RU2161967C2 - Compounds of 7-(2-imidazolinylamino)-quinoline used as agonists of alpha-2-adrenoreceptors - Google Patents

Abstract

FIELD: organic chemistry, medicine. SUBSTANCE: invention relates to novel derivatives of quinoline of the general formula (I)

where R means unsubstituted C₁-C₃-alkyl or C₂-C₃-alkenyl; R¹ is cyano-group that are agonists of alpha-2-adrenoreceptors and can be used for preparing drugs that are useful for treatment of patients with nose congestion, glaucoma, diarrhea, asthma. Compounds show the expressed antagonistic activity with respect to α-2-adrenoreceptors. EFFECT: new compounds indicated above, enhanced effectiveness in treatment. 9 cl, 1 tbl, 3 ex

Description

 A subject of the invention relates to certain substituted 7- (2-imidazolinylamino) quinoline compounds. It has been found that these compounds are alpha-adrenergic agonists and are suitable for the treatment of one or more respiratory disorders, in particular nasal congestion; eye disorders, in particular glaucoma, and gastrointestinal disorders, in particular diarrhea.

Information regarding alpha adrenergic receptors, agonists and antagonists in general and related to compounds similar in structure to the compounds of the present invention is described in the following references: Timmermans, PBMWM, FT Chiu and MJMC Thoolen, "12.1 α-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3, Membranes and Receptors, PG Sammes and JB Taylor, eds., Pergamon Press (1990), pp. 133-185: Timmermans, PBMWM and PA van Zweiten, "α-Adrenoreceptor Agonist and Antagonist", Drugs of Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, AAHP, JE Leysen, FHL Awouters and CJE Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the α ₁ -and α ₂ - Selectivity of Test Compounds; (2) α- Adrenoreceptor Agonist", European Lournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, PBMWM, A. de Jonge, MJMC Thoolen, B. Wiffert, H. Batink and PA van Zweiten, "Quantitative Relationship between α- Adrenergic Activity and Binding Affinity of α- Adrenoreceptor Agonist and Antagonist", Journal of Medicinal Chemistry, Vol . 27 (19-4), pp. 495-503; van Meel, JCA, A. deJonge, PBMWM Timmermans and PA van Zwieten, "Selecttivity of Some Alpha α-Adrenoreceptor Agonist for Peripheral α ₁ -and α ₂ - Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics, Vol . 219, N 3 (1981), pp. 760-767: Chapleo, CB, JC Doxey, PL Myers, M. Myers, CF C Smith and MR Stillings, "Effect of 1,4-Dioxany Substitution on the Adrenergic Activity of Some Standart α- Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622, Chapieo, C.V., RCM Butler, DC England, PL, Myers, AG Roach / CFC Smith, MR Stillings and IF Tulloch, "Heteroaromatic Analogues of the α-Adrenoreceptor Partial Agonist Clondine", J. Med. Chem., Vol 32 (1989), pp. 1627-160: Clare, KA /, MC Scrutton and NTThompson, "Effect α ₂ -Adrenoreceptor Agonist and of Related Compounds on Aggregation of and on Adenylat Cyclase Activity in, Human Platelets", Br. J. Pharmac., Vol. 82 (1984), pp 467-476: US Patent N 890 19 issued to Danielewicz, Snarey and Thomas on June 17, 1975: and US Patent N 5 091 528 issued to Gluchowski on February 25, 1992. However, many compounds are similar the structure of the compounds of the present invention do not possess the desired activity and specificity in the treatment of respiratory, ocular and gastrointestinal disorders.

 The subject of the present invention is, in particular, the fact that compounds, which, as shown, are effective against nasal congestion, often have undesirable side effects, for example, cause hypertension and insomnia, especially with systemic administration. There is a need for new drugs that provide relief from nasal congestion and do not cause unwanted side effects.

 The subject of the invention are compounds having significant activity in the prevention and treatment of nasal congestion.

 Another subject of the invention are those compounds that do not cause hypotension, drowsiness, hypertension, insomnia or other undesirable side effects, especially when administered systemically.

 The present invention also provides compounds for the treatment of cough, chronic pulmonary disease (CODO) and / or asthma.

 The subject of the invention are also compounds for the treatment of glaucoma and / or diarrhea.

 Another subject of the invention are compounds that have good activity when administered orally and / or topically dosed.

где
(a) R представляет собой незамещенный C₁-C-алкил или C₂-C₃- алкенил и
(b) R цианогруппа
Изобретение относится также к применению таких соединений для предупреждения или лечения других респираторных, глазных и/или желудочно-кишечных нарушений. Изобретение относится также к новым соединениям, имеющим указанное выше строение, где R' представляет собой водород или цианогруппу.An object of the invention relates to methods for treating nasal congestion, including administering to a human or lower animal in need of such treatment a safe and effective amount of a compound having the following structure:

Where
(a) R is unsubstituted C ₁ -C alkyl or C ₂ -C ₃ alkenyl; and
(b) R cyano group
The invention also relates to the use of such compounds for the prevention or treatment of other respiratory, ocular and / or gastrointestinal disorders. The invention also relates to new compounds having the above structure, where R 'represents hydrogen or a cyano group.

 The terms “alkyl” as used herein means a saturated hydrocarbon substituent that is straight or branched chain and is unsubstituted or substituted.

 The terms “alkenyl,” as used herein, means a hydrocarbon substituent with one double bond (otherwise saturated), which has a straight or branched chain and is unsubstituted or substituted.

В указанной выше формуле R представляет собой незамещенный C₁-C₃- алкил или алкенил, имеющий от 2 до 3 атомов углерода, R предпочтительно является алкилом. R более предпочтительно является метилом или этилом, наиболее предпочтительно метилом.The invention relates to compounds having the following formula:

In the above formula, R is unsubstituted C ₁ -C ₃ - alkyl or alkenyl having from 2 to 3 carbon atoms, R is preferably alkyl. R is more preferably methyl or ethyl, most preferably methyl.

где R и R' имеют значения, указанные ниже: N соединения 1; R - CH₃; CN - R^'.Preferred compounds of the subject invention are compounds having the formula

where R and R 'have the meanings indicated below: N of compound 1; R is CH ₃ ; CN - R ^' .

 The compounds of the subject invention are particularly suitable for the treatment of nasal congestion associated with allergies, colds and other nasal disorders associated with nasal congestion, as well as their consequences (complications), for example, sinusitis and otitis media. At the same time, it was found that unwanted side effects, such as hypotension, drowsiness, hypertension, or insomnia, can often be avoided. Not limited to the specific mechanism of action, it is believed that the compounds of the present invention have advantages over similar compounds in the treatment of nasal congestion due to their ability to interact with alpha-2-adrenergic receptors. It was found that the compounds of the subject invention are alpha-2 adrenergic agonists that cause narrowing of peripheral vascular channels in the nasal concha.

 The particular compounds of the subject invention do not possess or possess only weak alpha-1 agonist activity and have little or no effect on the central nervous system, even when dosed systemically.

 The compounds of the invention are also suitable for the treatment of ocular disorders associated with increased intraocular pressure, for example glaucoma. The compounds are administered orally or topically in the form of drops, gels or creams directly to the surface of the eye of a mammal.

 The compounds of the present invention are also useful for treating disorders of the gastrointestinal tract, for example diarrhea, by acting against the contractile and secretory functions of the gastrointestinal tract.

The pharmacological activity and selectivity of the compounds of the invention can be determined using the described test methods. The alpha-2 selectivity of these compounds is determined by measuring the affinity for receptor binding and in vitro functional activity in a number of tissues that are known to contain alpha-2 and / or alpha-1 receptors (See, for example, The Alpha- 2 Adrenergic Receptors. LE Limbird, ed., Humana Press, Cliffon, NJ). Typically, in rodents and other animal species, the following tests are carried out in vivo. The activity of the central nervous system is determined by measuring motor activity as an index of sedation. (See, e.g., Spyraki, C. and N. Fibiger, "Clonidine-induced Sedation in Rats: Evidence for Mediation by Postsynaptic Alpha-2-Adrenoreceptors", J. Neural Trans., Vol. 54 (1982), pp. 153-263). The activity of substances against nasal congestion is measured using a rhinomanometer, evaluating the resistance of the nasal airway. (See, for example, Salem, S. and E. Clemente, "A new Experimental Method for Evaluating Drugs in the Nasal Cavity", Arch. Otolarynng, Vol. 96 (1972), pp. 524-529). Anti-glaucoma activity is determined by measuring intraocular pressure (See, for example, Potter, D., "Adrenergic Pharmacology of Aquous Human Dynamics", Pharmacol. Rev., Vol. 13 (1981), pp. 133-153). Antidiarrheal activity is determined by measuring the ability of compounds to inhibit prostaglandin-induced diarrhea (See, for example, Thollander, M., P. Hellstrom and T. Svensson, "Suppression of Castor oil-induced Diarrhea by Alpha-2 Adrenoceptor Agonist", Aliment. Pharmacol. Therap., Vol. 5 (1991), pp. 255-262). Anti-asthma activity is determined by measuring the effect of the compound on bronchostenosis associated with pulmonary antigenic stimuli, e.g. inhaled antigens (See, e.g., Chang, JJ Musser and J. Hind, "Effect of a Novel Leukotriene D ₄ Antagonist with 5-Lipoxygenase and Cyclooxygenase inhibitory Activity , Wy45911, on Leukotriene-D ₄ - and Antigen-induced Bronchoconstriction in Guinea Pig ", Int. Arch. Allergy Appl. Immun., Vol. 86 (1988), pp. 48-54 and Delehunt, JA Perruchound, L. Yerger , B. Marchette, J. Stevenson and W. Abraham, "The Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Cheep", Am. Rev. Respir. Dis., Vol. 130 (1984 ), pp. 784-754). Antitussive activity is determined by measuring the number and latency of a cough reaction to respiratory antigenic stimuli, for example, inhaled citric acid. (See, for example, Callway, J. and R. King, "Effect of inhaled Alpha-2-Adrenoceptor and GABA _β- Receptor Agonists on Citric Acid-indused Cough and Tidal Volume Changes in Guinea Pigs", Eur. J. Pharmacol ., Vol. 220 (1992), pp. 187-195).

В указанной выше схеме, где R' представляет собой алкокси- или алкилтиогруппу, соответствующие гидрокси- или меркаптосоединения получают из конечных соединений при помощи стандартной методики деалкилирования (Bhatt, et al., "Cleavage of Ethers", Synthesis, 1983, pp. 249-281).Compounds of the present invention are synthesized using the following General method:

In the above scheme, where R 'is an alkoxy or alkylthio group, the corresponding hydroxy or mercapto compounds are prepared from the final compounds using a standard dealkylation procedure (Bhatt, et al., "Cleavage of Ethers", Synthesis, 1983, pp. 249- 281).

Synthesis Examples
The following non-limiting examples describe details of the synthesis of the 7- (2-imidazolinylamino) quinoline derivatives of the present invention.

8-Метил-7-нитрохинолин. Смесь 2-метил-3-нитроанилина (10 г), глицерина (20,57 г) и As₂O₅ · H₂O (Bacer, 88% As₂O₅, 8,5 г) медленно нагревают до 150^oC в открытой круглодонной колбе, затем перемешивают в течение 6 ч при 150^oC. Полученную смесь охлаждают до комнатной температуры и разбавляют водой (200 мл), затем добавляют гидроксид аммония (28-30%, 100 мл). Через приблизительно 10 мин раствор подкисляют до pH 5 ледяной уксусной кислотой и экстрагируют CH₂Cl₂ (3 х 200 мл). Объединенные экстракты промывают водой (200 мл), насыщенным раствором NaHCO₃ (200 мл), затем сушат над MgSO₄ и выпаривают на роторном испарителе. Неочищенный хинолин фильтруют через невысокий слой силикагеля, применяя CH₂Cl₂ в качестве растворителя. Фильтрат выпаривают в роторном испарителе и остаток перекристаллизуют из смеси гексан/CH₂Cl₂, получая 8-метил-7-нитрохинолин в виде рыжевато-коричневого твердого вещества.Example 1
Synthesis of 8-methyl-7- (2-imidazolinylamino) quinoline dihydrochloride

8-methyl-7-nitroquinoline. A mixture of 2-methyl-3-nitroaniline (10 g), glycerol (20.57 g) and As ₂ O ₅ · H ₂ O (Bacer, 88% As ₂ O ₅ , 8.5 g) is slowly heated to 150 ^o C in an open round bottom flask, then stirred for 6 hours at 150 ^° C. The resulting mixture was cooled to room temperature and diluted with water (200 ml), then ammonium hydroxide (28-30%, 100 ml) was added. After approximately 10 minutes, the solution was acidified to pH 5 with glacial acetic acid and extracted with CH ₂ Cl ₂ (3 x 200 ml). The combined extracts were washed with water (200 ml), saturated NaHCO ₃ solution (200 ml), then dried over MgSO ₄ and evaporated on a rotary evaporator. The crude quinoline was filtered through a short silica gel pad using CH ₂ Cl ₂ as solvent. The filtrate was evaporated on a rotary evaporator and the residue was recrystallized from hexane / CH ₂ Cl ₂ to give 8-methyl-7-nitroquinoline as a tan solid.

7-amino-8-methylquinoline. To a solution of 8-methyl-7-nitroquinoline (1.8 g) in methanol (20 ml) was added Pd / C (10%, 0.45 g) and ammonium formate (2.77 g). The mixture was stirred at room temperature for 30 minutes, then filtered through celite and the solid was washed with methanol. The filtrate was evaporated on a rotary evaporator and the residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The organic layer was dried over potassium carbonate, filtered and rotary evaporated to give 7-amino-8-methylquinoline as a yellow solid.

8-methyl-7-quinolinyl isothiocyanate. To a solution of di-2-pyridylthionocarbonate (DPT) (2.29 g) (Aldrich) and 4-dimethylaminopyridine (DMAP) (0.02 g), a solution of 7-amino-8-methylquinoline (1.3 g) in CH ₂ Cl ₂ (50 ml). The mixture was stirred for 5 hours at room temperature, then evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 25% solution of ethyl acetate in hexane, to give 8-methyl-7-quinolinylisothiocyanate as a pale yellow solid.

N- (8-Methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide. A solution of 8-methyl-7-quinolinyl isocyanate (1.36 g) in CH ₂ Cl ₂ (50 ml) was added dropwise to ethylene diamine (2.26 ml) in a solution of CH ₂ Cl ₂ (50 ml). The mixture was stirred for 30 minutes at room temperature and then evaporated on a rotary evaporator. The residue was suspended in CH ₂ Cl ₂ (50 ml) and diethyl ether (50 ml) and then filtered. The precipitate was dried in vacuo to give N- (8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide as a white powder.

8-methyl-7- (2-imidazolinylamino) quinoline dihydrochloride
A mixture of N- (8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide (0.94 g) and mercury acetate (1.18 g) in methanol (30 ml) was stirred for 4 hours at room temperature. The resulting black mixture was filtered through celite and the filtrate was concentrated. The residue was diluted with CH ₂ Cl ₂ (50 ml) and a saturated solution of NaHCO ₃ (20 ml) and the pH of the aqueous layer was adjusted to 10 by adding 50% sodium hydroxide. The layers were separated and the organic layer was dried (K ₂ CO ₃ ) and evaporated on a rotary evaporator. The residue was purified by flash chromatography on a short layer of silica gel using a 10% solution of methanol in chloroform containing 1% ammonium hydroxide. The product containing fractions were collected and evaporated on a rotary evaporator to give 8-methyl-7- (2-imidazolinylamino) quinoline as a yellow solid. The dihydrochloride salt is obtained by bubbling HCL through a cold solution of quinoline in methanol (20 ml). The methanol was evaporated on a rotary evaporator and the residue was recrystallized from methanol / diethyl ether to give 8-methyl-7- (2-imidazolinylamino) quinoline dihydrochloride.

4-Циано-2,6-динитротолуол. Раствор 4-цианотолуола (10,3 г) в тетраметиленсульфоне (65 мл) добавляют по каплям в раствор тетрафторбората нитрония (14,6 г) в тетраметиленсульфоне (130 мл). Реакционную смесь перемешивают в течение одного часа при 95^oC. В реакционную смесь медленно добавляют дополнительный тетрафторборат нитрония (15,58 г) и смесь затем перемешивают еще два часа. Смесь выливают в лед и разбавляют далее водой (500 мл). Продукты экстрагируют этилацетатом (4 х 500 мл). Объединенные экстракты сушат над сульфатом магния и выпаривают в роторном испарителе. Неочищенное оранжевое масло фильтруют через невысокий слой силикагеля, применяя 10%-ный раствор ацетата в гексане в качестве растворителя. Фильтрат испаряют в роторном испарителе, а остаток перекристаллизуют из горячего хлористого метилена, получая 4-циано-2,6-динитротолуол в виде белого твердого вещества.Example 2
Synthesis of 5-cyano-8-methyl-7- (2-imidazolinylamino) -quinoline monotartrate

4-cyano-2,6-dinitrotoluene. A solution of 4-cyanotoluene (10.3 g) in tetramethylene sulfone (65 ml) was added dropwise to a solution of nitronium tetrafluoroborate (14.6 g) in tetramethylene sulfone (130 ml). The reaction mixture was stirred for one hour at 95 ^° C. Additional nitronium tetrafluoroborate (15.58 g) was slowly added to the reaction mixture, and the mixture was then stirred for another two hours. The mixture was poured into ice and diluted further with water (500 ml). The products are extracted with ethyl acetate (4 x 500 ml). The combined extracts are dried over magnesium sulfate and evaporated on a rotary evaporator. The crude orange oil is filtered through a short layer of silica gel using a 10% solution of acetate in hexane as a solvent. The filtrate was evaporated on a rotary evaporator and the residue was recrystallized from hot methylene chloride to give 4-cyano-2,6-dinitrotoluene as a white solid.

4-cyano-2,6-diaminotoluene. A solution of 4-cyano-2,6-dinitrotoluene (8.55 g) in concentrated hydrochloric acid (70 ml) and glacial acetic acid (10 ml) is treated with metal tin (granules, 14.66 g), which is added slowly in this way so that the temperature does not exceed 50 ^° C. The reaction mixture is stirred at 50 ^° C. for 2.5 hours, then poured into ice and the pH is adjusted to 11 by the addition of concentrated ammonium hydroxide. The products are extracted with ethyl acetate (5 x 300 ml). The combined extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 50% solution of ethyl acetate in hexane, to give 4-cyano-2,6-diaminotoluene as a yellow solid.

7-amino-5-cyano-8-methylquinoline. A mixture of 4-cyano-2,6-diamino-toluene (3.56 g), ferric chloride hexahydrate (11.63 g) and zinc chloride (0.499 g) in ethanol (600 ml) is heated to 65 ^° C. For 90 min. a solution of 1,1,3-trimethoxypropane (5.23 g) in ethanol (90 ml) is added dropwise with a syringe. The reaction mixture was then refluxed for 2.5 hours, then cooled to room temperature and the solvent was evaporated on a rotary evaporator. The residue is mixed with 300 ml of water and the pH of the mixture is adjusted to 11 by the addition of concentrated ammonium hydroxide. The products are extracted with ethyl acetate (4 x 800 ml) and the combined extracts are dried over sodium sulfate and evaporated in a rotary evaporator. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexane to give 7-amino-5-cyano-8-methyl-quinoline as a yellow solid.

 5-cyano-8-methyl-7-quinolinyl isothiocyanate. To a solution of di-2-pyridylthionocarbonate (1.22 g) and 4-dimethylaminopyridine (0.08 g) in methylene chloride (60 ml) was added dropwise a solution of 7-amino-5-cyano-8-methylquinoline (1.22 g ) in methylene chloride (80 ml). The mixture was stirred for 4 hours at room temperature and then evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 25% solution of ethyl acetate in hexane, to give 5-cyano-8-methyl-7-quinolinylisothiocyanate as a yellow solid.

N- (5-Cyano-8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide
A solution of 5-cyano-8-methyl-7-quinolinyl isocyanate (0.85 g) in toluene (100 ml) was added dropwise to a solution of 1,2-ethylenediamine (1.94 g) in toluene (100 ml). After the reaction mixture was stirred at room temperature for 10 minutes, a yellow-white precipitate was observed. The precipitate was separated by filtration and dried in vacuo to give N- (5-cyano-8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide as a yellow-white solid.

 5-cyano-8-methyl-7 (2-imidazolinylamino) quinoline monotartrate.

 A mixture of N- (5-cyano-8-methyl-7-quinolinyl) - N'-2-aminoethylthiocarbamide (1.01 g) and mercury (II) acetate (1.61 g) in ethanol (70 ml) was stirred at room temperature temperature for 10 minutes The resulting black mixture was filtered through celite and the filtrate was evaporated by rotary evaporation. The residue was diluted with water (20 ml), adjusted to pH 10 by addition of a saturated potassium carbonate solution and extracted with methylene chloride (5 x 100 ml). The extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 10% solution of methanol in chloroform containing 1% ammonium hydroxide to give 5-cyano-8-methyl-7- (2-imidazolinylamino) quinoline as a yellow solid. It was dissolved in methanol (25 ml) and treated with a solution of L-tartaric acid (0.096 g) in methanol (25 ml). The solution was evaporated on a rotary evaporator to give a residue, which was recrystallized from a mixture of methanol and diethyl ether to isolate 5-cyano-8-methyl-7 (2-imidazolinylamino) quinoline monotartrate.

2,6-Динитро-4-Фтортолуол. Дымящую серную кислоту (180 мл) добавляют по каплям в 4-фтор-2-нитротолуол (50,21 г) в атмосфере аргона. Внутреннюю температуру смеси поддерживают при 0-5^oC, применяя баню лед/хлористый натрий. Предварительно образованную (баня со льдом) смесь дымящей азотной кислоты (30 мл) и дымящей серной кислоты (90 мл) добавляют по каплям в предыдущий раствор в течение трех часов. Реакционную смесь затем оставляют для нагревания до комнатной температуры. После перемешивания в течение двух час при комнатной температуре смесь выливают медленно в лед и продукты экстрагируют хлористым метиленом (4 х 500 мл). Объединенные экстракты сушат над сульфатом магния, фильтруют и выпаривают на роторном испарителе. Неочищенную смесь фильтруют через небольшой слой силикагеля, применяя 10%-ный раствор этилацетата в гексане в качестве растворителя, затем перекристаллизуют из смеси этилацетат/гексан, получая 2,6 - динитро-4-фтортолуол в виде бледно-желтого твердого вещества.Example 3
Synthesis of 5-Fluoro-8-methyl-7 (2-imidazolinylamino) quinoline sesquihydrochloride

2,6-dinitro-4-fluorotoluene. Fuming sulfuric acid (180 ml) was added dropwise to 4-fluoro-2-nitrotoluene (50.21 g) under argon. The internal temperature of the mixture was maintained at 0-5 ^° C. using an ice / sodium chloride bath. A pre-formed (ice bath) mixture of fuming nitric acid (30 ml) and fuming sulfuric acid (90 ml) is added dropwise to the previous solution over three hours. The reaction mixture is then left to warm to room temperature. After stirring for two hours at room temperature, the mixture was poured slowly into ice and the products were extracted with methylene chloride (4 x 500 ml). The combined extracts are dried over magnesium sulfate, filtered and rotary evaporated. The crude mixture was filtered through a small layer of silica gel using a 10% solution of ethyl acetate in hexane as a solvent, then recrystallized from ethyl acetate / hexane to give 2,6-dinitro-4-fluorotoluene as a pale yellow solid.

 2-amino-4-fluoro-6-nitrotoluene. A solution of 2,6-dinitro-4-fluorotoluene (8.1 g) in ethanol (130 ml) was treated dropwise with a solution of sodium sulfide nonahydrate (16.39 g) in water (90 ml). The mixture was stirred for 2.5 hours at room temperature, then diluted with water (500 ml) and extracted with ethyl acetate (4 x 500 ml). The combined extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 15% solution of ethyl acetate in hexane, to give 2-amino-4-fluoro-6-nitrotoluene as a solid.

7-amino-5-fluoro-8-methylquinoline. A mixture of 2-amino-4-fluoro-6-nitrotoluene (4.4 g), glycerol (7.5 g), arsenic oxide (V) hydrate (Aldrich, 54%, 5.0 g) and concentrated sulfuric acid (35 ml) is heated to 140 ^° C. for 4 hours. The reaction mixture is cooled to room temperature and diluted with water (300 ml). A concentrated solution of ammonium hydroxide was added to the mixture to establish a pH of 10 and extracted with ethyl acetate (6 x 300 ml). The combined extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified by flash chromatography on silica gel, eluting with a 25% solution of ethyl acetate in hexane, to give 7-amino-5-fluoro-8-methylquinoline as a solid.

 5-Fluoro-8-methyl-7-quinolinylisothiocyanate. A mixture of 7-amino-5-fluoro-8-methylquinoline (0.39 g) and thiophosgene (0.2 ml) in water (5 ml) and 1 N hydrochloric acid (5 ml) was stirred for 1.5 hours at room temperature. An additional amount of thiophosgene (0.1 ml) was added and the mixture was stirred for another hour. The mixture is treated with 1 N sodium hydroxide solution (25 ml) and extracted with methylene chloride (4 x 50 ml). The combined extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel using a 15% solution of ethyl acetate in hexane to give 5-fluoro-8-methyl-7-quinolinyl isothiocyanate as a tan solid.

 N- (5-Fluoro-8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide.

 A solution of 5-fluoro-8-methyl-7-quinolinyl isothiocyanate (0.38 g) in toluene (40 ml) was added dropwise to a solution of 1,2-ethylenediamine (0.78 g) in toluene (40 ml). The formation of a white precipitate is observed after stirring for 10 min at room temperature. The precipitate was separated by filtration and dried in vacuo to give N- (5-fluoro-8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide as a white solid.

 5-fluoro-8-methyl-7- (2-imidazolinylamino) quinoline sesquihydrochloride. A mixture of N- (5-fluoro-8-methyl-7-quinolinyl) -N'-2-aminoethylthiocarbamide (0.38 g) and mercury acetate (0.70 g) in ethanol (25 ml) was stirred for 10 min at room temperature . The resulting black mixture was filtered through celite and the filtrate was evaporated on a rotary evaporator. The residue was diluted with water (20 ml) and treated with a concentrated solution of ammonium hydroxide to establish a pH of 10. The product was dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with a 10% solution of methanol in chloroform containing 1% ammonium hydroxide. The product containing fractions were collected and rotary evaporated to give 5-fluoro-8-methyl-7- (2-imidazolinylamino) quinoline as a yellow solid. It is dissolved in 10 ml of methanol and cooled in an ice bath. Hydrogen chloride gas was bubbled into the solution for 5 minutes. The solution was evaporated on a rotary evaporator. The resulting residue was recrystallized from methanol / diethyl ether to give 5-fluoro-8-methyl-7- (2-imidazolinylamino) quinoline sesquihydrochloride as a yellow solid.

 The invention includes the use of a composition that contains a safe and effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The term “safe and effective amount” means an amount of a compound of the invention sufficient to substantially induce positive changes in the condition to be treated, but low enough to avoid serious side effects (with an acceptable benefit / risk ratio) within the scope of a thorough medical evaluation . The safe and effective amount of the compound of the subject will vary with the age and physical condition of the patient to be treated, the severity of the condition, the duration of treatment, the nature of the simultaneous therapy, the particular pharmaceutically acceptable carrier used and similar factors within the knowledge and opinion of the attending physician.

 The compositions of the invention preferably contain from about 0.0001% to about 99% by weight of a compound of the invention, more preferably from about 0.01% to about 90%, also preferably from about 10% to about 50%, also preferably from about 5% up to about 10%, also preferably from about 1% to about 5%, and also preferably from about 0.1% to about 1%.

 In addition to the compound of the invention, the compositions of the subject invention contain a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid excipients, diluents, or encapsulating substances that are suitable for administration to a human or lower animal. Used in the description, the term "compatible" means that the components of the composition are capable of mixing with the compound of the invention and with each other so that there is no interaction that could significantly reduce the pharmaceutical activity of the composition in normal use. Pharmaceutically acceptable carriers should, of course, be sufficiently pure and sufficiently toxic enough to be administered to a human or lower animal to be treated.

Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, for example lactose, glucose and sucrose; starches, for example corn starch and potato starch; cellulose and its derivatives, for example, carboxymethyl cellulose sodium, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; gelatin; talc: solid lubricants, such as stearic acid and magnesium stearin: calcium sulfate; vegetable oils, for example peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols, for example propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol, alginic acid; emulsifiers, for example Tween ^® ; wetting agents, for example sodium lauryl sulfate: coloring agents: perfumes; tabletting agents; stabilizers; antioxidants: preservatives; pyrogen-free water; isotonic saline and phosphate buffers.

 The choice of a pharmaceutically acceptable carrier that is used in combination with a compound of the invention is essentially determined by the manner in which the compound is to be administered.

 If the compound of the invention is to be injected, the preferred pharmaceutically acceptable carrier is a sterile saline solution with a blood-compatible suspending agent whose pH is set at about 7.4.

 A preferred method of administering the compounds of the invention is oral. Preferred unit dosage forms thereof are tablets, capsules, lozenges, chewable tablets, etc. Such unit dosage forms contain a safe and effective amount of a compound of the invention that is present in an amount of preferably from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 50 mg, even more preferably from about 0.5 mg up to about 25 mg, also preferably from about 1 mg to 10 mg. Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain pharmaceutically compatible excipients, for example, inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, for example starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants, for example magnesium stearin, stearic acid, talc. To improve the bulk characteristics of the powder mixture, silica can be used. Coloring agents such as FD & C colorants can be added to achieve the desired appearance. Sweeteners and perfumes, such as aspartame, saccharin, menthol, peppermint and fruit flavors, are suitable chewable tablets. Capsules typically contain one or more of the solid diluents described above. The choice of carrier components depends on secondary factors such as taste, price, and storage stability, which are not critical for the purpose of the subject invention, such a choice can easily be made by a person skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Such liquid oral compositions preferably contain from about 0.001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5%. Typical carrier components for syrups, elixirs, emulsions, and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. Typical suspending agents used to prepare the suspension include methyl cellulose, carboxymethyl cellulose sodium, Avicel ^® RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80: and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components, for example sweeteners, flavoring agents and coloring agents described above.

 Other compositions suitable for achieving systemic delivery of the compounds of the invention to the body include sublingual and buccal dosage forms. Such compositions typically contain one or more soluble excipients, for example sucrose, sorbitol and mannitol; binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. You can also include components that give flowability, lubricants, coloring agents, antioxidants and perfumes described above.

 A preferred route of administration of the compounds of the invention is a topical route of administration to a site where activity is desired; intranasal doses for eliminating nasal congestion, dosage forms for inhalation for asthma, eye drops, gels and creams for eye disorders and oral doses for gastrointestinal disorders.

 Preferred compositions of the subject invention include aqueous solutions containing a safe and effective amount of a compound of the invention for topical intranasal administration. Such compositions preferably contain from about 0.001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5%. Such compositions typically include a safe and effective amount of preservatives, for example benzalkonium chloride and thimerosal; buffers, for example phosphate and acetate; tonicity agents, for example sodium chloride; antioxidants, for example ascorbic acid; flavoring agents and acids and bases to establish certain pH values of these aqueous compositions, if necessary.

 Preferred compositions of the present invention include aqueous solutions, suspensions and dry powders containing a safe and effective amount of a compound of the invention for spraying and topical inhalation. Such compositions preferably contain from about 0.1% to about 50% of a compound of the invention, more preferably from about 1% to about 20%. Such compositions are usually contained in a container with attached spraying aids. Such compositions typically include propellants (carrier gas), for example chlorofluorocarbons 12/11 and 12/114: solvents, for example water, glycerol and ethanol; stabilizers, for example ascorbic acid, sodium metabisulfite; preservatives, for example cetylpyridinium chloride and benzalkonium chloride; tonicity agents, for example, sodium chloride and perfumes, for example, the sodium derivative of saccharin.

 Preferred compositions of the invention include aqueous solutions containing a safe and effective amount of a compound of the invention and preferred for topical intraocular administration. Such compositions preferably contain from about 0.0001% to about 5% of a compound of the invention, more preferably from about 0.01% to about 0.5%. Such compositions typically include one or more preservatives, for example benzalkonium chloride, thimerosal, phenylmercury (II) acetate; fillers, for example poloxamers, modified celluloses, povidone and purified water; tonicity agents, for example sodium chloride, mannitol and glycerin; buffers, for example acetate, citrate, phosphate and borate; antioxidants, for example sodium metasulfite, butylated hydroxytoluene and acetylcysteine; acids and bases that can be used to establish the pH of these finished dosage forms, if necessary.

Preferred compositions of the subject invention include solid forms, for example tablets and capsules, and liquids, for example solutions, suspensions and emulsions (preferably in soft gelatine capsules), containing a safe and effective amount of a compound of the invention and for local oral administration to the gastrointestinal tract . Such compositions preferably contain from about 0.01 mg to about 100 mg per dose, more preferably from about 0.1 mg to about 5 mg per dose. Such compositions can be coated with shells using conventional techniques, usually shells dependent on pH and time, whereby a compound of the invention is secreted in the gastrointestinal tract adjacent to the desired site of application or at a specific time to produce the desired effect. Such dosage forms typically contain (but may contain other components) one or more of the components: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit ^® coatings, waxes and shellac.

 The compositions of the invention may further include other drugs. Non-limiting examples of drugs that can be incorporated into compositions of the invention and typical dosage amounts thereof include: respiratory drugs: classic antihistamines, for example, chlorpheniramine in an amount of about 1 mg to about 4 mg per dose and diphenhydramine in an amount of about 10 mg to about 50 mg per dose; non-sedating antihistamines, for example terfenadine in an amount of from about 30 mg to about 60 mg per dose, loratadine in an amount of from about 5 mg per dose to about 10 mg per dose, and cetirizine in an amount of from about 5 mg per dose to about 10 mg per dose; expectorants, for example guaifenesin in an amount of about 100 mg to about 200 mg per dose: antitussives, for example, dextromethorphan in an amount of about 5 mg to about 30 mg per dose; and analgesics, for example ibuprofen in an amount of from about 100 mg to about 800 mg per dose and acetaminophen in an amount of from about 80 mg to about 1000 mg per dose; ophthalmic drugs: acetylcholinesterase inhibitors, for example echothiophate in an amount of from about 0.03% to about 0.25% in a solution for topical administration; gastrointestinal drugs: anti-diarrhea drugs, for example loperamide in an amount of about 0.1 mg to about 1.0 mg per dose and bismuth subsalicylate in an amount of about 25 mg to about 300 mg per dose.

 The present invention includes methods for preventing or treating nasal congestion by administering a safe and effective amount of a compound of the invention to a person or lower animal experiencing nasal congestion or at the risk of nasal congestion. Such nasal congestion can be associated with diseases or disorders in humans, which include, but are not limited to, seasonal allergic rhinitis, acute viral infections of the upper respiratory tract, sinusitis, chronic rhinitis and vasomotor rhinitis. Preferably, each administration contains a dose of a compound of the invention in the range of from about 0.001 mg / kg to about 10 mg / kg, more preferably from about 0.01 mg / kg to about 5 mg / kg, even more preferably from about 0.1 mg / kg to about 1 mg / kg. Oral administration of such doses is preferred. The frequency of administration of the compound in accordance with the present invention is preferably from one to six times a day, more preferably from two times to four times a day. Such doses and frequency of administration are also preferred for the treatment of other respiratory diseases, such as otitis media, cough, COPD and asthma.

 Another aspect of the invention includes methods for preventing or treating glaucoma by administering a safe and effective amount of a compound of the invention to a human or lower animal suffering from glaucoma or at risk of glaucoma. Preferably, each dose administered contains a compound of the invention in an amount of from about 0.01 μg / kg to about 10 mg / kg, more preferably from about 0.001 mg / kg to about 1 mg / kg, even more preferably from about 0.01 mg / kg to about 0.1 mg / kg. Intraocular administration of such doses is preferred. The frequency of administration of the compound in accordance with the invention is preferably from one to six times a day, more preferably from 2 times to 4 times a day.

Another object of the invention includes methods for the prevention or treatment of functional intestinal disorders, such as diarrhea,
the administration of a safe and effective amount of a compound of the invention to a human or lower animal suffering from diarrhea or at risk of diarrhea. Preferably, each dose administered contains a compound of the invention in the range of from about 0.001 mg / kg to about 10 mg / kg, more preferably from about 0.01 mg / kg to about 5 mg / kg, even more preferably from about 0.1 mg / kg to about 1 mg / kg. Oral administration of such doses is preferred. The frequency of administration of the compound in accordance with the invention is from one to six times a day, more preferably from 2 to 4 times a day.

Examples of compositions and methods
The following non-limiting examples illustrate compositions and methods of using the invention.

Example A
Oral composition in the form of tablets
Ingredient - Amount per tablet (mg)
Compound 3 - 20.0
Microcrystalline cellulose
(Avicel pH 102 ^® ) - 80.0
Dicalcium Phosphate - 96.0
Pyrogenic Silica (Cab-O-Sil ^® ) - 1.0
Magnesium Stearate - 3.0
Total - 200.0
One tablet is swallowed by a nasal congestion patient. Congestion is significantly reduced.

Example B
Chewable Tablet Composition
Ingredient - Amount per tablet (mg)
Compound 1 - 15.0
Mannitol - 255.6
Microcrystalline Cellulose (Avicel PH 101 ^® ) - 100.8
Dextrinized caxapose (Di-Pac ^® ) - 199.5
Orange Fragrance - 4.2
Sodium saccharin derivative - 1.2
Stearic acid - 15.0
Magnesium Stearate - 3.0
Yellow # 6 dye FD & C - 3.0
Pyrogenic Silica (Cab-O-Sil ^® ) - 2.7
Total - 600.0
One tablet is chewed and swallowed by a nasal congestion patient. Congestion is significantly reduced.

Example C
Pill-shaped sublingual composition
Ingredient - Amount per tablet (mg)
Compound 2 of the invention - 2.00
Mannitol - 2.00
Microcrystalline Cellulose (Avicel PH 101 ^® ) - 29.00
Mint fragrances - 0.25
Sodium saccharin derivative - 0.08
Total - 33.33
One tablet is placed under the tongue of a patient with nasal congestion and left to dissolve. Congestion is quickly and significantly reduced.

Example D
The composition in the form of an intranasal solution
Ingredient - Content (w / v%)
Compound 3 of the invention - 0.20
Benzalkonium Chloride - 0.02
Thimerosal - 0.002
d-Sorbitol - 5.00
Glycine - 0.35
Flavoring Additives - 0.075
Purified water - to balance
Total - 100.00
One tenth of a ml of the composition is sprayed from the vessel under pressure into each nostril of the patient with a stuffy nose. Congestion is significantly reduced.

Example E
Gel Intranasal Composition
Ingredient - Content (w / v%)
Compound 1 - 0.10
Benzalkonium Chloride - 0.02
Thimerosal - 0.002
Hydroxypropyl methylcellulose (Metolose 65SH400 ^® ) - 1.06
Flavors - 0.06
Sodium Chloride (0.65%) - to balance
Total - 100.00
One fifth of a ml of the composition is administered as drops from a pipette into each nostril of a patient with a stuffy nose. Congestion is significantly reduced.

Example F
Inhalation aerosol composition
Ingredient - Content (w / v%)
Compound 2 - 5.0
Alcohol - 33.0
Ascorbic acid - 0.1
Menthol - 0.1
Sodium saccharin derivative - 0.2
Propellant (F12, F114) - to balance
Total - 100.0
The aerosol composition is administered to a patient with asthma by inhalation of two jets from a metered-dose inhaler. The asthmatic condition is effectively alleviated.

Example G
Topical Ophthalmic Composition
Ingredient - Content (w / v%)
Compound 4 - 0.10
Benzalkonium Chloride - 0.01
Ethylenediaminetetraacetic acid - 0.05
Hydroxyethyl cellulose (Nastrol M ^® ) - 0.50
Sodium metabisulfite - 0.10
Sodium Chloride (0.9%) - to balance
Total - 100.0
One tenth of a ml of the composition is injected directly into each eye of a patient with glaucoma. Intraocular pressure is significantly reduced.

Example H
Liquid composition for oral administration
Ingredient - Amount / Dose 15 ml
Compound 3 - 15 mg
Chlorpheniramine Maleate - 4 mg
Propylene glycol - 1.8 g
Ethanol (95%) - 1.5 ml
Methanol - 12.5 mg
Eucalyptus Oil - 7.55 mg
Fragrances - 0.05 ml
Sucrose - 7.65 g
Carboxymethyl Cellulose (CMC) - 7.5 mg
Microcrystalline cellulose and CMC sodium salt (Avicel RC 591 ^® ) - 187.5 mg
Polysorb 80 - 3.0 mg
Glycerin - 300 mg
Sorbitol - 300 mg
Red # 40 dye FD & C - 3 mg
Sodium saccharin derivative - 22.5 mg
Primary Acid Sodium Phosphate - 44 mg
Sodium Citrate Monohydrate - 28 mg
Purified water - to balance
Total - 15 ml
A single dose in the form of 15 ml of a liquid composition is drunk by a patient with a stuffy nose and chronic runny nose due to allergic rhinitis. Congestion and runny nose are effectively reduced.

Example j
Liquid composition for oral administration
Ingredient - Amount / Dose 15 ml
Compound 4 - 30 mg
Sucrose - 8.16 g
Glycerin - 300 mg
Sorbitol - 300 mg
Methylparaben - 19.5 mg
Propylparaben - 4.5 mg
Menthol - 22.5 mg
Eucalyptus Oil - 7.5 mg
Fragrances - 0.07 ml
Red # 40 dye FD & C - 3.0 mg
Sodium saccharin derivative - 30 mg
Purified water - to balance
Total - 15 ml
One dose in the form of 15 ml of an alcohol-free liquid drug is drunk by a patient with a stuffy nose. Congestion is significantly reduced.

В указанной выше формуле R представляет собой незамещенный C₁-C₃-алкил или алкенил, имеющий 2-3 атома углерода. R предпочтительно является алканилом; более предпочтительно метилом или этилом, наиболее предпочтительно метилом. В указанной выше формуле R' предпочтительно представляет цианогруппу.The present invention also includes new compounds having the following formula:

In the above formula, R is unsubstituted C ₁ -C ₃ alkyl or alkenyl having 2 to 3 carbon atoms. R is preferably alkanyl; more preferably methyl or ethyl, most preferably methyl. In the above formula, R 'preferably represents a cyano group.

 Preferred are those new compounds of the above formula in which (1) R is methyl and R 'is hydrogen, (2) R is methyl and R' is cyano.

Biological Activity Data
At the end of the description, the table shows the activity data of the claimed compounds in comparison with the known compounds having antagonistic properties against α-2-adrenergic receptors. By known methods, a D50 dose is determined that provides a 50% reduction in locomotor activity in mice, which indicates activity in relation to the central nervous system; D40 NAR value, which shows resistance to the passage of air in the nasal cavity and confirms the effectiveness of the compound in the treatment of nasal congestion; CNS TI value, which shows the difference between the dose / response graph for a specific action (in this case, the resistance to air passage in the nasal cavity NAR) and the dose / response graph for the central nervous system. The higher the CNS TI value, the greater the difference between the dose / response graphs and, accordingly, the lower the CNS mediated side effects at the therapeutic dose.

 Compound 1 is the compound described in Example 1 of WO-A-9221349.

 Compound 2 is the compound of Example 2 of the present invention.

 Clonidine is a clinically used α-2 adrenergic receptor agonist (for the treatment of hypertension), which causes 50% of patients with a therapeutic dose.

2.2. Physico-chemical data for the intermediate and target compound of Example 2
4-cyano-2,6-dinitrotoluene
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.97 (s, 3H), 2.7 (s, 3H);
¹³ C-NMR (CDCl ₃ ) δ 151.8,132.5, 130.4.114.5, 112.3, 15.3;
MS (Cl) m / z 208 (M + H) ⁺
4-cyano-2,6-diaminotoluene
¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.4 (s, 2H), 2.0 (s, 3H);
¹³ C-NMR (CDCl ₃ ) δ 148.4, 121.1, 113.6, 110.3, 109.7, 10.6;
IR (film) 2218.8 cm ^-1 (CN)
7-amino-5-cyano-8-methylquinoline
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.8 (dd, J = 4.0 Hz, J = 1.5 Hz, 1H), 8.1 (, dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.3 (dd, J = 8.4 Hz, J = 4.0 Hz, 1H), 5.9 (s, 2H), 2.4 (s, 3H);
¹³ C-NMR (CD ₃ OD) δ 150.7, 147.0, 146.6, 132.4, 123.9, 119.7, 119.3, 118.4, 117.1, 106.3, 10.8;
MC (Cl) m / z 184 (M + H) ⁺
IR (film 2226 cm ^-1 (CN)
5-cyano-8-methyl-7-isothiocyanate quinoline
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.0 (dd, J = 4.0 Hz, J = 1.8 Hz, 1H), 8.4 (, dd,) 3 J = 8.4 Hz, J = 1.8 Hz, 1H) 7.7 (s, 1H); 7.5 (dd, J = 8.4 Hz, J = 4.0 Hz, 1H); 2.9 (s, 3H);
¹³ C-NMR (CD ₃ OD) δ 151.7, 146.6, 140.06, 139.0, 133.3, 130.2, 125.9, 123.0, 115.4,109.0,13.7;
M- (5-cyano-8-methyl-7-quinolinyl) -N'-2-aminoethyl thiourea
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.0 (dd, J = 4.4 Hz, J = 1.5 Hz, 1H), 8.4 (, dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 8.3 (br.s, 1H), 7.7 (dd, J = 8.4 Hz, J = 4.4 Hz, 1H), 3.4 (br.m, 2H), 2.7 (t, J = 5.5 Hz, 2H), 2.6 (s, 3H);
¹³ C-NMR (CD ₃ OD) δ 181.4, 150.9, 146.4, 143.8, 134.1, 132.7, 124.7, 122.8, 116.6,105.0,47.2,12.6;
5-cyano-7- (2-imidazolininylaino) -8-integlquinoline tartrate.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.0 (dd, J = 4.4 Hz, J = 1.8 Hz, 1H), 8.4 (, dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 8.1 (s, 1H), 7.7 (dd, J = 8.4 Hz, J = 4.4 Hz, 1H), 4.0 (s, 2H), 3.6 (s, 4H), 2.7 (s, 3H);
¹³ C-NMR (CD ₃ OD) (free base) δ 160.0, 151.7, 149.3, 148.8, 136.4, 134.5, 133.3, 125.5, 122.2, 117.9, 108.7,43.6, 12.9;
MS (Cl) m / z 252 (M + H) ⁺ ;
Elemental analysis: C ₁₄ H ₁₃ N ₅ C ₄ H ₆ O ₆ 0.5H ₂ O
Calculated: C 52.68; H 4.91; N 17.07
Found: C, 52.67; H 4.53; N 17.00
Mp = 180.2 ^° C (decomp.).

Claims (9)

1. Derivatives of 7- (2-imidazolinylamino) quinoline of the general formula

where R is unsubstituted C ₁ - C ₃ alkyl or C ₂ - C ₃ alkenyl;
R ¹ represents a cyano group. 2. The compound of claim 1, wherein R is unsubstituted C ₁ - C ₃ alkyl.  3. The compound according to claim 1, in which R is methyl.  4. The compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of nasal congestion.  5. The compound according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of glaucoma.  6. The compound according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of diarrhea.  7. The compound according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of asthma.  8. The compound according to any one of claims 1 to 3 for oral administration.  9. The compound according to any one of claims 1 to 3 for topical administration to nasal tissue.

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