RU2079492C1 - Derivative of 1,8-acridinedione, pharmaceutical composition for bladder relaxing, substance relaxing bladder, methods of synthesis (variants) - Google Patents

Abstract

FIELD: organic chemistry and technology. SUBSTANCE: product: 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-[2H, 5H]-acridine- -dione is synthesized by interaction of 3-cyanobenzaldehyde with ammonium salt and 1,3-cyclohexanedione or by interaction of 3-amino-2-cyclohexa-1-one with 3-cyanobenzaldehyde or its reactive derivative. Proposed compound shows relaxing action on bladder and can be used as an active component in pharmaceutical composition. EFFECT: improved method of synthesis, enhanced effectiveness. 5 cl, 1 dwg

Description

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

 DE 2003 148 discloses a number of 1,4-dihydropyridine derivatives which have a wide and multifaceted spectrum of pharmacological action. The work indicates that the described compounds mainly have a strong antispasmodic effect on the muscles, in particular on the smooth muscles of the gastrointestinal tract, genitourinary tract, and the respiratory system of the body. Another important field of action of these compounds is the cardiovascular system, where these compounds exhibit a “cardioprotective” effect and an action that lowers blood pressure in mammals with normal and high blood pressure, which allows them to be used as antihypertensive agents.

 It was unexpectedly discovered that the new compound has the ability to relax the tissue of the smooth muscles of the bladder. In addition, this compound has the ability to selectively affect the muscle of the bladder, without exerting a significant effect on the cardiovascular system, which was established by measuring heart rate and blood pressure. Therefore, this compound can be mainly used for the treatment of urinary incontinence in patients, in particular in elderly people, who are contraindicated in drugs that affect the cardiovascular system, in particular drugs with antihypertensive effect.

 As indicated above, the present invention relates to 9- (3-cyanophenyl) -3,4,6,7,9,10-hexahydro-1,8- (2H, 5H) -acridinedione.

 The present invention also relates to acid addition salts of the aforementioned compound prepared with sufficiently strong acids bearing a physiologically acceptable anion.

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

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

The compound of the present invention can be obtained by known methods commonly used to obtain compounds with a similar structure. These methods for preparing the compound are another distinguishing feature of the present invention and are illustrated by the following description of procedures. The necessary starting materials (if they are not commercially available) for the implementation of the methods described below can be obtained using the standard technique for the synthesis of organic chemical compounds, which is usually used to obtain structurally similar compounds, or a technique similar to the specified standard technique, or using technique described in the example. The specified method is mainly carried out:
(a) by reacting a benzaldehyde of formula II or its acetal or semi-acetal with ammonia or an ammonium salt (such as ammonium acetate) and 1,3-cyclohexanedione. This synthesis can be carried out by the method described by Abou-Ghazbia in "Heterocycles", 1986, 24 (5), 1347-1353, using 3-cyanobenzaldehyde instead of said heterocyclic aldehyde. Suitable reaction conditions are also described by Antaki in J. Chem. Soc. 1963, 4877, and Ranz et al. In US Pat. No. 3,901,710;
(b) by reacting a compound of formula II with the corresponding benzaldehyde of formula II (see drawing) or its acetal, or semi-acetal, or its reactive derivative. This reaction can be carried out as described by Chaabau et al. In J. Chem. Soc. Pezkin 1, 1978, 1583, or Eynde et al. In Tetrahedzon, 1992, Vol. 48, N 7, p. 1263-1268.

Reaction (a) is usually carried out at a temperature ranging from 0 to 100 ^° C., and preferably at elevated temperature, for example from 35 to 90 ^° C. Suitable solvents for this reaction are alcohols, for example methanol or ethanol, and carboxylic acids, for example acetic acid. If necessary, ammonium can be used in the form of ammonium hydroxide.

If benzaldehyde or its acetal or hemiacetal is used in reaction (b), the reaction is usually carried out in the presence of an acid catalyst, for example hydrochloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid. The reaction temperature may vary from 0 to 100 ^° C., and preferably from 25 to 40 ^° C. Suitable solvents for this reaction are alcohols, for example ethanol.

 If a reactive benzaldehyde derivative is used in reaction (b), then such a derivative may be, for example, N- (alpha-chlorophenylmethyl) pyridinium chloride. 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 resulting N- (alpha-chlorophenylmethyl) pyridinium chloride can be reacted with a compound of formula III.

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

 When using the compound of the present invention for the treatment of urinary incontinence, this compound is usually administered in the form of an appropriate pharmaceutical composition, which includes the compound in combination with a pharmaceutically acceptable diluent or carrier, said composition being prepared in a form suitable for the chosen route of administration, preferably the oral route introduction. The above compositions are also a hallmark of the present invention. These compositions can be prepared by conventional methods using standard excipients or binders and in various dosage forms. For example, they may be in the form of tablets, capsules, solutions or suspensions for oral administration.

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

 According to another embodiment, the present invention relates to the use of 9- (3-cyanophenyl) -3,4,7,9,10-hexahydro-1,8- (2H, 5H) -acridinedione or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, intended for the treatment of urinary incontinence.

 Bladder tissue is known to be readily excitable, and urinary incontinence can be caused by unregulated or unstable contractions of the bladder. In addition, it is known that compounds that open potassium channels of cells can contribute to the relaxation of smooth muscles. Without claiming to be a specific theory, it can, however, be asserted with confidence that the compound of the present invention acts by opening potassium channels in the cells of the bladder, thereby contributing to relaxation of the smooth muscle of the bladder and thus preventing or reducing uncontrolled contractions of the bladder bladder infections that can cause urinary incontinence.

 The required dose of the administered compound depends on various factors well known to specialists, in particular on the route of administration, the severity of the disease, and also on the age and weight of the patient. Basically, the compound of formula I (see drawing) is intended for administration to a warm-blooded animal (eg, human) in an effective daily dose of more than 0.05, for example, from about 0.01 to about 10 mg / kg body weight. For the indicated dose range, an oral route of administration is preferred. It was found that for rats, this compound is active and selective at oral doses of 0.1; 0.3; 1.0 and 3.0 mg / kg. It was also found that for dogs, this compound is active and selective at an oral dose of 3 mg / kg. It should be borne in mind that the exact range of doses at which this compound gives a selective effect depends on the particular type of animal being processed. This interval can be determined by conventional methods. Generally speaking, the intended selective effect can be obtained by administering to an individual a compound of the present invention at an oral dose of 3 mg / kg or less, for example 1 mg / kg or less. In some cases, a selective effect can be obtained at a dose of 0.3 mg / kg or less, for example at 0.1 mg / kg or less.

 It will be appreciated by any person skilled in the art that a compound of formula I can be administered together with other therapeutic or prophylactic agents and / or compatible medications. Laboratory tests in animals using doses several times the minimum effective dose showed that the compound of the present invention does not produce any undesirable side effects.

The following is a description of specially conducted in vitro trials that illustrate the effect of the compound of formula I as a smooth muscle relaxant, and also as a therapeutic agent for urinary incontinence. The compound of the present invention, tested in the test described below, showed 1C ₅₀ 1.2 ± 0.4 μM. The term “1C ₅₀ ” means a concentration of a test compound that causes a 50% reduction in bladder contractions in an in vitro test.

Test 1. Male albino Haztley guinea pigs (450-500 g) were killed by decapitation. Then the lower abdominal cavity was opened and the bladder was found. This bladder was cleaned of the surrounding connective and adipose tissue. Then, two pelvic nerves were cut off on the surface of the bladder adjacent to the peritoneum, and the body of the bladder was removed above the entrance to the ureter. The isolated bladder was washed with a Krebs-Henseleit buffered solution (composition, mM: NaCl 118.0; KCl 4.7; MgSO ₄ 1.2; KH ₂ PO ₄ 1.2; CaCl ₂ 2.5; NaHCO ₃ 25; D- Glucose 11.1), and then placed on buffer-soaked gauze in Petri dishes. Then the bladder dome was cut off and discarded.

 After that, a longitudinal incision was made in the middle of the peritoneal wall of the bladder with scissors, and the resulting flat bladder was placed on gauze. Stripes were cut from the edge of the dome and from the edge of the base and discarded. The remaining middle part of the organ was cut into two transverse (horizontal) strips, approximately 2.0 mm wide. These two strips were cut in half in the middle of the dorsal part, resulting in four strips of the same size. Thus, each strip contained the dorsal and abdominal parts of the bladder.

 Each individual strip was tied directly at one end to a glass supporting rod, and tied at the other end to a black woven silk thread (4-0). The glass rods were firmly fixed in 20 ml in a tissue bath, and this thread was connected to a force-displacement transducer (Grass model FTO3).

Tissues were immersed in a Krebs-Henseleit buffered solution. This bath solution was heated to 37 ^° C. and 5% CO ₂ and 95% O _{2 were} sparged vigorously. The resulting solution should have a pH of about 7.4.

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

 The recorder was calibrated at 5 mV / cm, and this calibration was checked for linearity using masses of 5 and 0.5 g.

 Tissue was incubated in buffer for 15 minutes without load, and then 30 minutes under tension. The applied preliminary tensile force was 2 g, which was weakened to about 1 g. The fabric was washed with an interval of 15 minutes, adjusting the tension to 2 g immediately before washing. After this 45-minute equilibration period, an initiation dose of 15 mM KCl (total concentration in the bath) was administered. After 10 minutes, the tissue was washed, and then washed two more times at 15-minute intervals, bringing the tension to 2 g before each washing.

 When, after the last washing, the tissue relaxation reached a steady state, another 15 mm KCl was added. After the tissue reached a steady state, data was collected on the Biowindows Data Acquisition system. This data collection was carried out by averaging the data obtained over 5 minutes, sampling the data at 32 Hz. After collecting the data, the test compounds were added cumulatively in 1/2 units increments. The contact time for each dose was 10 minutes, with the last 5 minutes corresponding to the period of collection of response data for the dose. If 30 μM of the test compound did not eliminate the mechanical activity of the organ tissue, then 30 μM cromacalim was added to obtain the maximum response. The effects of the compounds were expressed as a percentage of the maximum relaxation of agonist-induced tension.

 It should be emphasized that the effectiveness of the compounds of the present invention can be illustrated using standard in vivo tests. The following is a description of such a standard test conducted to evaluate the ability of a test compound to relax smooth muscles.

 Test 2. Male Wistar rats weighing 450-550 g were anesthetized with 20 mg / kg Nembutal (intraperitoneally, i. P.) And 80 mg / kg Ketamine (i.p.). To prevent respiratory failure, the trachea was cannulated. Body temperature was maintained using a heating pad. Arterial blood pressure and heart rate were measured using a pressure transducer connected to a polyethylene tube (PE 50), which was inserted into the right artery. A cannula was inserted into the right jugular vein to administer the drug. The bladder was exposed through midline laparotomy and was freed from the urine by light manual pressure. A catheter (PE 50) was inserted through the top of the canopy of the bladder into its cavity by about 3-4 mm and was ligated with thread (4-0 silk) to prevent leakage. A bladder catheter was connected to a pressure sensor to measure pressure in the bladder. Then the bladder was again placed in the abdominal cavity, and the incision was sutured, except for the place where the catheter was. Then the bladder was left for approximately 15 minutes so that it reached a balanced state. After the equilibration period, the rats were injected with saline directly into the bladder at a rate of 0.05 ml / mm for the entire duration of the experiment. Then, the pressure in the bladder was monitored at the onset of bladder contractions. When contractions began, the animal was left for 30-45 minutes before administering the drug to establish a clear picture of contractions in his bladder.

 Test compounds were then administered intravenously with a dose limit of 3 mg / kg. In this model, a well-known drug was also evaluated, namely cromacalim (Smithkline-Beecham), which was administered intravenously in doses of 0.05 to 0.5 mg / kg.

 The in vivo analysis described above allows the determination of both blood pressure and the cystometric activity of test compounds. Blood pressure was measured immediately after administration of the drug, as well as 5, 15 and 30 minutes after its administration. In order to induce urination, contractions were induced by slowly continuous infusion of saline directly into the bladder. For each compound, the average change (relative to the control, in sec) of the duration of the interval between contractions over an approximately 20-minute period was recorded.

 The following is a description of the in vivo test, which was carried out in addition to the tests described above and which can be used to confirm the activity of the test compound and, in addition, its selectivity for the bladder without significant effects on the cardiovascular system when administered orally. In this test, the compound of the present invention showed activity and selectivity at oral doses of 0.1; 0.3; 1.0 and 3.0 mg per kg of body weight.

 Test 3. Male Wistar rats (400-500 g) were anesthetized with 50 mg / kg Nembutal intramuscularly (i.p.). In each rat, a section of the peritoneum was shaved, as well as the front and upper parts of the neck, and povidone iodine was applied to the skin. A catheter was inserted into the carotid artery, for which the left carotid artery was exposed by a small ventral-cervical incision. The exposed area was washed with a 2% lidocaine HCl solution to relax the vessel. A catheter 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 into the neck of the neck, filled with heparin (1000 units / ml) and sealed. A catheter was then inserted into the bladder, for which the bladder was exposed through a mid abdominal incision. The trocar was driven through the abdominal muscle about 1 cm from the upper end of the incision, and then subcutaneous tunneling was performed before excretion through the skin at the occipital part of the neck. After that, a catheter filled with saline was passed through a trocar. A small hole was made in the dome of the bladder using an Accu-Temp thermocaut. A catheter was inserted into the bladder and strengthened by ligating with a 4-0 silk thread. The catheter was washed with saline, and attention was paid to its patency. The outer end of the catheter was hermetically sealed to prevent leakage of urine. Then the abdominal muscles and skin were sutured. Both catheters were inserted through a stainless steel anchor (Instech) button, which was then sutured into the subcutaneous muscle at the explantation point. The skin was sutured at the top of the button. After this, the animals were left alone to exit anesthesia.

 24-48 hours after the described surgical operation, each rat was placed in a cage to maintain metabolism and, via an anchor button, connected to an Instech spring-hinged device to protect catheters from damage and to allow the animal to move freely around the cage. A carotid catheter was connected to a Gould P23X1 pressure sensor for measuring blood pressure. A bladder catheter was connected to a saline infusion pump and to a pressure transducer via a tube (PE 50) and a 4-way stopcock. A scale and a collection cup were placed under the cage to measure outgoing urine.

 Rats were weighed, an oral dose was simulated (a dosing needle was inserted, but no liquid was infused), and transvesical infusion of physiological saline (0.18 ml / min) was started, which was continuously carried out throughout the experiment. Changes in blood pressure, heart rate, intravesical pressure, and the amount of urine exiting were recorded either on a Grass recorder or on a Gould Ta4000 recorder. The animals were then left to balance until a clear pattern of urination was established (approximately 45-90 minutes). At this stage, the baseline level of each experimental parameter was recorded, after which rats were orally administered via a tube with a corresponding dose of compounds (in 75% PEG 400 physiological excipient) at such concentrations that the volume was 1 mg / kg body weight. The effect of the compound on the experimental parameters was monitored for 5 hours after administration.

 The experimental results obtained for the interval between contractions, as well as for heart rate, were expressed as the average percentage ± sr. Art. osh (standard error of measurements) deviations from the baseline, where each animal was itself as a control. The value of blood pressure was expressed as mean ± SEM (mmHg) deviation from the baseline.

 In addition, it was shown that the compound of the present invention also exhibits activity and selectivity in in vivo tests on dogs.

 Test 4. Well trained, conscious females of a short-legged hound were injected with a Foley catheter balloon to drain residual urine. Using a four-position valve, the catheter was connected to a pressure sensor (Grass model), and the pressure in the bladder was recorded on a dinograph. Permanent catheters were then inserted into the carotid artery through surgical implantation in dogs. When connected to pressure sensors and a recording device, the carotid artery catheter was left to simultaneously monitor blood pressure and heart rate together with the pressure in the bladder, the data of which was received from a permanent Foley catheter balloon inserted into the bladder.

 After a 15-minute equilibration period, a sterile saline solution was injected into the bladder using a four-position stopcock in a 30 ml injection of a loading dose until a prolonged increase in pressure in the bladder (10-12 mm Hg) was observed. After this, a series of injections was introduced with a smaller amount of solution (10-15 ml) until a spontaneous contraction of the bladder begins. The total infusion volume was approximately 100-200 ml, depending on the particular animal used. In this case, baseline systological and diastological blood pressure, as well as heart rate, were simultaneously measured. The control period of continuous spontaneous contractions of the bladder, during which basic measurements of the interval of contractions (in seconds) were performed, was 30-60 minutes, after which the number of contractions of the bladder in one hour was estimated.

 Then, by test feeding by mouth, the test compounds were administered as a suspension in a water-suspended vehicle. In this case, blood pressure was constantly measured, and the heart rate was measured every 15 minutes during the first two hours after the dose and every 30 minutes during the 3rd and 4th hours. Bladder pressure and intervals between contractions were monitored for 4 hours after an oral dose.

 Each dog was allowed to rest between experiments for at least 1 week. To prepare and acclimatize to a sedentary state and caterization, calm and sociable dogs were chosen. If the animal as a result of the procedures showed distress or malaise, then this animal was not used for the described test model.

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

The present invention is illustrated by the following examples, in which (unless otherwise specified):
(I) the temperature is given in degrees Celsius (198>C; the procedures were performed at room temperature or at ambient temperature, that is, in the range of 18-25 ^o C;
(Ii) melting points are given without correction, and reduction (decomp.) Means decomposition; reducible melting points obtained for materials manufactured in accordance with the description; polyformism can lead to the release of materials with different melting points in some experiments;
(Iii) all products obtained are essentially pure, as was confirmed by TLC, and have satisfactory spectra obtained by nuclear magnetic resonance (NMR), and satisfactory microanalysis data;
(Iv) exits are for illustrative purposes only;
(V) chemical symbols have their usual meanings; the following abbreviations are used: vol. volume; wt. weight; so pl. melting point, l - liter, mm millimole; g gram; mg milligram; min minutes; hour clock; and
(VI) NMR data are presented as δ values in parts per million (ppm) relative to trimethylsilane (TMS) (internal standard) with an operating frequency of 300 MHz and using d ₆ -dimethyl sulfoxide as a solvent; when specifying the waveform, standard abbreviations were used;
(VII) mass spectroscopy (MS) was carried out at an electron energy of 70 eV in the chemical ionization mode with direct injection of the sample; only mass spectra corresponding to undissociated molecules are given.

Example 1. 9- (3-Cyanophenyl) -3,4,6,7,9,10-hexahydro-1,8- (2H, 5H) -acridinedione
A mixed mixture of 3-cyanobenzaldehyde (1.48 g), 1,3-cyclohexanedione (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 was collected and dried in vacuo to give the desired acridione (3.22 g); so pl. 285-288 ^o C; NMR: 1.80-1.93 (m, 4); 2.19-2.22 (m, 4); 2.50-2.54 (m, 4); 4.91 (s, 1); 7.37-7.42 (m, 1); 7.48-7.54 (m, 3); 9.55 (s, 1);
MS: m / z 319 (M + 1).

Elemental analysis for C ₂₀ H ₁₈ N ₂ O ₂ :
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) -acridinedione
To a mixed mixture of 3-amino-2-cyclo-gen-1-one (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 resulting solid was filtered, washed thoroughly with water and then ethanol. After drying under conditions at 50 C / 0, 2 mm Hg. received the target compound as a pale yellow solid (3.89 g), so pl. - 303-7 ^o C (decomp.).

MS: (C1, CH ₄ ) 319 (M + 1).

Elemental analysis for C ₂₀ H ₁₈ N ₂ O ₂ :
Calculated: C75.44; H5.71; N 8.80.

 Found: C75.42; H5.70; N8.66.

 The NMR spectrum is identical to the spectrum of the product of example 1.

Example 3.9- (3-Cyanophenyl)) - 3,4,6,7,9,10-hexahydro-1,8- (2H, 5H) -acridinedione
A mixed solution of thionyl chloride (2.86 g) in 24 ml of methylene chloride in the presence of nitrogen was cooled in an ice bath at -10 ^° C and treated with a solution of pyridine (1.90 g) in 12 ml of methylene chloride in a weak stream. Then a solution of 3-cyanobenzaldehyde (2.62 g) in 10 ml of methylene chloride was added as a weak stream, and the mixture was stirred in an ice bath from -10 ^° C to 0 ^° C for 1 hour. Then, one part of 3-amino-2-cyclohexen-1-one (6.67 g) was added and washed in 10 ml of methylene chloride. After stirring methylene chloride overnight at ambient temperature, the solvent was removed in vacuo and the resulting orange solid was triturated with water. The solids were collected by suction filtration, washed thoroughly with water and then ethanol, and dried in vacuo at 60 ^° C / 0.2 mm Hg, whereby the desired compound (3.86 g) was obtained as a pale yellow solid ; so pl. 302-305 ^o C (decomp.).

MS (Cl, CH ₄ ): 319 (M + 1). The NMR spectrum is identical to the spectrum of the product of example 1.

 Example 4

The following are the most typical dosage forms containing compounds intended for administration to humans for therapeutic or prophylactic purposes:
(a) Tablet (mg / tablet)
Compound 50.0
Mannitol, Farm. USA 223.75
Croscarmellose sodium 6.0
Corn Starch 15.0
Hydroxypropyl methylcellulose (HPMC), Pharm. US 2.25
Magnesium Stearate 3.0
(b) Capsule (mg / tablet)
Compound 10.0
Mannitol, Farm. US 488.5
Croscarmellose sodium 15.0
Magnesium Stearate 1.5
The above preparations can be obtained by standard methods well known in the art. These tablets may be enteric coated by standard methods, for example a cellulose acetate phthalate coating.

Claims (4)

1. The derivative of 1,8-acridinedione of the formula I

2. A pharmaceutical composition for bladder relaxation, including dihydropyridine derivatives, characterized in that it contains an effective amount of a compound according to claim 1.  3. A substance that relaxes the bladder, characterized in that it is a derivative of 1,8-acridinedione of the formula I, described in claim 1.  4. The method of obtaining the compounds of formula I according to claim 1, characterized in that 3-cyanobenzaldehyde is reacted with an ammonium salt and 1,3-cyclohexane dione.  5. The method of obtaining the compounds of formula I according to claim 1, characterized in that 3-amino-2-cyclohexene-1-OH is reacted with 3-cyanobenzaldehyde or a reactive derivative thereof.