, 24 (5), 1347-1353, using 3-cyanobenzaldehyde instead of the specified heterocyclic aldehyde. Suitable reaction conditions are described also in Antaki J. Chem. Soc. 1963, 4877, and Ranz and others in the U.S. patent N 3901710;

(b) by reaction of compounds of formula II with the corresponding benzaldehyde of the formula II (see drawing) or its acetal or Polyacetal, or its reactive derivative. This reaction can be carried out in accordance with the description Chaabau etc. in J. Chem. Soc. Pezkin 1, 1978, 1583, or Eynde and others in Tetrahedzon, 1992, Vol. 48, No. 7, R. 1263-1268.

Reaction (a) is usually carried out at a temperature in the range from 0 to 100oC, and preferably at elevated temperature, for example from 35 to 90oC. Suitable solvents for this reaction are alcohols, such as methanol or ethanol, and carboxylic acids, for example acetic acid. If necessary, ammonium can be used as gereally usually carried out in the presence of an acid catalyst, for example hydrochloric acid, sulfuric acid, acetic acid or p-toluensulfonate acid. The reaction temperature can vary from 0 to 100oC, and preferably from 25 to 40oC. Suitable solvents for this reaction are alcohols, such as ethanol.

If in the reaction (b) is a reactive derivative of benzaldehyde, so derived may be, for example, N-(alpha-chloroformate)pyridinium chloride. So, for example, benzaldehyde can be treated with thionyl chloride and pyridine in the presence of a halogenated hydrocarbon solvent, such as dichloromethane, after which the obtained N-(alpha-chlorophenylacetyl)pyridinium chloride may be subjected to reaction with the compound of the formula III.

The necessary starting materials (if not on sale) for carrying out the above procedures can be obtained using the standard technique of synthesis of organic compounds, which are usually used to obtain structurally similar compounds, or techniques, similar to the above described procedure, or procedures described in the examples.

When using the compounds of the present invention for the treatment of urinary incontinence it with the second compound in combination with a pharmaceutically acceptable diluent or carrier, moreover, the above composition is prepared in a form suitable for the chosen route of administration, preferably oral route of administration. The above compositions are also a distinguishing feature of the present invention. These compositions can be obtained by conventional methods using standard fillers or binders and in different dosage forms. For example, they can be made in the form of tablets, capsules, solutions or suspensions for oral administration.

The compound of the present invention can be used for medicinal or therapeutic purposes by introducing this compound to the patient in the initial or advanced stages of incontinence. The compound of the present invention can also be used in prophylactic or preventive purposes by introducing connections to prevent possible development of urinary incontinence, for example, patients who suffered from this disease in the past.

According to another variant, the present invention relates to the use of 9-(3-cyanophenyl)-3,4,7,9,10-hexahydro-1,8-(2H, 5H)-acridinone or its pharmaceutically acceptable salt for the manufacture of medicinal preparations is GKO excitable, and incontinence may be caused by irregular or unstable contractions of the bladder. In addition, it is known that the connection opening potassium channels of the cells, may contribute to the relaxation of smooth muscles. Without pretending to any particular theory, it is possible, however, to assert with confidence that the compound of the present invention operates by opening potassium channels in the cells of the bladder, thereby, the relaxation of smooth muscles of the bladder and thus preventing or reducing uncontrolled bladder contractions, which can cause incontinence.

The required dose of the input connection depends on various factors well known in the art, in particular from the method of administration, the severity of the disease, the age and weight of the patient. In General, the compound of the formula I (see drawing) is intended for the introduction of a warm-blooded animal (e.g., human) in an effective daily dose of more than 0,05, for example from about 0.01 to about 10 mg/kg of body weight. This range of doses is preferred oral route of administration. It was found that in rats the compound is aktivnye is active and selective oral dose of 3 mg/kg It should be noted that the exact spacing of the doses at which this connection gives a selective effect depends on the particular species of animal to be treated. This interval can be determined by conventional methods. Generally speaking, the proposed selective effect can be obtained with the introduction of the individual compounds of the present invention in the oral dose of 3 mg/kg or less, for example 1 mg/kg or below. In some cases, the selective effect can be obtained at the dose of 0.3 mg/kg or lower, for example at 0.1 mg/kg or below.

Any expert it is clear that the compound of the formula I can be introduced together with other therapeutic or preventive agents and/or compatible drugs. Laboratory tests on animals using doses several times higher than the minimum effective dose, showed that the compound of the present invention does not have any unwanted side effects.

Below is a description of specifically conducted in vitro tests, in which is illustrated the action of the compounds of formula I as a relaxant of smooth muscle and as a therapeutic agent for the treatment of urinary incontinence.. the Ermin "1C50" means the concentration of test compound which causes 50% reduction of the contractions of the urinary bladder in vitro test.

Test 1. Male albino Guinea pigs Haztley (450-500 g) were killed by decapitation. Then opened the lower abdomen and found the bladder. This bubble was purified from the surrounding connective tissue and fatty tissue. Then cut two pelvic nerve on the surface of the bladder adjacent to the peritoneum, and the body of the bladder was removed above the entrance to the ureter. Dedicated bladder was washed buffered solution of Krebs-Henseleit (composition, mm: NaCl To 118.0; KCl 4,7; MgSO41,2; KH2PO41,2; CaCl22,5; NaHCO325; D-Glucose of 11.1) and then placed on saturated buffer gauze in Petri dishes. Then cut off the dome of the bladder and discard.

Then the scissors did a longitudinal section through the middle of the abdominal wall of the bladder, and the resulting flat bladder was put on the gauze. From the edge of the dome and the edge of the base of the cut strips and discard. The remaining middle part of the body cut in two transverse (horizontal) strips, approximately a width of 2.0 mm, These two strips cut PM each strip contained the dorsal and ventral parts of the bladder.

Each individual strip one end of which is directly tied to the glass supporting rod, the other end tied to a black braided silk sutures (4-0). Glass rods securely strengthened in 20 ml tissue bath and found the thread connected with the sensor force-displacement (Grass model FTO3).

The fabric was immersed in a buffered solution of Krebs-Henseleit. This solution for a bath heated to 37oC and vigorously was barbotirovany 5% CO2and 95% O2. The resulting solution should have a pH of about 7.4.

The sensors were connected to a chart recorder (Grass model 7E) and the signal processing system (Modular Instrument Micro 5000), as well as to the system software (Biowindow Data Acquisition Software (firmware Microsoft OS/2 with IBM joint personal computer (PC)).

The recorder was calibrated at 5 mV/cm, and the calibration was checked for linearity using mass 5 and 0.5 g

The tissue was incubated in the buffer for 15 minutes with no load, and then 30 minutes in tension. Applied pre-tension was 2 g, which was diminished to about 1, the Fabric was washed with 15 minutes interval, corradini initiating dose of 15 mm KCl (total concentration in the bath). After 10 minutes, the fabric was rinsed, and then washed two more times in 15-minute intervals, bringing the tension up to 2 g before each washing.

After the last wash relaxation of tissue to reach steady state, then added another 15 mm KCl. After the fabric has reached steady state, conducted the data collection system Biowindows Data Acquisition. This collection of data was performed by averaging data obtained within 5 minutes, by retrieving data at 32 Hz. After collecting the data, was added compound cumulative method increments of 1/2 unit contact Time for each dose was 10 minutes and the last 5 minutes corresponded to the period of data collection response to the dose. If 30 μm of the test compounds did not eliminate the mechanical activity of tissue, to obtain the maximum response was added to 30 μm cromakalim. The effect of the compounds was expressed in percentage of the maximal relaxation induced by agonist tension.

It should be specially pointed to the fact that the effectiveness of the compounds of the present invention can be illustrated by using a standard in vivo tests. Below is a description of such standard tests conducted by the Wistar rats weighing between 450 and 550 g were anestesiologi 20 mg/kg of Nembutal (intraperitoneally, i. p. ) and 80 mg/kg ketamine (i.p.). To prevent breathing the trachea was Coulibaly. Body temperature was maintained using a heating pad pillows. Arterial blood pressure and heart rate was measured using a pressure sensor connected to a polyethylene tube (PE 50), which was introduced in the right artery. In the right jugular vein was inserted cannula for injection of a medicinal product. The bladder was exposed through a midline laparotomy and was released from the urine of a slight manual pressure. A catheter (PE 50) was introduced through the top of the dome of the bladder in its cavity by about 3-4 mm and was tied with thread (4-0 silk) to avoid leakage. The bladder catheter was connected to a pressure transducer to measure pressure in the bladder. Then the bladder was again placed in the abdominal cavity, and the incision was sutured, with the exception of the place where the catheter. Then the bladder was left for approximately 15 minutes to ensure that it has reached a balanced state. After a period of equilibration rats were injected saline solution directly into the bladder with a speed of 0.05 ml/mm during the whole time of the experiment. Then the pressure in the bladder controlled NGO funds were left for 30-45 minutes to establish a clear picture cuts his bladder.

He then entered the compound intravenously with a maximum dose of 3 mg/kg In this model was also evaluated known drugs, namely cromakalim (Smithkline-Beecham), which was administered intravenously in doses of 0.05 to 0.5 mg/kg

The above in vivo analysis allows you to determine how blood pressure and sistematicheskoju activity of the tested compounds. Blood pressure was measured immediately after the introduction of the medicinal product and after 5, 15 and 30 minutes after his introduction. In order to appeal urination reduction induced by slow continuous infusion of saline solution directly into the bladder. For each connection was detected average change (relative to control, in seconds) duration of the interval between contractions for about 20-minute period.

Below is a description of tests in vivo, which was conducted in addition to the above tests and which can be used to confirm the activity of the test compounds and, in addition, the selectivity of its action in relation to the bladder without significant effects on the cardiovascular system oral is ruralnih doses of 0.1; of 0.3, 1.0 and 3.0 mg per kg of body weight.

Test 3. Male Wistar rats (400-500 g) were anestesiologi 50 mg/kg of Nembutal intramuscular injection (i.p.). Each rat shaved area of the abdomen, as well as the front and upper part of the neck, and the skin was applied povidone-iodine. In the carotid artery is injected with a catheter, which left carotid artery was exposed through a small ventral cervical incision. An open area was washed with 2% HCl-solution of lidocaine for relaxation of the vessel. The catheter is filled with 0.9% saline, was injected into the artery approximately 2.4 cm so that the end was in the aortic arch. The distal end of the catheter was inserted in Zagrebacka part of the neck, filled with heparin (1000 units/ml) and sealed. Then he introduced a catheter into the bladder, which exposed the bladder through a midline abdominal incision. Trocar drove through the abdominal muscle about 1 cm from the upper end of the section, and then spent the subcutaneous tunnelization before excretion through the skin at the back of the neck. After that, through the trocar missed filled with saline catheter. In the dome of the bladder was making a small hole through thermocautery Accu-Temp. The catheter was inserted into the bladder and strengthened by applying ligatures of silk nor ermetico was sealed to avoid leakage of urine. Then the abdominal muscles and skin were sutured. Both catheter is threaded through the button stainless steel anchor (Instech), which is then sewn into the subcutaneous muscle at the point of explantation. The skin was stitched at the top of the button. After that, animals were left alone for recovery from anesthesia.

24-48 hours after this surgery, each rat was placed in a cage for maintaining metabolism and through anchor buttons were connected to the spring-hinge device Instech to protect the catheter from damage and to provide the animal to freely move around the cage. The carotid artery catheter was connected to a pressure transducer Gould P23X1 for measuring blood pressure. The bladder catheter was connected to a pump for infusion of saline solution and to the pressure sensor through the tube (PE 50) and the 4-way shut-off valve. Under the cage was placed scales and the national Cup for measuring urine coming.

Rats were weighed, simulated oral dose of (insert dosing needle, but the liquid was poured), and started transmasculine a saline infusion (of 0.18 ml/min), which is continuously conducted throughout the experiment. Changes in blood pressure is about on the recorder Grass or to a recording device Gould Ta4000. Then the animals were left to trim until then, until a clear picture of urination (approximately 45-90 minutes). At this stage register reference level of each experimental parameter, after which the rats orally through a feeding tube were feeding with the appropriate dose of the compounds (75% PEG 400 physiological filler) in such concentrations that the amount was 1 mg/kg of body weight. The effects of compounds on experimental parameters were monitored during 5 hours after dosing.

The experimental results obtained for the interval between contractions, and heart rate, expressed as the average percentage cf. Art. Osh. (the standard error of measurement) deviations from baseline, where each animal itself was as a control. The blood pressure value was expressed as mean cf. Art. Osh (mm RT.St) deviation from baseline level.

In addition, it was shown that the compound of the present invention also shows the activity and selectivity when tested in vivo in dogs.

Test 4. Well-trained, in the minds of females short-legged hound was introduced catheter-balloon Foley for ss), and record the pressure in the bladder on denegrate. Then the dogs surgically implant was inserted in the carotid artery permanent catheters. When connected to the pressure sensors and the registering device of the carotid artery catheter was left for simultaneous control of blood pressure and heart rate together with blood pressure in the bladder, the data which was received from the permanent catheter-balloon Foley introduced into the bladder.

After a 15-minute period of equilibration in the bladder with four-way shut-off valve was injected with a sterile saline solution in 30 ml injection loading dose until then, until you experience a continuous increase in pressure in the bladder (10-12 mm RT.article). After that, he introduced a series inyecci with a smaller amount of solution (10-15 ml) until then, until the start of spontaneous bladder contraction. The total volume of infusion was approximately 100-200 ml depending on specifically used the animal. At the same time was measured baseline sitologically, diastolicheskoe blood pressure and heart rate. The control period of continuous spontaneous decrease in the l 30-60 minutes, and then estimated the number of contractions of the bladder for one hour.

Then by probe oral feeding was introduced compound in suspension in videosperuanos the filler. Constantly measured blood pressure and heart rate were measured every 15 minutes during the first two hours after administration of the dose and every 30 minutes during the 3rd and 4th hours. The pressure of the bladder and the intervals between the contractions were monitored for 4 hours after administration of the oral dose.

Each dog was allowed to rest between experiments, at least for 1 week. For training and acclimatization to the sedentary state and catherization chose a calm and sociable dogs. If the animal procedures were found distress or discomfort, then this animal is not used to describe the model tests.

In this test, the compound showed activity and selectivity at a dose of 3 mg/kg

The present invention is illustrated in the following examples, in which (if it is not specifically mentioned):

(I) temperatures are given in degrees Cellsite (198>C; procedures were performed at room rate is us without amendments, and reduction (decomp.) indicates decomposition; the melting points obtained for the materials made in accordance with the description; preformism can lead to the selection of materials with different melting points in some experiments;

(III) all resulting products are mainly clean, which was confirmed by TLC, and have satisfactory spectra, obtained by nuclear magnetic resonance (NMR), and satisfactory data microanalysis;

(IV) the outputs are given only for illustrative purposes;

(V) chemical symbols have their usual meanings; the following abbreviations are used: about. volume; wt. weight; so pl. melting point, l - liter, mm millimoles; g gram; mg-milligram; min, minute; hour clock; and

(VI) NMR data are given as values in parts per million (ppm) relative to trimethylsilane (TMS) (internal standard) with an operating frequency of 300 MHz and using the d6the dimethyl sulfoxide as a solvent; when specifying a waveform used standard abbreviations;

(VII) mass spectroscopy (MS) was performed at an electron energy of 70 eV mode chemical ionization with direct sample injection; identifies only the mass spectra, BR>
The stirred mixture of 3-cyanobenzaldehyde (1.48 g), 1,3-cyclohexandione (2,53 g) and ammonium acetate (1.24 g) in ethanol (20 ml) was heated under reflux for 18 hours. The mixture was poured into water, and the resulting yellow solid substance was collected and dried under vacuum, resulting in a received target Grindin (3,22 g); so pl. 285-288oC; NMR: 1,80-of 1.93 (m,4); 2,19-2,22 (m,4); 2,50-of 2.54 (m,4); 4,91 (C,1); 7,37-7,42 (m,1);of 7.48-rate of 7.54 (m, 3); of 9.55 (s,1);

MS: m/z 319 (M+1).

Elemental analysis for C20H18N2O2:

Calculated: C 75,44; H5,71; N 8,80.

Found: C75,27; H 5,66: N 8,77.

Example 2. 9-(3-Cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinium

To a stirred mixture of 3-amino-2-cyclopenten-1-it (4,45 g) and 25 ml of ethanol was added 32 ml of 1 N. HCl, then 3-cyanobenzaldehyde (2,62 g) and the mixture was stirred at ambient temperature overnight. The obtained solid was filtered, thoroughly washed with water and then ethanol. After drying under conditions at 50 C/0, 2 mm RT.article received target compound as a pale yellow solid (3,89 g), so square - 303-7oC (with decomp.).

MC:(C1, CH4) 319 (M+1).

Elemental analysis for C20H18N2O2:

Calculated: C75,44; H5,71; N8,80.

MC (Cl, CH4): 319 (M+1). The NMR spectrum is identical to the spectrum of the product of example 1.

Example 4.

Below are the most typical dosage forms containing compounds is the Compound 50,0

Mannitol, Pharm. USA 223,75

Nitrocresols 6,0

Corn starch 15,0

The hypromellose (HPMC), Pharm. USA OF 2.25

Magnesium stearate 3,0

(b) Capsule (mg/tablet)

Connection 10,0

Mannitol, Pharm. USA 488,5

Nitrocresols 15,0

Magnesium stearate 1.5 to

These drugs can be obtained by standard methods, well known to specialists. These tablets can be coated intersolubility coating by standard means, for example a coating of azettftalat cellulose.

1. Derivative of 1,8-acridinone formula I

< / BR>
2. Pharmaceutical composition for relaxation of the bladder, including derivatives of dihydropyridines, characterized in that it contains an effective amount of the compounds under item 1.

3. Substance, relaxing the bladder, characterized in that it is a derivative of 1,8-acridinone formula I, characterized in p. 1.

4. The method of obtaining the compounds of formula I on p. 1, characterized in that 3-cyanobenzaldehyde subjected to interaction with the ammonium salt and 1,3-cyclohexane-dione.

5. The method of obtaining the compounds of formula I on p. 1, characterized in that 3-amino-2-cyclohexen-1-the

 

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