WO2009071906A1

WO2009071906A1 - Derivatives of 1-[(imidazolidin-2-yl)imino)]indazole

Info

Publication number: WO2009071906A1
Application number: PCT/GB2008/004024
Authority: WO
Inventors: Franciszek Saczewski; Apolonia Rybczynska; Anita Kornicka; Jaroslaw Saczewski; Daqing Ma; Mervyn Maze
Original assignee: Imperial Innovations Limited; Medical University Of Gdansk
Priority date: 2007-12-05
Filing date: 2008-12-05
Publication date: 2009-06-11
Also published as: PL212581B1; PL383955A1; EP2227464A1

Abstract

The invention provides a compound of formula (I) wherein R1 denotes hydrogen, methyl or phenyl; R2, R3, R4 and R5 denote hydrogen, halogen, preferably a chlorine atom, alkyl, preferably methyl, alkoxyl, preferably methoxyl; m denotes a number 0 or 1; and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, p-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride. The use of the compounds as α2-adrenergic receptor agonists is also provided.

Description

Derivatives of l-[(imidazolidin-2-yl)imino)]indazole

The invention relates to novel derivatives of l-[(imidazolidin-2-yl)imino)]indazole and their use as highly selective agonists of α₂/Ii receptors. The compounds find use as antihypertensive agents. In addition, they have also been found to have sedative and cytoprotective activity and can be co-administered with drugs such as benzodiazepines allowing lower dosages of the latter to be used to obtain their effect.

©^-Adrenoceptors are widely expressed in many tissue types and mediate a multitude of functions in both peripheral organs and within the central nervous system, and the α₂- adrenoceptor agonists represent a unique class of compounds due to a wide range of medicinal uses reported in the literature.^1"5 For example, activation of central α₂- adrenoceptors in the brain stem has been utilized clinically for many years in the treatment of hypertension.²'³ However, this original explanation has later been challenged by a concurrent 'imidazoline hypothesis' which assumes the existence of the imidazoline receptors and attributes the sympathoinhibition to activation of Ij imidazoline receptors in the medulla oblongata.^6"10

Nevertheless, due to some degree of similarity between the two receptor classes and the fact that most α₂-adrenoceptor agonists, including prototypical clonidine, also have comparable affinity for Ij imidazoline receptors, it is still difficult to dissociate imidazoline receptors from α₂-adrenoceptors both pharmacologically and functionally. Moreover, α₂-adrenoceptors and imidazoline receptors usually co-localize in the central nervous system which raises a question as to whether a link between these two types might exist. In this context, a comprehensive review by Szabo should be mentioned,¹¹ in which a critical analysis of the above hypotheses led the author to a conclusion that the sympathoinhibitory effects of clonidine-like drugs are best explained by activation of ^-adrenoceptors. On the other hand, Bousquet pointed out that it is possible to produce a hypotensive effect by activating either α₂-adrenoceptors or imidazoline receptors within the central nervous system, and a potentiating interaction exists between these two receptor classes.¹² Whether the mechanism of this interaction involves molecular receptor-receptor interference on the ventral medullary cardiovascular neurons or an interaction between receptors located on different neuronal structures but with effects converging to inhibit the vasomotor tone remains to be demonstrated. To achieve this goal, however, new compounds with imidazoline structure and a very high selectivity for α₂-adrenoceptors vis a vis imidazoline Ii receptors will be required.

Currently, a growing interest in the field of developing highly selective 01₂-adrenoceptor agonists has been stimulated by their potential applications as analgesic, sedative, anxiolytic, hemodynamic-stabilizing and organ-protective agents.¹³'¹⁴ Prominent examples of such compounds include imidazole-containing dexmedetomidine ^15>1 and spirooxazoline derivative S18616.¹⁷ Mivazerol is an example of the imidazole derivative designed for the prevention of myocardial infraction in perioperative patients,¹⁸'¹⁹ while spiroimidazoline S19014 has been assessed as anti-migraine agent.^20'22 Other effects of clonidine-like agents on central noradrenergic transmitter and modulator functions which are not related to hypertension include the stimulation of human growth hormone and decreasing the output of nearly all secretory glands, such as lacrimal, salivary, gastric secretory and sweat glands.²³

Derivatives of 4-(2-imidazolin-2-ylamino)-lH-indazole are known in the art (for example Swiss patent No. 579076, German patent No. 2416024, US patent No. 4036976), derivatives of 6-(imidazolin-2-ylamino)indazole (US patent No. 4436913), derivatives of 6-(imidazolin- 2-ylamino)indazole (patent WO 98/23609) and derivatives of 7-(imidazolin-2- ylamino)indazole (German patent No. 2258318). These compounds are characterized by antihypertensive activity. Derivatives of 6-(imidazolin-2-ylamino)indazole, which are α₂- adrenergic receptor agonists, are also known from WO 98/23609.

We have now synthesised new derivatives of l-[(imidazolidin-2-yl)imino)]indazole, which have particular advantages in terms of their selectivity and also have been shown to have additional properties which make them useful in a range of clinical situiations.

Thus, in a first aspect the present invention provides l-[(imidazolidin-2-yl)imino)]indazole compounds of the formula I:

I wherein R¹ denotes hydrogen, methyl or phenyl;

R², R³, R⁴ and R⁵ denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl; m isO or 1 ; and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, /Moluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.

A particularly preferred compound of formula I is one wherein R¹, R², R³, R⁴ and R⁵ denote hydrogen, the letter m is the number 1 , and HX denotes hydrogen chloride, which is characterized by high affinity for a₂-adrenergic receptors (Kj = 19.4 nM), and when administered intravenously to rats at a dose of 0.1 mg/ kg it lowers arterial blood pressure by 31.99 ± 3.72 mmHg after 35 min. In its turn, a derivative of general formula I, in which R¹, R², R³ and R⁴ denote hydrogen, R⁵ denotes methyl, the letter m is the number 1 and HX denotes hydrogen chloride was characterized by potent hypotensive and diuretic action.

In addition, intermediate compounds of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole of general formula II:

II

wherein R¹ denotes hydrogen, methyl or phenyl; and

R², R³, R⁴ and R⁵ denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl, represent a second aspect of the invention.

A method for the preparation of compounds of formula I is also provided in which a compound of formula III:

III

in which R¹ denotes hydrogen, methyl or phenyl; and

R², R³, R⁴ and R⁵ denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl is reacted with N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione in an environment of anhydrous dimethylformamide in the presence of triethylamine and mercury chloride.

Following addition of ethyl acetate, the precipitate of inorganic salts is filtered and the filtrate is washed with a saturated aqueous solution of sodium chloride and after drying the organic fraction over MgSO₄ the ethyl acetate is distilled off under reduced pressure, whereas the oily, relatively dry residue is separated on silica gel.

The product obtained, being a derivative of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole of general formula II, is reacted with 50% solution of trifluoroacetic acid in methylene chloride, after which the methylene chloride and excess trifluoroacetic acid are distilled off under reduced pressure, whereas water is added to the oily, relatively dry residue, and a product that is a derivative of general formula I, wherein m is 0, is isolated from this solution or mixture by precipitation with 10% aqueous NaOH solution, and is transformed to the corresponding salt of general formula I, in which R¹, R², R³, R⁴, R⁵ have the meaning defined above, the letter m is the number 1 , and HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, p-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.

In an alternative method, compounds of formula I can be prepared by reacting corresponding 1-aminoindazoles with tert-butyl 2-(methylthio)-4,5-dihydroimidazole-l-carboxylate using a slightly modified procedure described previously for the synthesis of guanidine derivatives ( S. R. Mundla, L. J. Wilson, S. R. Klopfenstein, W. L. Seibel, N. N. Nikolaides; A novel method for the efficient synthesis of 2-arylamino-2-imidazolines; Tetrahedron Lett., 2000, 41, 6563). According to our procedure, the nucleophilic substitution of the methylthio group with 1-aminoazole is accompained by deprotection of the imidazoline nitrogen atom, i.e. the synthesis of l-[(imidazolidin-2-yl)imino]indazole is accomplished in one step"

In a fourth aspect, the present invention provides a compound of formula I as defined herein for use in medicine. In a further aspect the present invention provides a pharmaceutical formulation comprising at least one compound of formula I or as defined herein and optionally one or more excipients, carriers or diluents.

The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-lOOmg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25- 50mg/day 40-80mg/day or 60-100mg/day. For compounds of formula I, doses in the range 100-lOOOmg/day are provided, preferably either 100-400mg/day, 300-600mg/day or 500- lOOOmg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffϊnic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The invention also relates to the use of compounds of formula I, having an effect on α₂- adrenergic receptors and hypotensive and diuretic action, for the production of agents used in the treatment of diseases of the circulatory system, especially arterial hypertension in patients with nephropathy, as well as effects of hypopituitarism, glaucoma, spastic states, dependence on opiates and alcohol, diarrhoea and analgesics.

So far the results of pharmacological investigations in vitro and in vivo of selected compounds of general formula 1, in which R¹, R², R³, R⁴, R⁵ have the meaning defined above, the letter m is the number 1 , and HX denotes hydrogen chloride, showed that as a rule these compounds have high affinity for α₂-adrenergic receptors and hypotensive action, examples of which are shown in Table 1, as well as diuretic action, examples of which are shown in Table 2.

As a result these compounds and their analogues of general formula 1 , acting via the α₂- adrenergic receptors, can find application in medical practice as hypotensive agents, antidiarrheals, analgesics, as well as in therapy of glaucoma, spastic states, effects of hypopituitarism and dependence on opiates and alcohol and as a tool for investigating the function of the α₂-adrenergic receptors. These compounds, owing to the hypotensive and diuretic action, may also find application in the treatment of arterial hypertension in patients with nephropathy.

In addition, the compounds allow the use of sub-therapeutic doses of known sedatives, such as benzodiazepines, eg midazolam. This is particularly advantageous when sedating patients in intensive care situations, in view of the potential for CNS damage when using benzodiazepines as a sedative.

In further aspects the present invention provides: i) a compound of formula I for use as a cytoprotective agent or as a sedative; ii) a pharmaceutical composition comprising at least one compound of formula I and a benzodiazepine .

The invention will now be described with reference to the following examples, which should not be regarded as in any way limiting the invention.

Example I

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.33 g (0.0025 mol) of 1-aminoindazole in 3 cm³ of anhydrous dimethylformamide, after which it is cooled, and 1.0 g HgCl₂ (0.0037 mol) is added at a temperature of 0⁰C. Stirring is continued for 20 minutes at a temperature of 0⁰C and for 5 days at ambient temperature (20-22⁰C), after which 40 cm³ ethyl acetate is added. After stirring for 1 hour, the precipitate of inorganic salts is filtered off and washed with three 10 cm³ portions of ethyl acetate. Then the filtrate is washed with three 20 cm³ portions of saturated aqueous NaCl solution and after drying the organic fraction over MgSO₄, the solvent is distilled off under reduced pressure. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetatexhloroform mixture, 0.1 : 10 (v/v). We obtain, successively, 0.28 g (25%) of unreacted N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.69 g (70%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n-heptane.

We obtained 0.58 g (59%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]- imino}indazole, melting in the range 128-130⁰C. IR_RBΓ spectrum (cm^"1): 2980, 2935, 2900 (CH), 1745, 1715 (C=O), 1630, 1610 (C=N). Analysis: Calculated for C₂₀H₂₇N₅O₄: 17.44% N; Found: 17.32% N.

A solution of 0.8 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole obtained in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride is stirred for 2 hours at ambient temperature (20-22⁰C), after which the excess trifluoroacetic acid and methylene chloride are distilled off under reduced pressure. 7 cm³ water is added to the oily residue, and while stirring, at a temperature of 0-5⁰C, 10% aqueous NaOH solution is added dropwise to pH 10-10.5. The precipitate is filtered off, washed with 2 cm³ water and is dried at a temperature that is gradually raised to 100⁰C. The precipitate obtained is purified by crystallization from 2-propanol.

We obtained 0.24 g (60%) of l-[(imidazolidin-2-yl)imino]indazole, melting in the range 172- 174⁰C. IR_KBΓ spectrum (cm^"1): 3225, 3160 (NH), 3005, 2945, 2855 (CH), 1630, 1610 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 3.01-3.65 (m, 4H, 2xCH₂-imidaz.), 6.48 (s, IH, NH), 6.63 (s, IH, NH), 7.05-7.29 (m, 3H, 3xCH-arom.), 7.55-7.79 (m, IH, CH-arom.), 7.85 (s, IH, H-3) ppm.

7 cm³ of anhydrous methanol is added to 0.2 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]indazole obtained and after cooling, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, while stirring, at a temperature of 0-5⁰C. Stirring is continued for 30 minutes at room temperature (20-22⁰C), after which the methanol is distilled off under reduced pressure from the solution obtained. The dry residue is purified by crystallization from a mixture of anhydrous ethanol and ether (1 :5 v/v).

We obtained 0.18 g (75%) of l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 195-196°C. IR_KBr spectrum (cm^"1): 3275, 3130, 3035, 2980, 2900, 2660 (NH^®, CH), 1650, 1625 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 3.72 (s, 4H, 2xCH₂- imidaz.), 7.25-7.33 (m, IH, CH-arom.), 7.54 (d, J = 4.0 Hz, 2H, 2xCH-arom.), 7.86 (d, J = 8.0 Hz, IH, CH-arom.), 8.25 (s, IH, H-3), 8.97 (s, 2H, 2xNH), 12.59 (s broad, IH, NH^Φ) ppm.

Example II

1.12 g (0.0037 mol) of N,N^'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.42 g (0.0025 mol) of l-amino-4-chloroindazole in 3 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0⁰C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 :2 (v/v).

We obtained, successively, 0.22 g (20%) of unreacted N,N'-di(tert-butoxycarbony l)imidazolidine-2-thione and 0.6 g (55%) of raw 4-chloro-l-{[l,3-di(tert-butoxy carbonyl)imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n- heptane.

We obtained 0.39 g (36%) of 4-chloro-l-{[l,3-di(teit-butoxycarbonyl)imidazolidin-2- yl]imino}indazole, melting in the range 122-125°C. IR_KBΓ spectrum (cm^"1): 2975, 2930, 2910 (CH), 1745, 1710 (C=O), 1640, 1605 (C=N). Analysis: Calculated for C₂₀H₂₆ClN₅O₄: 16.06% N; Found: 16.32% N.

A solution of 0.87 g (0.002 mol) of the 4-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}indazole obtained in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride is stirred for 2 hours at room temperature (20-22⁰C), after which the excess trifluoroacetic acid and methylene chloride are distilled off under reduced pressure. 10 cm³ water is added to the oily residue and, after cooling, while stirring at a temperature of 0-5°C, 10% aqueous NaOH solution is added dropwise to pH 10-10.5. The precipitate is filtered off, washed with 2 cm³ water and, after drying, is purified by crystallization from acetonitrile.

We obtained 0.36 g (76%) of 4-chloro-l-[(imidazolidin-2-yl)imino]indazole, melting in the range 194-196°C. IR_KBr spectrum (cm^"1): 3230, 3175 (NH), 3005, 2945, 2875 (CH), 1625, 1610 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 3.37 (s, 4H, 2xCH₂-imidaz.), 6.47 (s, IH, NH), 6.74 (s, IH, NH), 7.12 (d, J = 6.3 Hz, IH, H-7), 7.21-7.33 (m, 2H, H-5 and H-6), 7.91 (s, IH, H-3) ppm.

7 cm³ of anhydrous methanol is added to 0.24 g (0.001 mol) of the 4-chloro-l-[(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example I.

We obtained 0.18 g (69%) of 4-chloro-l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 215-217⁰C. IR_KBΓ spectrum (cm^"1): 3140, 3060, 2675 (NH^®, CH), 1640, 1610 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 3.72 (s, 4H, 2xCH₂-imidaz.), 7.38 (d, J = 6.8 Hz, IH, H-7), 7.53-7.55 (m, 2H, H-5 and H-6), 8.33 (s, IH, H-3), 8.94 (s, 2H, 2xNH), 12.73 (s broad, IH, NH^®) ppm. Example HI

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g of triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.42 g (0.0025 mol) of l-amino-5-chloroindazole in 3 cm³ of anhydrous dimethylformamide, after which it is cooled and 1.0 g HgCl₂ (0.0037 mol) is added at a temperature of 0°C, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 :2 (v/v).

We obtained, successively, 0.28 g (25%) of unreacted N,N'-di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.81 g (74%) of raw 5-chloro-l-{[l,3-di(tert-butoxycarbonyl) imidazolidin-2-yl]imino}indazole, which is purified by crystallization from n-heptane.

We obtained 0.5 g (46%) of 5-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yl]imino}indazole, melting in the range 176-177°C. IR_KBr spectrum (cm^"1): 2980, 2920, 2910 (CH), 1735, 1710 (C=O), 1630 (C=N). Analysis: Calculated for C₂₀H₂₆ClN₅O₄: 16.06% N; Found: 16.11% N.

0.87 g (0.002 mol) of the 5-chloro-l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2- yyll]]iimmiinnoo}}iinnddaazzoollee oobbttaaiinneedd iiss ddiissssoollvveedd iinn 88 ccmm³³ ooff 5500^% solution of trifluoroacetic acid, after which the same procedure is followed as in Example II.

We obtained 0.3 g (64%) of 5-chloro-l-[(imidazolidin-2-yl)imino]indazole, melting in the range 159-160⁰C. IR_RBΓ spectrum (cm^'1): 3230, 3175 (NH), 2990, 2895 (CH), 1630 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 3.37 (s, 4H, 2xCH₂-imidaz.), 6.48 (s, IH, NH), 6.69 (s, IH, NH), 7.24 (d, J = 8.8 Hz, IH, H-7), 7.34 (d, J = 8.8 Hz, IH, H-6), 7.76 (s, IH, H- 4), 7.86 (s, IH, H-3) ppm. ¹³C NMR spectrum (125 MHz, DMSO-d₆): δ = 42.3, 43.5 (C-4 and C-5-imidaz.), 112.3, 120.2, 122.8, 124.9, 126.2, 127.9 (6C-arom.), 135.1 (C-3), 164.9 (C-2- imidaz.) ppm.

7 cm³ of anhydrous methanol is added to 0.24 g (0.001 mol) of the 5-chloro-l-[(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example I. The dry residue obtained is purified by crystallization from acetonitrile.

We obtained 0.15 g (57%) of 5-chloro-l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 181-182°C. IR_KBΓ spectrum (cm^"1): 3175, 3055, 2880, 2650 (NH^®, CH), 1640, 1615 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 3.71 (s, 4H, 2xCH₂- imidaz.), 7.54 (d, J = 8.8 Hz, IH, H-7), 7.60 (d, J = 8.8 Hz, IH, H-6), 7.97 (s, IH, H-4), 8.23 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.72 (s broad, IH, NH^®) ppm.

Example IV

1.12 g (0.0037 mol) of N,N-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-3-methylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).

We obtained, successively, 0.20 g (18%) of unreacted N,N'-di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.74 g (71%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-3-methylindazole, which is purified by crystallization from n-heptane.

We obtained 0.51 g (49%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- methylindazole, melting in the range 55-59°C. IR_KBΓ spectrum (cm^"1): 2980, 2940, 2880 (CH), 1750, 1720 (C=O), 1655, 1615 (C=N). Analysis: Calculated for C₂₁H₂₉N₅O₄: 16.85% N; Found: 16.52% N.

0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- methylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II. We obtained 0.21 g (50%) of l-[(imidazolidin-2-yl)imino]-3-methylindazole, melting in the range 157-159°C. IR_KBΓ spectrum (cm^"1): 3220, 3195 (NH), 3050, 2895 (CH), 1635, 1605 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 2.48 (s, 3H, CH₃-3), 3.38 (s, 4H, 2xCH₂-imidaz.), 6.48 (s, IH, NH), 6.59 (s, IH, NH), 6.92-7.05 (m, IH, CH-arom.), 7.19-7.35 (m, 2H, 2xCH-arom.), 7.55-7.70 (m, IH, CH-arom.) ppm. ¹³C NMR spectrum (50 MHz, DMSOd₆): δ = 12.0 (CH₃-3), 41.9, 43.0 (C-4 and C-5-imidaz.), 109.9, 119.1, 120.0, 120.7, 125.4, 135.7 (6C-arom.), 137.1 (C-3), 164.0 (C-2-imidaz.) ppm.

7 cm³ of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-3-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in

We obtained 0.14 g (60%) of l-[(imidazolidin-2-yl)imino]-3-methylindazole hydrochloride, melting in the range 193-195°C. IR_RBΓ spectrum (cm^"1): 3140, 2920, 2620 (NH^®, CH), 1655, 1615 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 2.52 (s, 3H, CH₃-3), 3.74 (s, 4H, 2xCH₂-imidaz.), 7.25-7.33 (m, IH, CH-arom.), 7.46-7.58 (m, 2H, 2xCH-arom.), 7.82-7.86 (m, IH, CH-arom.), 8.95 (s, 2H, 2xNH), 12.38 (s broad, IH, NH^®) ppm.

Example V

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-4-methylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of O⁰C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).

We obtained, successively, 0.22 g (20%) of unreacted N₅N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.90 g (87%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-4-methylindazole, which is purified by crystallization from a mixture of ethyl acetate and n-heptane (1: 10 v/v). We obtained 0.54 g (52%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methylindazole, melting in the range 133-135°C. IR_KBΓ spectrum (cm^"1): 2975, 2930, 2895 (CH), 1745, 1715 (C=O), 1680, 1605 (C=N). Analysis: Calculated for C₂₁H₂₉N₅O₄: 16.85% N; Found: 16.89% N.

0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.24 g (56%) of l-[(imidazolidin-2-yl)imino]-4-methylindazole, melting in the range 159-162°C. IR_KBr spectrum (cm^"1): 3190, 3120 (NH), 3010, 2945, 2920, 2875 (CH), 1630, 1610 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 2.52 (s, 3H, CH₃-4), 3.37 (s, 4H, 2xCH₂-imidaz.), 6.46 (s, IH, NH), 6.63 (s, IH, NH), 6.75-6.89 (m, IH, CH-arom.), 7.02-7.25 (m, 2H, 2xCH-arom.), 7.90 (s, IH, H-3) ppm. ¹³C NMR spectrum (50 MHz, DMSO-d₆): δ = 18.3 (CH₃-4), 41.8, 43.1 (C-4 and C-5-imidaz.), 107.7, 119.8, 122.2, 125.5, 126.7, 130.4 (6C-arom.), 135.9 (C-3), 163.9 (C-2-imidaz.) ppm.

7 cm³ of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-4-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example I.

We obtained 0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-4-methylindazole hydrochloride, melting in the range 194-196°C. IR_KBΓ spectrum (cm^"1): 3125, 3005, 2910, 2860, 2610 (NH^®, CH), 1645, 1615 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 2.59 (s, 3H, CH₃-4), 3.72 (s, 4H, 2xCH₂-imidaz.), 7.07 (d, J = 6.8 Hz, IH, H-5), 7.33 (d, J = 8.3 Hz, IH, H-7), 7.41 (dd, J = 6.8 Hz, J = 8.3 Hz, IH, H-6), 8.32 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.59 (s broad, IH, NH^®) ppm.

Example VI

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-5-methylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of O⁰C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).

We obtained, successively, 0.20 g (18%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.70 g (67%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-5-methylindazole, which is purified by crystallization from n-heptane.

We obtained 0.46 g (44%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-5- methylindazole, melting in the range 164-166°C. IR_KBΓ spectrum (cm^"1): 2975, 2930, 2890 (CH), 1725, 1690 (C=O), 1660, 1620 (C=N). Analysis: Calculated for C₂₁H₂₉N₅O₄: 16.85% N; Found: 16.63% N.

0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-5- methylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.24 g (56%) of l-[(imidazolidin-2-yl)imino]-5-methylindazole, melting in the range 175-177⁰C. IR_KBΓ spectrum (cm^'1): 3215, 3160 (NH), 3005, 2860 (CH), 1620 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 2.37 (s, 3H, CH₃-5), 3.36 (s, 4H, 2xCH₂-imidaz.), 6.47 (s, IH, NH), 6.60 (s, IH, NH), 7.09 (d, J = 8.7 Hz, IH, H-6), 7.24 (d, J = 8.7 Hz, IH, H- 7), 7.42 (s, IH, H-4), 7.74 (s, IH, H-3) ppm. ¹³C NMR spectrum (50 MHz, DMSO-d₆): δ = 21.0 (CH₃-5), 41.6, 42.8 (C-4 and C-5-imidaz.), 109.7, 119.2, 121.7, 126.6, 127.2, 128.5 (6C- arom.), 134.7 (C-3), 163.5 (C-2-imidaz.) ppm.

7 cm³ of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-5-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example I. We obtained 0.14 g (58%) of l-[(imidazolidin-2-yl)imino]-5-methylindazole hydrochloride, melting in the range 180-183°C. IR_KBr spectrum (cm^"1): 3165, 3095, 3010, 2950, 2750, 2625 (NH^®, CH), 1660, 1635 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 2.42 (s, 3H, CHs-5), 3.71 (s, 4H, 2xCH₂-imidaz.), 7.33-7.45 (m, 2H, H-6 and H-7), 7.61 (s, IH, H-4), 8.14 (s, IH, H-3), 8.92 (s, 2H, 2xNH), 12.45 (s broad, IH, NH^®) ppm.

Example VII

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-6-methylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).

We obtained, successively, 0.19 g (17%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.58 g (56%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-6-methylindazole, which is purified by crystallization from n-heptane.

We obtained 0.4 g (38%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methylindazole, melting in the range 129-131°C. IR_KBr spectrum (cm^'1): 3000, 2975, 2930 (CH), 1745, 1710 (C=O), 1655, 1620 (C=N). Analysis: Calculated for C₂₁H₂₉N₅O₄: 16.85% N; Found: 16.82% N.

0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.29 g (67%) of l-[(imidazolidin-2-yl)imino]-6-methylindazole, melting in the range 216-219⁰C. IR_KBr spectrum (cm^'1): 3245, 3150 (NH), 2980, 2945, 2885 (CH), 1635 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 2.40 (s, 3H, CH₃-6), 3.36 (s, 4H, 2xCH₂-imidaz.), 6.40 (s, IH, NH), 6.58 (s, IH, NH), 6.84-6.89 (m, IH, H-5), 7.10 (s, IH, H- 7), 7.54 (d, J = 8.4 Hz, IH, H-4), 7.77 (s, IH, H-3) ppm. 7 cm³ of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-6-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/ 100 cm³ is added dropwise, after which the same procedure is followed as in We obtain 0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-6-methylindazole hydrochloride, melting in the range 197-199°C. IR_KBr spectrum (cm^"1): 3245, 3075, 2980, 2910, 2700 (NH^®, CH), 1635, 1620 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 2.45 (s, 3H, CH₃-6), 3.66 (s, 4H, 2xCH₂-imidaz.), 7.08 (d, J = 8.4 Hz, IH, H-5), 7.29 (s, IH, H-7), 7.69 (d, J = 8.4 Hz, IH, H-4), 8.10 (s, IH, H-3), 8.56 (s, 2H, 2xNH), 12.31 (s broad, IH, NH^Θ) ppm.

Example VIII

1.12 g (0.0037 mol) of N,N^'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.37 g (0.0025 mol) of l-amino-7-methylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl₂ (0.0037 mol) is added. Stirring is continued for 20 minutes at a temperature of 0⁰C and for 3 days at ambient temperature (20- 22°C), after which it is heated for 6 hours at a temperature of 65°C. After cooling to room temperature, 40 cm ethyl acetate is added to the mixture, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 3 (v/v).

We obtained, successively, 0.28 g (25%) of unreacted N,N'-di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.37 g (36%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-7-methylindazole, which is purified by crystallization from n-heptane.

We obtained 0.25 g (24%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-7- methylindazole, melting in the range 160-162°C. IR_KBΓ spectrum (cm^"1): 3000, 2980, 2930, 2900 (CH), 1715 (C=O), 1650 (C=N). Analysis: Calculated for C₂iH₂₉N₅O₄: 16.85% N; Found: 16.61% N.

0.83 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-7- methylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.3 g (70%) of l-[(imidazolidin-2-yl)imino]-7-methylindazole, melting in the range 201-204⁰C. IR (cm^"1): 3210, 3170 (NH), 3060, 2950, 2870 (CH), 1635 (C=N). ¹H NMR spectrum (500 MHz, DMSOd₆): δ = 2.61 (s, 3H, CH₃-7), 3.36-3.40 (m, 4H, 2xCH₂-imidaz.), 6.20 (s, IH, NH), 6.62 (s, IH, NH), 6.88-6.96 (m, 2H, H-5, H-6), 7.47 (d, J = 7.8 Hz, IH, H- 4), 7.80 (s, lH, H-3) ppm.

7 cm³ of anhydrous methanol is added to 0.21 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-7-methylindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example I.

0.15 g (63%) of l-[(imidazolidin-2-yl)imino]-7-methylindazole hydrochloride is obtained at a temperature of 189-190⁰C. IR_KBr spectrum (cnT¹): 3240, 3070, 2975, 2915, 2710 (NH^®, CH), 1645, 1625 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 2.55 (s, 3H, CH₃-7), 3.74 (s, 4H, 2xCH₂-imidaz.), 7.12-7.29 (m, 2H, H-5, H-6), 7.66 (d, J = 7.7 Hz, IH, H-4), 8.21 (s, IH, H-3), 8.97 (s, 2H, 2xNH), 12.78 (s broad, IH, NH^®) ppm.

Example IX

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.41 g (0.0025 mol) of l-amino-4-methoxyindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0⁰C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The dry residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1:2 (v/v).

We obtained, successively, 0.22 g (20%) of unreacted N,N -di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.81 g (75%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-4-methoxyindazole, which is purified by crystallization from n-heptane.

We obtained 0.56 g (51%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methoxyindazole, melting in the range 132-134°C. IR_KBr spectrum (cm^"1): 3000, 2970, 2930, 2885 (CH), 1715, 1705 (C-O), 1650, 1615 (C=N). Analysis: Calculated for C₂₁H₂₉N₅O₅: 16.23% N; Found: 15.94% N.

0.86 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-4- methoxyindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.28 g (61%) of l-[(imidazolidin-2-yl)imino]-4-methoxyindazole, melting in the range 170-172⁰C. IR_KBΓ spectrum (cm^"1): 3320, 3250, 3150 (NH), 2990, 2890 (CH), 1635, 1610 (C=N). ¹H NMR spectrum (500 MHz, DMSO-d₆): δ = 3.37 (s, 4H, 2xCH₂-imidaz.), 3.91 (s, 3H, CH₃O-4), 6.45 (s, IH, NH), 6.48 (d, J = 7.3 Hz, IH, 5-H), 6.64 (s, IH, NH), 6.91 (d, J = 8.3 Hz, IH, U-T), 7.16-7.19 (m, IH, H-6), 7.82 (s, IH, H-3) ppm. ¹³C NMR spectrum (125 MHz, DMSO-d₆): δ = 42.3, 43.5 (C-4, C-5-imidaz.), 55.9 (CH₃O-4), 99.6, 103.5, 113.9, 125.8, 127.0, 138.2 (6C-arom.), 153.5 (C-3), 164.5 (C-2-imidaz.) ppm.

7 cm³ of anhydrous methanol is added to 0.23 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-4-methoxyindazole obtained and after cooling, while stirring at a temperature of 0- 5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm is added dropwise, after which the same procedure is followed as in Example I.

We obtained 0.16 g (59%) of l-[(imidazolidin-2-yl)imino]-4-methoxyindazole hydrochloride, melting in the range 202-204⁰C. IR_KBr spectrum (cm^"1): 3285, 3080, 3005, 2690, 2560 (NH^®, CH), 1645, 1610 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 3.72 (s, 4H, 2xCH₂- imidaz.), 3.96 (s, 3H, CH₃O-4), 6.75 (d, J = 7.9 Hz, IH, H-5), 7.07 (d, J = 8.1 Hz, IH, H-7), 7.45 (t, IH, H-6), 8.20 (s, IH, H-3), 8.94 (s, 2H, 2xNH), 12.59 (s broad, IH, NH^®) ppm.

Example X 1.12 g (0.0037 mol) of N,N'-di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.41 g (0.0025 mol) of l-amino-6-methoxyindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The dry residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1:2 (v/v).

We obtained, successively, 0.24 g (21%) of unreacted N,N -di(tert-butoxycarbonyl) imidazolidine-2-thione and 0.79 g (73%) of raw l-{[l,3-di(tert-butoxycarbonyl)imidazolidin- 2-yl]imino}-6-methoxyindazole, which is purified by crystallization from ethyl acetate.

We obtained 0.6 g (55%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methoxyindazole, melting in the range 178-179°C. IR_KBΓ spectrum (cm^"1): 2995, 2975, 2930, 2890 (CH), 1715, 1705 (C=O), 1680, 1625 (C=N). Analysis: Calculated for C₂iH₂₉N₅O₅: 16.23% N; Found: 16.21% N.

0.86 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-6- methoxyindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II.

We obtained 0.33 g (72%) of l-[(imidazolidin-2-yl)imino]-6-methoxyindazole, melting in the range 178-18O⁰C. IR_KBr spectrum (cπT¹): 3295, 3215 (NH), 2965, 2865 (CH), 1635, 1605 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 3.41 (s, 4H, 2xCH₂-imidaz.), 3.81 (s, 3H, CH₃O-6), 6.55 (s, IH, NH), 6.61 (s, IH, NH), 6.69-6.72 (m, 2H, H-5, U-T), 7.56 (d, J = 9.2 Hz, IH, H-4), 7.78 (s, IH, H-3) ppm.

7 cm³ of anhydrous methanol is added to 0.23 g (0.001 mol) of the l-[(imidazolidin-2- yl)imino]-6-methoxyindazole obtained and after cooling, while stirring at a temperature of 0-

5°C, 0.78 cm³ (0.0012 mol) of methanolic solution of hydrogen chloride of density

5.67 g/100 cm³ is added dropwise, after which the same procedure is followed as in Example

I.

We obtained 0.17 g (63%) of l-[(imidazolidin-2-yl)imino]-6-methoxyindazole hydrochloride, melting in the range 193-195°C. IR_KBr spectrum (cm^'1): 3175, 3080, 2970, 2900, 2780, 2750 (NH^®, CH), 1645, 1625 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 3.73 (s, 4H, 2xCH₂-imidaz.), 3.85 (s, 3H, CH₃O-6), 6.89 (dd, J = 8.7 Hz, J = 2.1 Hz, IH, H-5), 6.99 (s, IH, H-7), 7.70 (d, J = 8.7 Hz, IH, H-4), 8.11 (s, IH, H-3), 8.93 (s, 2H, 2xNH), 12.43 (s broad, IH, NH^®) ppm.

Example XI

1.12 g (0.0037 mol) of N,N -di(tert-butoxycarbonyl)imidazolidine-2-thione and 0.88 g triethylamine (1.21 cm³, 0.0087 mol) are added, while stirring, to a solution of 0.52 g (0.0025 mol) of l-amino-3-phenylindazole in 5 cm³ of anhydrous dimethylformamide, after which it is cooled and, at a temperature of 0°C, 1.0 g HgCl₂ (0.0037 mol) is added, then continuing as in Example I. The oily residue is separated on silica gel (MN-kieselgel 60, 0.04-0.063 mm) in ethyl acetate: chloroform mixture, 0.1 : 7 (v/v).

We obtained, successively, 0.22 g (20%) of unreacted N,N -di(tert- butoxycarbonyl)imidazolidine-2-thione and 0.85 g (71%) of raw l-{[l,3-di(tert- butoxycarbonyl)imidazolidin-2-yl]imino}-3-phenylindazole, which is purified by crystallization from n-heptane.

We obtained 0.6 g (50%) of l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- phenylindazole, melting in the range 66-69⁰C. IR_KBr spectrum (cm^"1): 2980, 2935, 2895 (CH), 1750, 1720 (C=O), 1650, 1615 (C=N). Analysis: Calculated for C₂₆H₃ ,N₅O₄: 14.66% N; Found: 14.32% N.

0.96 g (0.002 mol) of the l-{[l,3-di(tert-butoxycarbonyl)imidazolidin-2-yl]imino}-3- phenylindazole obtained is dissolved in 8 cm³ of 50% solution of trifluoroacetic acid in methylene chloride, after which the same procedure is followed as in Example II. The precipitate is filtered off, washed with 2 cm³ water and is purified by crystallization from ethanol.

We obtained 0.34 g (61%) 3 -phenyl- l-[(imidazolidin-2-yl)imino]indazole, melting in the range 188-190⁰C. IR_KBΓ spectrum (cm^'1): 3405, 3210 (NH), 3060, 2980, 2955, 2890 (CH), 1650, 1605 (C=N). ¹H NMR spectrum (200 MHz, DMSO-d₆): δ = 3.43 (s, 4H, 2xCH₂- imidaz.), 6.69 (s, IH, NH), 6.74 (s, IH, NH), 7.14-7.21 (m, IH, CH-arom.), 7.31-7.55 (m, 5H, Ph), 8.0-8.07 (m, 3H, 3xCH-arom.) ppm.

7 cm³ of anhydrous methanol is added to 0.28 g (0.001 mol) of the 3 -phenyl- 1- [(imidazolidin- 2-yl)imino]indazole obtained and after cooling, while stirring at a temperature of 0-5°C,

1 "X

0.78 cm (0.0012 mol) of methanolic solution of hydrogen chloride of density 5.67 g/100 cm is added dropwise, after which the same procedure is followed as in Example I. The dry residue obtained is purified by crystallization from a mixture of anhydrous ethanol and ether

(1:7 v/v).

We obtained 0.18 g (56%) of 3 -phenyl- l-[(imidazolidin-2-yl)imino]indazole hydrochloride, melting in the range 218-221°C. IR_KBΓ spectrum (cm^'1): 3265, 3115, 3000, 2910, 2805, 2775 (NH^®, CH), 1645, 1615 (C=N). ¹H NMR spectrum (200 MHz, DMSOd₆): δ = 3.77 (s, 4H, 2xCH₂-imidaz.), 7.37-7.47 (m, IH, CH-arom.), 7.51-7.63 (m, 5H, Ph), 8.0-8.04 (m, 2H, 2xCH-arom.), 8.18-8.22 (m, IH, CH-arom.), 9.08 (s, 2H, 2xNH), 12.64 (s broad, IH, NH^®) ppm.

Example XII: Preparation of l-[(Imidazolidin-2-yl)imino]indazole

A solution of 1-aminoindazole (0.62 g, 4.6 mmol) and tert-butyl 2-(methylthio)-4,5- dihydroimidazole-1-carboxylate (1.1 g, 5.1 mmol) in acetic acid (2 mL) was stirred at 60-62 ⁰C (oil bath) for 15 hours. Then the solvent was evaporated under reduced pressure. The viscous residue was treated with water (5 mL) and the resulting suspension was made alkaline with 15% aqueous Na₂CO₃ solution (pH 9) and extracted with dichloromethane (3 x 15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtrated and evaporated. The viscous residue was treated with diethyl ether (10 mL) and the solid product thus obtained was filtered off, washed with diethyl ether (4 x 5 mL) and dried. Yield 0.52 g (55%); mp 171-173 °C ¹H NMR (200 MHz, DMSO-d6) δ = 3.38 (s, 4H, CH2), 6.47 (s, IH, NH), 6.52 (s, IH, NH), 7.01-7.08 (m, IH, CH), 7.22-7.37 (m, 2H, CH), 7.69 (d, J = 8.1 Hz, IH, CH), 7.87 (s, IH, 3-H); IR (KBr) cm⁴ 3225, 3160, 3005, 2945, 2855, 1630, 1610, 1515, 1405, 1285, 1200, 1055, 905, 835, 735. Example XIII

Pharmacology. Radioligand Binding Assays. Ii-Binding Site Assay. Kidneys were obtained post-mortem from male Sprague Dawley rats (250-280 g) and crude P₂ membranes prepared according to methods of Lione et alP [³H]clonidine (3 nM, Perkin Elmer) was bound in the presence of 10 μM rauwolscine to preclude binding to α₂-adrenoceptors, the specific component was defined by 10 μM rilmenidine, under these conditions the site labeled is a model of the central I₁ binding site.⁵⁴ Membrane aliquots (400 μl, 0.2-0.5 mg protein) were incubated with 11 concentrations of the test compound over the range 0.01 μM - 100 mM. Incubations were carried out 50 mM Tris-HCl buffer (pH 7.4) at room temperature for 45 min. Bound ligand and free radioactivity were separated by rapid filtration through pre- soaked (0.5% polyethylamine) glass-fibre filters (Whatman GFB). Trapped ligand was determined by liquid scintillation counting and data analysed by GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, California, USA) to yield IC₅₀ values (the concentration of drug that displaces 50% of specifically bound [³H]clonidine).

α₂- and ^-Binding Site Assays. Crude P₂ brain membranes were prepared as follows. All procedures were carried out at 4 ⁰C unless otherwise stated, rat brains (male Sprague Dawley rats 250-280 g) were taken and homogenised in 10 vols of ice cold buffer (50 mM Tris-HCl, 1 mM MgCl₂ and 320 mM sucrose, pH 7.4). The homogenate was centrifuged (1000xg for 10 min) and the precipitate discarded. The supernatant was centrifuged a second time (32000xg for 20 min) and the supernatant discarded, with the remaining precipitate making up the crude P₂ membrane preparation. This was washed twice in excess buffer (50 mM Tris-HCl, ImM MgCl₂) at room temperature, 30 mL were added, the precipitate re- suspended and centrifuged (32000xg for 20 min). The washed membrane preparations were stored at - 70 °C until use. Prior to use they were thawed and washed (as above) a further two times. Membrane aliquots (400 μl, 0.2-0.3 mg protein) were incubated with 11 concentrations of the test compound over the range 0.01 nM - 100 μM in the presence of the selective I₂ binding site ligand [³H]2BFI⁵⁵ (1 nM) or the α₂-adrenoceptor antagonist [³H]RX821002⁴⁴ (1 nM), to final volume of 500 μl. Non-specific binding was determined using 10 μM BU224⁵⁶, I₂ binding and 10 μM rauwolscine, α₂-adrenoceptor binding. Each incubation was performed in triplicate, at room temperature and allowed to reach equilibrium (45 min). Bound and free radioactivity were separated by rapid filtration through pre-soaked (0.5% polyethyleimine) glass-fibre filters (Whatman GF/B). Filters were then washed twice with 5 mL of ice-cold buffer and membrane bound radioactivity remaining on the filters was determined by liquid scintillation counting. Data were analysed by iterative non-linear regression curve fitting procedures in GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, California, USA). Each experiment was analysed individually and the equilibrium dissociation constant (K,), determined by the method of Cheng and Prusoff⁵⁷ and the resulting values are given as means ±SEM for 3-4 separate experiments.

In Vivo Studies: Mean Arterial Blood Pressure (MAP) and Heart Rate (HR) in Rats.

Male Wistar rats, weighing 200-250 g, were purchased from the Animal House of the Polish Academy of Sciences, Warsaw, Poland. All experiments were approved by the Local Ethical Committee on Animal Experiments. The animals were fed a commercial rodent chow (Labofeed-B, Poland) and tap water, available ad libitum. Rats were anaesthetized by i.p. injection of thiopental (Sandoz, Austria) at the dose 70 mg/kg body weight and maintained under anaesthesia by thiopental supplementation (30 μg/kg/min) during the experiment. The animals were placed on a heated table, and body temperature was maintained between 36 and 37 ⁰C. Tracheostomy was performed in all experimental groups. Catheters were inserted into the carotid artery for pressure and heart rate monitoring, into a jugular vein for infusions, and into the bladder for free diuresis. Blood pressure and heart rate were constantly monitored to the end of experiment.

After all surgical procedures, a 40 min recovery period was allowed to established steady state. During the whole experiment rats were infused with isotonic saline (Fresenius Kabi, Poland) supplemented with thiopental at the rate of 1.2 mL/h.

After 40 min of saline infusion, the tested compound was administrated as 100 μl bolus through venous catheter at dose 0.1 mg/kg. The antagonist of α₂-adrenoceptors (RX821002) was given i.v. at the dose of 5 or 10 μg/kg 5 min. before the tested compound 13k.

Arterial blood pressure and heart rate were monitored directly and sampled continuously at 100 Hz, as we described previously,⁴¹ using Biopac Systems, Inc., Model MP 100 (Goleta, CA, USA). The results of measurements were elaborated with the help of the ACQKnowledge (Goleta, CA, USA) measurement system that is selected, scaled and filtered to remove accidental signal disturbances. The recorded time domain transient data have been presented as a graphs with the help of Excel (Microsoft, USA).

Statistical ANOVAs of mean arterial blood pressure (MAP) and heart rate (HR) were performed for ΔMAP and ΔHR, calculated as the difference in MAP and in HR between sequential measurements and the time of compound application ("time 0") for each group, as we described previously.⁴¹ This allowed for direct comparison of responses to treatment between groups when baselines differed. Data were analyzed by ANOVA with repeated measures, using Statistica StatSoft software (StatSoft, Inc., Tulsa, USA), after test compounds or vehicle treatment. When the effect was significant, post hoc comparisons were performed using Duncan and Fisher tests. A value of/? < 0.05 was considered statistically significant.

Table 1. Affinity for α₂-adrenergic receptors and maximum hypotensive effect of selected compounds according to formula 1 for m = 1, HX = HCl

*Tests conducted at the University of Alberta, Edmonton (Canada).

** Tests conducted in the Pathophysiology Institute of the Gdansk Medical Academy on rats of the Wistar strain. a) Affinity constant of the test compound for the α₂-adrenergic receptors in the rat brain expressed in nM. b) Time after which the maximum drop in arterial blood pressure was observed after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg.

c) Maximum drop in arterial blood pressure after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg expressed as mean value ± SE. Table 2. Diuretic activity of selected compounds according to formula 1 for m=l, HX=HCl

* Tests conducted in the Pathophysiology Institute of the Gdansk Medical Academy on rats of the Wistar strain. a) Number of experimental animals used. b) Time of observation of diuresis before (-40 - 0 min) and after (0 - 90 min) intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg. c) Diuresis after intravenous administration of the test compound to rats in a single dose of 0.1 mg/ kg expressed as mean value ± SE.

Example XIV

Sedative effect of a novel adrenoceptor agonist 7 Cl-Marsanidine (Rl, R2, R3 and R4 are H and R5 is Cl)

Adult Sprague Dawley rats (weight 250-300 g) were used for the following experiments. First, the effect of Midazolam, a benzodiazepine receptor agonist, on sedation measured with the loss righting reflex (LORR) was determined. Midazolam was administered i.p. from doses of 0.5 mg/kg to 40 mg/kg. It revealed that midazolam at the highest dose tested caused LORR in 100% subjects. Second, the combined effect of the compound + midazolam on LORR was investigated. At the fixed dose (500 μg/kg) of the compound followed by variable doses of midazolam, the results showed that the compound remarkably reduced the dose of midazolam required to induce LORR in 100% subjects from 40 mg/kg to 2.5 mg/kg, indicating that the compound synergistically enhanced the sedative effect of midazolam (figure 1)

In addition, facilitation by midazolam of the sedative response of 7-chloro-marsanidine could be blocked by flumazenil, a benzodiazepine antagonist, indicating that this is a general property of benzodiazepines and not restricted to midazolam.

Cytoprotective effect of a novel adrenoceptor agonist 7 Cl-Marsanidine

HK-2 cells, derived from adult human kidney proximal tubular epithelial cells, were used for the cytoprotective experiments. They were cultured at 37⁰C in RPMI 1640 medium supplemented with 10% foetal bovine serum, 2mM L-glutamine, and 100U/mL penicillin streptomycin in a humidified air/ 5% CO₂ atmosphere. They were treated by depriving the culture medium of glucose and oxygen (OGD) in the absence or presence of the compound at doses ranging from 0.01 to 1 nM after reaching 80% confluence. The cell viability was measured with MTT assay. It can be seen that the cell death was attenuated by the compound in a dose dependent manner. This effect was abolished by an adrenoceptor antagonist of Atipamezole (10 nM). The compound or Atipamezole at the highest studied dose did not cause any cell death. These data suggest that the compound has cytoprotective property and the effect is due to its action on alpha-2 adrenoceptor (figure 2). References

1. Koblinger, W. Drugs as Tools in Research on Adrenoceptors. Naunyn-Schmied. Arch. Pharmacol. 1986, 332, 113-117.

2. Armach, B. T. Unique Presynaptic oc₂-Receptors and Specificity of the Antihypertensive Agent Moxonidine. Arzneim.-Forsch. Drug Res. 1988, 38, 1435-1441.

3. Van Zweiten, P. A. Pharmacology of Alpha₂-Adrenoceptor Agonist Rilmenidine. Am. J. Cardiol. 1988, 61, D6-D14.

4. Koblinger, W.; Pichler, L. Centrally Acting Drugs (Clonidine, Methyldopa, Guanfacine). In Handbook of Experimental Pharmacology. Pharmacology of Antihypertensive Therapeutics. Eds Ganten, D. and Murlow, P. J.; Springer- Verlag, Berlin, vol. 93, p.227.

5. Ruffolo Jr., R. R.; Nichols, A. J.; Stadel, J. M.; Hieble, J.P. Pharmacologic and Therapeutic Applications of α₂- Adrenoceptor Subtypes. Annu. Rev. Pharmacol. Toxicol. 1993, 32, 243- 279.

6. Verbeuren, T. J.; Yuan, A. T. D., Koenig-Bererd, E.; Viton, P. Rilmenidine. Cardiovascular Drug. Rev. 1990, 8, 56-66.

7. Bousquet, P.; Bricca, G.; Dontenwill, M.; Feldman, J.; Greney, H.; Belcourt, A.; Stutzmann, J.; Tibrica, E. From the α₂-Adrenoceptors to the Imidazoline Preferring Receptors. Fundam. Clin. Pharmacol. 1992, <J (Suppl. 1) 15a.

8. Chrisp, P.; Faulds, D. Moxonidine. Drugs 1992, 44, 993-995.

9. Molderings, G. J.; Gothert, M. Imidazoline Binding Sites and Receptors in Cardiovascular Tissue. Gen. Pharmac. 1999, 32, 17-22.

10. Ernsberger, P.; Damon, T. H.; Graff, L. M.; Schafer, S. G., Christen, M. O. Moxonidine a Centrally Acting Antihypertensive Agent is a Selective Ligand for I [-Imidazoline Sites. J. Pharmacol. Exp. Ther. 1993, 264, 172-176.

11. Szabo, B. Imidazoline Antihypertensive Drugs: a Critical Review on Their Mechanism of Action. Pharmacol. Ther. 2002, 93, 1-35.

12. Bousquet, P. Identification and Characterization Of I₁ Imidazoline Receptors. Their Role in Blood Pressure Regulation. Am. J. Hypertension 2000, 13, 845-848.

13. Sanders, R. D.; Maze, M. α- Adrenoceptor Agonists. Curr. Opinion Invest. Drugs. 2007, 8, 25-33.

14. Mantz, J. Alpha₂- Adrenoceptor Agonists: Analgesia, Sedation, Anxiolysis, Haemodynamics, Respiratory Function and Weaning. Bailliere 's Clinical Anesthesiology 2000, 14, 433-448.

15. Gerlah, A. T. Dexmedetomidine: An Updated Review. Ann. Pharmacother. 2007, 41, 245-252.

16. Pandharipande, P. P.; Pun B. T.; Herr, D. L.; Maze, M.; Girard, T. D.; Miller, R. R.; Shintani, A. K.; Thompson, J. L.; Jackson, J. C; Deppen, S. A.; Stiles, R. A.; Dittus, R. S.; Bernard, G. R.; Ely, E. W. Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The Mends Randomized Controlled Trial. JAMA. 2007, 298, 2644-2653.

17. Millan, M. J.; Dekeyne, A.; Newman-Tancredi, A.; Cussac, D.; Audinot, V.; Milligan, G.; Duqueyroix, D.; Girardon, S.; Mullot, J.; Boutin, J. A.; Nicolas, J.-P.; Renouard-Try, A.; Lacoste, J.-M.; Cordi, A.A. S18613 a Highly Potent, Spiroimidazoline Agonist at α₂- Adrenoceptors: I. Receptor Profile, Antinociceptive and Hypothermic Actions in Comparison with Dexmedetomidine and Clonidine. J. Pharmacol. Exp. Ther. 2000, 295, 1192-1205.

18. Richer, C; Gober, J.; Noyer, M.; Wulfert, E.; Giudicelli, J. F. Peripheral Alpha₂- Adrenoceptor-Mediated Sympathoinhibitory Effects of Mivazerol. Fundam. Clin. Pharmacol. 1996, 10, 529-537.

19. Priebe, H. -J. Perioperative Myocardial Infraction - Aetiology and Prevention. Br. J. Anaesth. 2005, 95, 3-19. 20. Cordi, A. A.; Lacoste, J. M.; Descombes, J.-J.; Courchay, Ch.; Vanhautte, P. M.; Laubie, M.; Verbeuren, T. J. Design, Synthesis and Structure - Activity Relationships of a New Series of α₂-Adrenergic Agonists : Spiro [( 1 ,3-Diazacyclopent- 1 -ene)-5 ,2'-( 1 ' ,2',3 ',4'- tetrahydronaphthalene)]. J. Med. Chem. 1995, 38, 4056-4069.

21. Cordi, A. A.; Lacoste, J. M.; Le Borgne, F.; Herve, Y.; Vaysse-Ludot, L.; Descombes, J.- J.; Courchay, Ch.; Laubie, M.; Verbeuren, T. J. (S)-Spiro[(l,3-Diazacyclopent-l-ene)-5,2'- (7'-methyl-l',2',3',4'-tetrahydronaphthalene)]: Resolution, Stereospecific Synthesis and Preliminary Pharmacological Characterization as a Potential α- Adrenergic Agonist. J. Med. Chem. 1997, 40, 2931-2935.

22. Kapoor, K.; Willems, E. W.; Maassen VanDenBrink, A.; Hillgers, J. P. C; Cordi, A. A.; Vaysettes-Courchay, C. Assessment of Anti-Migraine Potential of a Novel α- Adrenoceptor Agonist S 19014: Effects on Porcine Carotid and Regional Haemodynamics and Human Coronary Artery. Cephalalgia 2004, 24, 425-438.

23. Stahle, H. A Historical Perspective: Development of Clonidine. Bailliere 's Clinical Anesthesiology 2007, 14, 237-246.

Claims

CLAIMS:

1. A compound of the formula I:

I wherein R¹ denotes hydrogen, methyl or phenyl;

R², R³, R⁴ and R⁵ denote hydrogen, halogen, preferably a chlorine atom, alkyl, preferably methyl, alkoxyl, preferably methoxyl; m denotes a number 0 or 1 ; and

HX denotes sulfuric, phosphoric, acetic, malonic, fumaric, oxalic, lactic, tartaric, citric, gluconic, /7-toluenesulfonic, methanesulfonic acid, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.

2. A compound as claimed in claim 1 wherein R¹, R², R³, R⁴ and R⁵ denote hydrogen; m is 1 ; and

HX denotes hydrogen chloride.

3. A compound as claimed in claim 1 wherein R¹, R², R³ and R⁴ denote hydrogen; R⁵ denotes methyl; m is 1 ; and HX denotes hydrogen chloride.

4. A compound of general formula II:

II

wherein R¹ denotes hydrogen, methyl or phenyl;

R², R³, R⁴ and R⁵ denote hydrogen, halogen preferably a chlorine atom, alkyl preferably methyl or alkoxyl preferably methoxyl.

5. A method for the preparation of a compound as defined in claim 1, comprising reacting a compound of formula III:

III

wherein R¹ denotes hydrogen, methyl or phenyl;

6. A compound as claimed in any one of claims 1 to 3 for use in medicine.

7. A pharmaceutical formulation comprising at least one compound as claimed in claim 1 and optionally one or more excipients, carriers or diluents.

8. A compound as claimed in any one of claims 1 to 3 for use as a α₂-adrenergic receptor agonist.

9. A compound as claimed in claim 8 for use as a hypotensive or diuretic agent.

10. A compound as claimed in claim 8 which is for use in treating diseases of the circulatory system, such as arterial hypertension in patients with nephropathy, as well as effects of hypopituitarism, glaucoma, spastic states, dependence on opiates and alcohol, diarrhoea and analgesics.

11. A compound as claimed in any one of claims 1 to 3 for use as a sedative or anaesthetic.

12. A compound as claimed in any one of claims 1 to 3 for use as a cytoprotective agent.

13. A pharmaceutical composition comprising at least one compound as claimed in claim 1 and a benzodiazepine .