The compound 7-(2-imidazolidinone) quinoline, suitable as agonists alpha-2-adrenergic receptors

 

(57) Abstract:

The invention relates to the field of organic chemistry and medicine and relates to new quinoline derivatives of General formula I, where R represents unsubstituted C1-C3-alkyl or C2-C3alkenyl; R1is cyano, which are agonists alpha-2-adrenergic receptors and can be used when obtaining drugs suitable for the treatment of nasal congestion, glaucoma, diarrhea, asthma. Compounds have high antagonistic activity against-2-adrenergic receptors and is more effective in treating the above diseases. 8 C.p. f-crystals, 1 table.

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

Information related to alpha-adrenergic receptors, agonists and antagonists in General and related compounds similar in structure to compounds nastojasih is hemistry, Vol. 3, Membranes & Receptors, P. G. Sammes and J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185: Timmermans, P. B. M. W. M. and P. A. van Zweiten, "- Adrenoreceptor Agonist and Antagonist", Drugs of the Future, Vol. 9, No 1, (January, 1984), pp. 41-55; Megens, A. A. H. P. , J. E. Leysen, F. H. L. Awouters and C. J. E. Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the1-and2- Selectivity values of Test Compounds; (2) - Adrenoreceptor Agonist", European Lournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wiffert, H. Batink and P. A. van Zweiten, "Quantitative Relationship between - Adrenergic Activity and Binding Affinity of - Adrenoreceptor Agonist and Antagonist", Journal of Medicinal Chemistry, Vol. 27 (194), pp. 495-503; van the meel, J. C. A., A. deJonge, P. B. M. W. M. Timmermans and P. A. van Zwieten, "Selecttivity of Some Alpha - Adrenoreceptor Agonist for Peripheral1-and2- Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767: Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C Smith and M. R. Stillings, "Effect of 1,4-Dioxany Substitution on the Adrenergic Activity of Some standard - Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622, Chapieo, C. C., R. C. M. Butler, D. C. England, P. L., Myers, A. G. Roach/ C. F. C. Smith, M. R. Stillings and I. F. Tulloch, "Heteroaromatic Analogues of the - Adrenoreceptor Partial Agonist Clondine", J. Med. Chem., Vol 32 (1989), pp. 1627-160: Clare, K. A/, M. C. Scrutton and N. T. Thompson, "Effect2-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: U. S. Patent N 890 19 issued to Danielewicz, Snarey and Thomas on June 17, 1975: and U. S. Patent No. 5 091 528 issued to Gluchowski on February 25, 1992. However, many compounds with similar structure to the compounds of the present izobreteny the violations.

The object of the present invention relates, in particular, the fact that the compounds, which, as shown, are an effective means against nasal congestion, often have undesirable side effects, such as causing hypertension and insomnia, especially when the system introduction. There is a need for new medicines that provide relief from nasal congestion and do not cause unwanted side effects.

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

Another subject of the invention are such compounds that do not cause hypotension, drowsiness, hypertension, insomnia or have other unwanted side effects, especially when the system introduction.

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

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

Another subject of the invention are compounds that have good activity in oral and/or is a, includes introduction to the human or lower animal in need of such treatment, a safe and effective amount of a compound having the following structure:

< / BR>
where

(a) R is an unsubstituted C1-C-alkyl or C2-C3alkenyl and

(b) R cyano

The invention relates also to the use of such compounds for the prevention or treatment of respiratory, eye and/or gastrointestinal disorders. The invention relates to new compounds having the above structure wherein R' represents hydrogen or cyano.

The terms "alkyl", as used here, refers to a saturated hydrocarbon Deputy who has a normal or branched chain unsubstituted or substituted.

The terms "alkenyl", as used here, denotes a hydrocarbon Deputy with one double bond (in other cases it is saturated), which has a normal or branched chain unsubstituted or substituted.

The invention relates to compounds having the following formula:

< / BR>
In the above formula R represents an unsubstituted1-C3- alkyl or alkenyl having from 2 to 3 atoms oldpattern the stands.

Preferred compounds of the subject invention are compounds having the formula

< / BR>
where R and R' have the meanings specified below: N connection 1; R is CH3; CN - R'.

Compounds of the subject invention is specifically 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), such as sinusitis and otitis. At the same time, it has been found that undesirable side effects, such as hypotension, drowsiness, hypertension or insomnia can often be avoided. Not limited to a particular mechanism of action, I believe 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. Found that the compounds of the subject invention are agonists alpha-2-adrenergic receptors, which cause constriction of peripheral vascular channels in the nasal cavities.

Specific compounds of the subject invention do not have or have only weak activity of alpha-1-agonist, and have little effect or no effect on zgodny also for the treatment of eye disorders associated with elevated intraocular pressure such as glaucoma. Compounds administered orally or topically in the form of drops, gels or creams directly on the surface of the eye of a mammal.

Compounds of the present invention is also suitable for the treatment of disorders of motor function of the gastrointestinal tract, such as diarrhea, by action against the contractile and secretory function of the gastrointestinal tract.

The pharmacological activity and selectivity of the compounds of the invention can be determined using the described methods of testing. Alpha-2-selectivity of these compounds is determined by measuring the affinity for binding to the receptor and in vitro functional activity in a number of tissues, which are known to contain alpha - 2 and/or alpha-1 receptors (See, for example, The Alpha-2 Adrenergic Receptors. L. E. Limbird, ed., Humana Press, Spandex, NJ). Typically, rodents and other animals spend in vivo following tests. The activity of the Central nervous system is determined by measuring locomotor activity as an index of sedatives. (See, for example, 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). Active substances against C is. (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). Antiglaucoma activity is determined by measurement of intraocular pressure (Cm. 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 induced prostaglandin diarrhea (See,for example, Thollander, M., P. Hellstrom and T. Svensson, "Suppression of Castor oil-induced Diarrhea by Alpha-2 Adrenoceptor Agonist", aliment oil displayed pure. Pharmacol. Therap., Vol. 5 (1991), pp. 255-262). Anti-asthma activity is determined by measuring the activity of a compound on bronchostenosis associated with pulmonary antigenic stimuli, such as exposure to inhaled antigens (See. for example, Chang, J. J. Musser and J. Hind, "Effect of a Novel Leukotriene D4Antagonist with 5 - Lipoxygenase and Cyclooxygenase inhibitory Activity, Wy45911, on Leukotriene-D4- and Antigen-induced Bronchoconstriction in Guinea Pig", Int. Arch. Allergy Appl. Immun., Vol. 86 (1988), pp. 48-54 and Delehunt, J. A. 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 Chirp", Am. Rev. Respir. Dis., Vol. 130 (1984), pp. 784-754). Antitussive activity determined by measuring the number and latency of the cough response to respiratory antigenic stimulus, such as inhaled citric acid. (See,for example, Callway, J. and R. King, "Effect of inhaled Alpha-2-Adrenoc the means of the present invention are synthesized using the following General method:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
In the above scheme, where R' is an alkoxy - or allylthiourea corresponding hydroxy - or mercaptoethane get out of the final compounds using standard techniques dealkylation (Bhatt, et al., "Cleavage of Ethers", Synthesis, 1983, pp. 249-281).

Examples of syntheses

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

Example 1

The dihydrochloride synthesis of 8-methyl-7-(2-imidazolidinone)quinoline

< / BR>
8-Methyl-7-nitroquinoline. A mixture of 2-methyl-3-nitroaniline (10 g), glycerol (20,57 g) and As2O5H2O (Bacer, 88% As2O5, 8.5 g) is slowly heated to 150oC in an open round-bottom flask, and then stirred for 6 h at 150oC. the resulting mixture was cooled to room temperature and diluted with water (200 ml), then add ammonium hydroxide (28-30%, 100 ml). After approximately 10 min, the solution is acidified to pH 5 glacial acetic acid and extracted with CH2Cl2(3 x 200 ml). The combined extracts washed with water (200 ml), a saturated solution of NaHCO3(200 ml), then dried over MgSO4and evaporated on a rotary evaporator. Untreated hanovarian in a rotary evaporator and the residue will recrystallized from a mixture of hexane/CH2Cl2getting 8-methyl-7-nitroquinoline in the form of a reddish-brown solid.

7-Amino-8-methylinosine. To a solution of 8-methyl-7-nitroquinoline (1.8 g) in methanol (20 ml) is added Pd/C (10%, 0.45 g) and ammonium formate (2,77 g). The mixture is stirred at room temperature for 30 min, then filtered through celite and the solid part was washed with methanol. The filtrate is evaporated on a rotary evaporator and the residue partitioned between H2O and CH2Cl2. The organic layer is dried over potassium carbonate, filtered and evaporated on a rotary evaporator, receiving 7-amino-8-methylinosine in the form of a yellow solid.

8-Methyl-7-chinainternational. To a solution of di-2 - pyridylmethylamine (DPT) (to 2.29 g) (Aldrich) and 4 - dimethylaminopyridine (DMAP) (0.02 g) is added dropwise a solution of 7-amino-8-methylinosine (1.3 g) in CH2Cl2(50 ml). The mixture is stirred for 5 h at room temperature, then evaporated on a rotary evaporator. The residue is purified flash chromatography on silica gel with elution 25% solution of ethyl acetate in hexane, receiving 8-methyl-7-chinainternational in the form of a pale yellow solid.

N-(8-Methyl-7-chinoline)-N'-2-aminoethylthiomethyl. A solution of 8-methyl-7-chinainternational stirred for 30 min at room temperature and then evaporated on a rotary evaporator. The residue is suspended in CH2Cl2(50 ml) and diethyl ether (50 ml) and then filtered. The precipitate is dried in vacuum, obtaining N-(8-methyl-7-chinoline)-N'-2-aminoethylthiomethyl in the form of a white powder.

The dihydrochloride 8-methyl-7-(2-imidazolidinone)quinoline

A mixture of N-(8-methyl-7-chinoline)-N'-2-aminoethylethanolamine (0,94 g) and acetate mercury (1.18 g) in methanol (30 ml) is stirred for 4 h at room temperature. Received the black mixture was filtered through celite and the filtrate concentrated. The residue was diluted with CH2Cl2(50 ml) and a saturated solution of NaHCO3(20 ml) and the pH of the aqueous layer set to 10 by adding 50% aqueous sodium hydroxide. The layers are separated and the organic layer is dried (K2CO3) and evaporated in a rotary evaporator. The residue is purified flash chromatography on a small layer of silica gel, using 10% solution of methanol in chloroform containing 1% ammonium hydroxide. The fractions containing the product are collected and evaporated in a rotary evaporator, receiving 8-methyl-7-(2 - imidazolidinone)quinoline as a yellow solid. Dihydrochloride salt is produced by bubbling HCL through a cold solution of quinoline in methanol (20 ml). The methanol is evaporated in a rotary evaporator and the residue will recrystallized from a mixture of the
Synthesis monotremata 5-cyano-8-methyl-7-(2-imidazolidinone)-quinoline

< / BR>
4-Cyano-2,6-dinitrotoluene. A solution of 4-ceanataur (10.3 g) in tetramethylsilane (65 ml) is added dropwise into a solution of tetrafluoroborate nitronium (14.6 g) in tetramethylsilane (130 ml). The reaction mixture is stirred for one hour at 95oC. the reaction mixture is slowly added tetrafluoroborate nitronium (15,58 g) and the mixture is then stirred for another two hours. The mixture was poured into ice and diluted with further water (500 ml). The products are extracted with ethyl acetate (4 x 500 ml). The combined extracts are dried over magnesium sulfate and evaporated in a rotary evaporator. The crude orange oil is filtered through a low layer of silica gel, using 10% solution of acetate in hexane as solvent. The filtrate is evaporated in a rotary evaporator, and the residue will recrystallized from hot methylene chloride, receiving 4-cyano-2,6-dinitrotoluene in the form of 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 a metal tin (granules, 14,66 g), which is added slowly so that the temperature and set pH 11 by addition of concentrated ammonium hydroxide. The products are extracted with ethyl acetate (5 x 300 ml). The combined extracts dried over sodium sulfate and evaporated in a rotary evaporator. The residue is purified flash chromatography on silica gel, elwira 50% solution of ethyl acetate in hexane, receiving 4-cyano-2,6-diaminotoluene in the form of a yellow solid.

7-Amino-5-cyano-8-methylinosine. A mixture of 4-cyano-2,6-diamino-toluene (of 3.56 g), ferric chloride uranyl (11,63 g) and zinc chloride (0,499 g) in ethanol (600 ml) is heated to 65oC. for 90 min using a syringe add dropwise a solution of 1,1,3-trimethoxypropane (5,23 g) in ethanol (90 ml). The reaction mixture is then 2.5 h refluxed, then cooled to room temperature and the solvent is evaporated on a rotary evaporator. The residue is mixed with 300 ml of water and the pH of the mixture set 11 by the addition of concentrated ammonium hydroxide. The products are extracted with ethyl acetate (4 x 800 ml) and the combined extracts dried over sodium sulfate and evaporated in a rotary evaporator. The residue is purified flash chromatography on silica gel with elution with 50% ethyl acetate in hexane, receiving 7-amino-5-cyano-8-methyl-quinoline as a yellow solid.

5-Cyano-8-methyl-7-chinainternational who have dropwise a solution of 7-amino-5-cyano-8-methylinosine (1.22 g) in methylene chloride (80 ml). The mixture is stirred for 4 h at room temperature and then evaporated on a rotary evaporator. The residue is purified flash chromatography on silica gel with elution 25% solution of ethyl acetate in hexane, receiving 5-cyano-8-methyl-7-chinainternational in the form of a yellow solid.

N-(5-Cyano-8-methyl-7-chinoline)-N'-2 - aminoethylthiomethyl

A solution of 5-cyano-8-methyl-7-chinainternational of 0.85 g) in toluene (100 ml) is added dropwise to a solution of 1,2-Ethylenediamine (1,94 g) in toluene (100 ml). After stirring the reaction mixture at room temperature for 10 minutes to observe the appearance of a yellow-white precipitate. The precipitate was separated by filtration and dried in vacuum, obtaining N-(5-cyano-8 - methyl-7-chinoline)-N'-2-aminoethylthiomethyl in the form of a yellow-white solid.

Monetarist 5-cyano-8-methyl-7(2-imidazolidinone)quinoline.

A mixture of N-(5-cyano-8-methyl-7-chinoline)- N'-2-aminoethylethanolamine (1.01 g) and acetate mercury (II) (1,61 g) in ethanol (70 ml) was stirred at room temperature for 10 minutes Received a black mixture was filtered through celite and the filtrate is evaporated with a rotary evaporator. The residue was diluted with water (20 ml), set pH 10 by addition of saturated potassium carbonate solution and the former is the body. The residue is purified flash chromatography on silica gel with elution 10% solution of methanol in chloroform containing 1% ammonium hydroxide, receiving 5-cyano-8-methyl-7-(2 - imidazolidinone)quinoline as a yellow solid. It is dissolved in methanol (25 ml) and treated with a solution of L-tartaric acid (0,096 g) in methanol (25 ml). The solution is evaporated on a rotary evaporator, obtaining a residue, which is recrystallized from a mixture of methanol and diethyl ether to highlight monotremata 5-cyano-8-methyl-7(2 - imidazolidinone)quinoline.

Example 3

Synthesis of sesquichloride 5-fluoro-8-methyl-7 (2-imidazolidinone)quinoline

< / BR>
2,6-Dinitro-4-Vtortola. Fuming sulfuric acid (180 ml) is added dropwise 4-fluoro-2-nitrotoluene (50,21 g) in an argon atmosphere. The internal temperature of the mixture support at 0-5oC, using a bath of ice/sodium chloride. Pre-formed (bath with ice) mixture of fuming nitric acid (30 ml) and fuming sulfuric acid (90 ml) is added dropwise to the previous solution within three hours. The reaction mixture was then left to warm to room temperature. After stirring for two hours at room temperature the mixture was poured slowly into ice and the product and evaporated on a rotary evaporator. The crude mixture is filtered through a small layer of silica gel, using 10% solution of ethyl acetate in hexane as solvent, and then recrystallized from a mixture of ethyl acetate/hexane, obtaining 2,6 - dinitro-4-vtortola in the form of a pale yellow solid.

2-Amino-4-Fluoro-6-nitrotoluene. A solution of 2,6-dinitro-4 - portaluri (8.1 g) in ethanol (130 ml) is treated dropwise with a solution of nonahydrate of sodium sulfide (16,39 g) in water (90 ml). The mixture is stirred for 2.5 h at room temperature, then diluted with water (500 ml) and extracted with ethyl acetate (4 x 500 ml). The combined extracts dried over sodium sulfate and evaporated in a rotary evaporator. The residue is purified flash chromatography on silica gel with elution with a 15% solution of ethyl acetate in hexane, obtaining 2-amino-4-fluoro-6-nitrotoluene in the form of a solid substance.

7-Amino-5-fluoro-8-methylinosine. A mixture of 2-amino-4-fluoro-6-nitrotoluene (4.4 g), glycerol (7.5 g), hydrate of oxide of arsenic (V) (Aldrich, 54%, 5.0 g) and concentrated sulfuric acid (35 ml) is heated to 140oC for 4 h, the Reaction mixture was cooled to room temperature and diluted with water (300 ml). The mixture was added concentrated ammonium hydroxide solution to establish a pH of 10 and extracted with neochischennyh the product was then purified flash chromatography on silica gel with elution 25% solution of ethyl acetate in hexane, getting 7-amino-5-fluoro-8 - methylinosine in the form of a solid substance.

5-fluoro-8-methyl-7-chinainternational. A mixture of 7-amino-5-fluoro-8-methylinosine (0.39 g) and thiophosgene (0.2 ml) in water (5 ml) and 1 N hydrochloric acid (5 ml) is stirred for 1.5 h at room temperature. Add more thiophosgene (0.1 ml) and the mixture is 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 dried over sodium sulfate and evaporated on a rotary evaporator. The residue is purified flash chromatography on silica gel using 15% aqueous solution of ethyl acetate in hexane, receiving 5-fluoro-8-methyl-7 - chinainternational in the form of a reddish-brown solid.

N-(5-fluoro-8-methyl-7-chinoline)-N'-2-aminoethylthiomethyl.

A solution of 5-fluoro-8-methyl-7-chinainternational (0,38 g) in toluene (40 ml) is added dropwise to a solution of 1,2-Ethylenediamine (0,78 g) in toluene (40 ml). The formation of white precipitate was observed after stirring for 10 min at room temperature. The precipitate was separated by filtration and dried in vacuum, obtaining N-(5-fluoro-8 - methyl-7 - chinoline)-N'-2-aminoethylthiomethyl in the form of a white solid.

Sesquipedale (0,38 g) and acetate mercury (0,70 g) in ethanol (25 ml) is stirred for 10 min at room temperature. Received the black mixture was filtered through celite and the filtrate is evaporated in a rotary evaporator. The residue was diluted with water (20 ml) and treated with concentrated ammonium hydroxide solution to establish a pH of 10. The product is dried over sodium sulfate and evaporated on a rotary evaporator. The residue is purified flash chromatography on silica gel, elwira 10% solution of methanol in chloroform containing 1% ammonium hydroxide. The fractions containing the product are collected and evaporated on a rotary evaporator, receiving 5-fluoro-8-methyl-7-(2-imidazolidinone) quinoline as a yellow solid. It is dissolved in 10 ml of methanol and cooled in an ice bath. In the solution for 5 min bubbled gaseous hydrogen chloride. The solution is evaporated on a rotary evaporator. Educated the rest will recrystallized from methanol/diethyl ether, receiving sesquihydrate 5-fluoro-8-methyl-7-(2-imidazolidinone) quinoline as a yellow solid.

The invention includes the use of a composition, which contains a safe and effective amount of a compound of the invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The term "safe and effective amount" means the amounts which need to be treated, but low enough to avoid serious side effects (at a reasonable relation to the benefit/risk) within the scope of a thorough medical evaluation. Safe and effective amount of the compounds 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 concurrent therapy, the specific applicable pharmaceutically acceptable carrier and the like factors within the knowledge and opinions of a treating physician.

Compositions of the invention preferably contain from about 0,0001% to about 99% by weight of compounds of the invention, more than before respectfully from about 0.01% to about 90%, also preferably from about 10% to about 50%, also preferably from about 5% to about 10%, also preferably from about 1% to about 5% and preferably from about 0.1% to about 1%.

In addition to the compounds of the invention compositions of the subject invention contain a pharmaceutically acceptable carrier. Used in the description of the term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or kapsulirujushchej substances that are suitable for you composition is able to be mixed with the compound of the invention and with each other so to no interaction which would substantially reduce the pharmaceutical activity of the composition under ordinary use. Pharmaceutically acceptable carriers must, of course, be sufficiently pure and are sufficiently little toxic, so you can enter the human or lower animal, which must be treated.

Some examples of substances which can serve as pharmaceutically acceptable carriers or components of them, are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc: solid lubricants, such as stearic acid and stearine magnesium: calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol, alginic acid; emulsifiers, such as Tween; wetting agents, such sodium lauryl sulfate: painting means: perfumes; tabletiruemye means the buffer solutions.

The choice of pharmaceutically acceptable carrier, which is used in combination with the compound of the invention is essentially determined by the way in which the connection must be entered.

If the connection of the invention need to be injected, the preferred pharmaceutically acceptable carrier is sterile saline solution with a compatible blood suspendium means, the pH is set to about 7.4.

The preferred method of introducing the compounds of the invention for oral administration. The preferred uniform dosage form are tablets, capsules, cakes, chews, etc. Such uniform dosage forms contain a safe and effective amount of the compounds of the invention, which is present in quantities of preferably from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 50 mg, more preferably from about 0.5 mg to about 25 mg, also preferably from about 1 mg to 10 mg of Pharmaceutically acceptable carriers that are suitable for obtaining a uniform dosage forms for oral administration are well known in this field. Tablets usually contain pharmaceutically compatible auxiliary and cellulose; binders, for example starch, gelatin and sucrose; dezintegriruetsja tools, such as starch, alginic acid and croscarmellose; lubricants, such as stearine magnesium, stearic acid, talc. To improve the bulk characteristics of the powder mixture can be applied silicon dioxide. To achieve the desired appearance you can add coloring tools, such as dyes, FD & C Sweeteners and flavouring agents, such as aspartame, saccharin, menthol, peppermint and fruit fragrances are suitable utilities for chewable tablets. Capsules typically contain one or more solid diluents described above. The selection of carrier components depends on secondary factors such as taste, price, and stability during storage, which is not critical for the purposes of the subject invention, this choice can easily make a specialist in this field.

Oral compositions include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers that are suitable for such compositions are well known in this area. Such liquid oral compositions preferably contain from about 0,001% to about 5% of the compounds is of exiros, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Used to obtain a suspension typical suspendresume tools include methylcellulose, sodium carboxymethyl cellulose, AvicelRC-591, tragakant and sodium alginate; typical wetting means comprise lecithin and Polysorbate 80: typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, corrigentov and dyes described above.

Other compositions suitable for attaining systemic delivery of the compounds of the invention in the body, include sublingual and buccal dosage forms. Such compositions typically contain one or more soluble substances, fillers, such as sucrose, sorbitol and mannitol; a binder such as Arabian gum, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. You can also include components which impart flowability, lubricants, coloring tools, antioxidants and perfumes, as described above.

Preferred Spock; intranasal doses to eliminate nasal congestion, pharmaceutical forms for inhalation in asthma, eye drops, gels and creams for eye disorders and oral dose for gastrointestinal disorders.

Preferred compositions of the subject invention include aqueous solutions containing a safe and effective amount of the compounds of the invention, intended for local intranasal. Such compositions preferably contain from about 0,001% to about 5% of the 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, such as benzalkonium chloride and thimerosal; buffers, such as phosphate and acetate; isotonic agents such as sodium chloride; antioxidants, such as ascorbic acid; aromatic funds and acids and bases to establish certain values of the pH 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 the compounds of the invention, intended for spraying and m the I invention, more preferably from about 1% to about 20%. Such compositions typically contain container with attached means for spraying. Such compositions typically include propellants (carrier gas) such as chlorofluorocarbons 12/11 and 12/114: solvents such as water, glycerol and ethanol; stabilizers such as ascorbic acid, sodium metabisulfite; preservatives, for example the chloride of cetylpyridinium and benzalkonium chloride; tonics, such as sodium chloride and odorants, such as 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 local intraocular injection. Such compositions preferably contain from about 0,0001% to about 5% of the compound of the invention, more preferably from about 0.01% to about 0.5%. Such compositions typically include one or more preservatives, such as benzalkonium chloride, thimerosal, acetate finalstate (II); fillers, for example poloxamer, modified cellulose, povidone, purified water; tonics, such as sodium chloride, mannitol and glycerin; buffers, such as acetate, citrate,Stein; acids and bases that can be used to establish a pH of these finished dosage forms, if necessary.

Preferred compositions of the subject of the present invention include solid forms such as tablets and capsules, and liquids, such as solutions, suspensions and emulsions (preferably in soft gelatin capsules) containing a safe and effective amount of a compound of the invention and intended for local introduction into the gastrointestinal tract through the mouth. 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 membranes using conventional techniques, usually dependent on the pH of the medium and the time the shells, allowing the connection of the invention is secreted in the gastrointestinal tract adjacent to the desired application site or at a certain time to provide the desired action. Such dosage forms typically contain (but may contain other components) one or more of the components: acetate-phthalate cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose, ethylcellulose, shell, Eudragitthe wax is limiting examples of drugs you can enter in the composition of the invention and a typical metered quantity of them include: respiratory drugs: classical antihistamines, such as chlorpheniramine in the amount of from about 1 mg to about 4 mg per dose and diphenhydramine in the amount of from about 10 mg to about 50 mg per dose; resedation antihistamines, such as terfenadine in the 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 the amount of from about 5 mg per dose to about 10 mg per dose; expectorants, such as guaifenesin in the amount from about 100 mg to about 200 mg per dose: antitussives, such as dextromethorphan in an amount of from about 5 mg to about 30 mg per dose; and analgesics, such as ibuprofen in the amount from about 100 mg to about 800 mg per dose and acetaminophen in quantities of from about 80 mg to about 1000 mg per dose; ophthalmic drugs: acetylcholinesterase inhibitors, such as echothiophate in the amount of from about 0.03% to about 0.25% solution for topical administration; gastrointestinal medicines: the remedy against diarrhea, such as loperamide in an amount of from about 0.1 mg to about 1.0 mg per dose and subsalicylate bismuth in an amount of from about what I nasal congestion the introduction of safe and effective amount of compounds of the invention to a human or lower animal, experiencing nasal congestion or risk of nasal congestion. This nasal congestion may be associated with diseases or disorders in humans, which include, but are not limited to, seasonal allergic rhinitis, acute viral infectious disease of the upper respiratory tract, sinusitis, chronic rhinitis and vasomotor rhinitis. Preferably, each injection contained a dose of a compound of the invention in the range 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, Preferably oral administration of the dose. The frequency of introduction of compounds in accordance with the present invention is preferably from one to six times per day, more preferably from two times to four times per day. Such a dose and frequency of their administration is preferred for the treatment of other respiratory diseases, such as otitis media, cough, COPD and asthma.

Another object of the invention includes methods of preventing or treating glaucoma introduction of safe and effective amount of compounds of the invention to a human or lower animal suffering from glaucoma or have the I in the 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, Preferably intraocular introduction of such doses. The frequency of introduction of a joint in accordance with the invention is preferably from one to six times per day, more preferably from 2 times to 4 times per day.

Another object of the invention includes methods of preventing or treating functional gastrointestinal disorders such as diarrhea,

the introduction of safe and effective amount of compounds of the invention to a human or lower animal suffering from diarrhea or have the risk of diarrhoea. Preferably, each of the input dose contained a compound of the invention in the range 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, Preferably oral administration of the dose. The frequency of introduction of a joint in accordance with the invention is from one to six times per day, more preferably from 2 to 4 times a day.

Examples of compositions and methods

The following non-limiting examples illustrate the compositions and methods of use the STV on the tablet (mg)

Connection 3 - 20,0

Microcrystalline cellulose

(Avicel pH 102) - 80,0

Dicalcium phosphate - 96,0

Fumed silica (Cab-O-Sil) - 1,0

Magnesium stearate - 3,0

All 200,0

One tablet eaten by the patient with nasal congestion. The congestion is greatly reduced.

The example IN

The composition is in the form of chewable tablets

The ingredient Quantity per tablet (mg)

Connection 1 - 15,0

Mannitol - 255,6

Microcrystalline cellulose (Avicel PH 101) - 100,8

Dextrinization sucrose (Di-Pac) - 199,5

Orange perfume - 4.2V

Sodium derivative of saccharin - 1,2

Stearic acid - 15,0

Magnesium stearate - 3,0

Yellow # 6 lake, FD & C 3,0

Fumed silica (Cab-O-Sil) - 2,7

All of 600.0

One tablet chew and eaten by the patient with nasal congestion. The congestion is greatly reduced.

Example WITH

The sublingual composition in tablet form

The ingredient Quantity per tablet (mg)

Compound 2 of the invention is 2.00

Mannitol - 2,00

Microcrystalline cellulose (Avicel PH 101) - 29,00

Mint fragrances is with a stuffy nose and leave to dissolve. Stuffy quickly and significantly reduced.

Example D

The composition is in the form of intranasal solution

Ingredient Content (wt./vol.%)

Compound 3 of the invention - 0,20

The benzalkonium chloride - 0.02

Thimerosal - 0,002

d-Sorbitol - 5,00

Glycine - 0,35

Flavouring agents - 0,075

Purified water to balance

Just 100,00

One-tenth ml of the composition POPs out of the vessel under the action of pressure in each nostril of a patient with a blocked nose. The congestion is greatly reduced.

Example E

Intranasal composition in gel form

Ingredient Content (wt./vol.%)

Connection 1 - 0,10

The benzalkonium chloride - 0.02

Thimerosal - 0,002

The hypromellose (Metolose 65SH400) was 1.06

Flavouring agents - 0,06

Sodium chloride (0.65%) are to balance

Just 100,00

One-fifth of ml of the composition is administered in the form of drops from a pipette into each nostril of a patient with a blocked nose. The congestion is significantly reduced.

Example F

Inhalation aerosol composition

Ingredient Content (wt./vol.%)

Connection 2 - 5,0

Alcohol - 33,0

Ascorbic acid - 0,1

Aerosol composition is administered to a patient with asthma by inhalation of the two jets from a metered dose inhaler with the issue. Asthmatic condition effectively facilitated.

Example G

Ophthalmic composition for local application

Ingredient Content (wt./vol.%)

Connection 4 - 0,10

The benzalkonium chloride is 0.01

Ethylenediaminetetraacetic acid - 0,05

Hydroxyethylcellulose (Nastrol M) - 0,50

Metabisulphite sodium - 0,10

Sodium chloride (0.9 per cent) to balance

Just 100,0

One-tenth ml of the composition is injected directly into each eye of a patient with glaucoma. Intraocular pressure is greatly reduced.

Example H

Liquid composition for oral administration

Ingredient: Amount per dose 15 ml

Connection 3 - 15 mg

The chlorpheniramine maleate 4 mg

Propylene glycol and 1.8 grams

Ethanol (95%) - 1.5 ml

Methanol - 12.5 mg

Eucalyptus oil - 7.55 mg

Perfumes - 0.05 ml

Sucrose - of 7.65 g

Carboxymethylcellulose (CMC) - 7.5 mg

Microcrystalline cellulose and sodium salt of CMC (Avicel RC 591) - 187.5 mg

Polisorb 80 - 3.0 mg

Glycerin is 300 mg

Sorbitol 300 mg

Red #40 lake, FD & C 3 mg

Sodium derivative of saccharin - 22,5 mg

Monopotassium phosphate sodium 44 mg

Monohydrate citrate NAT who provides the patient with a blocked nose and chronic runny nose due to allergic rhinitis. Stuffy and runny nose effectively reduced.

Example J

Liquid composition for oral administration

Ingredient: Amount per dose 15 ml

Connection 4 - 30 mg

Sucrose - 8,16 g

Glycerin is 300 mg

Sorbitol 300 mg

Methylparaben - 19.5 mg

Propylparaben - 4.5 mg

Menthol - 22,5 mg

Eucalyptus oil - 7.5 mg

Odorants of 0.07 ml

Red #40 lake, FD & C 3.0 mg

Sodium derivative of saccharin - 30 mg

Purified water to balance

Only 15 ml

A single dose of 15 ml of alcohol-free liquid medicines consumed by the patient with a blocked nose. The congestion is greatly reduced.

The present invention also includes novel compounds having the following formula:

< / BR>
In the above formula R represents an unsubstituted1-C3-alkyl or alkenyl having 2-3 carbon atoms. R preferably is elkayam; more preferably the stands or ethyl, most preferably the stands. In the above formula R' preferably represents cyano.

Preferred the new compounds of the above formula in which (1) R is the stands and R' is hydrogen, (2) is isane, the table presents data activity of the claimed compounds in comparison with known compounds with antagonistic properties against-2-adrenergic receptors. By known methods determine the D50 is the dose that provides a 50% reduction in locomotor activity in mice, which indicates activity against Central nervous system; the size of the D40 NAR, which shows resistance to airflow in the nasal cavity and confirms the effectiveness of the compounds in the treatment of nasal congestion; the magnitude of CNS TI, which indicates the difference between the schedule according to the dose/response for a particular action (in this case the resistance to airflow in the nasal cavity NAR) and schedule the dose/response for the Central nervous system. The higher the value CNS TI, the greater the difference between the graphs of dose/response and correspondingly less mediasuite CNS side effects at therapeutic dose.

Connection 1 connection described in Example 1 of WO-A-9221349.

Connection 2 connection Example 2 of the present invention.

Clonidine is clinically used agonist-2-adrenergic receptors (for treatment of hypertension), causing 50% of patients at therapeutic dose.

2.2
1H-NMR (300 MHz, CDCl3) 8.97(c, 3H), 2.7(s, 3H);

13C-NMR (CDCl3) 151.8,132.5, 130.4,114.5, 112.3, 15.3;

MC (Cl) m/z 208 (M+N)+< / BR>
4-cyano-2,6-diaminotoluene

1H-NMR (300 MHz, CDCl3) 6.4(s, 2H), 2.0(s, 3H);

13C-NMR(CDCl3) 148.4, 121.1, 113.6, 110.3, 109.7, 10.6;

IR (film) 2218.8 cm-1(CN)

7-amino-5-cyano-8-methylinosine

1H-NMR (300 MHz, DMSO-d6) 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);

13C-NMR (CD3OD) 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)+< / BR>
IR (film 2226 cm-1(CN)

5-cyano-8-methyl-7-izotiocianatochalcone

1H-NMR (300 MHz, DMSO-d6) 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);

13C-NMR (CD3OD) 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-chinoline)-N'-2-amino-ethyl thiourea

1H-NMR (300 MHz, DMSO-d6) 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(Shir.s, 1H), 7.7(DD, J=8.4 Hz, J=4.4 Hz, 1H), 3.4(Shir.m, 2H), 2.7(t, J= 5.5 Hz, 2H), 2.6 (s,3H);

13C-NMR (CD3OD) 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-imidazolidinone)-8-interinale tartrate.

1H-NMR (300 MHz, DMSO-d6) 9.0(DD, J=4.4 G Is B>OD) (free base) 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;

MC (Cl) m/z 252 (M+H)+;

Elemental analysis: C14H13N5C4H6O60.5 H2O

Calculated: 52,68; H 4,91; N 17,07

Found: 52,67; H a 4.53; N 17,00

So pl. = 180,2oC (decomp.).

1. Derivatives of 7-(2-imidazolidinone)quinoline General formula

< / BR>
where R is unsubstituted WITH1- C3alkyl or C2- C3alkenyl;

R1represents cyano.

2. Connection on p. 1, in which R represents unsubstituted WITH1- C3alkyl.

3. Connection on p. 1, in which R is methyl.

4. The compound according to any one of paragraphs.1 to 3 to obtain drugs for the treatment of nasal congestion.

5. The compound according to any one of paragraphs.1 to 3 for receiving medicines to prevent or treat glaucoma.

6. The compound according to any one of paragraphs.1 to 3 for receiving medicines to prevent or treat diarrhea.

7. The compound according to any one of paragraphs.1 to 3 for receiving medicines to prevent or treat asthma.

8. The compound according to any one of paragraphs.1 - 3 for oral administration.

 

Same patents:

The invention relates to new biologically active compounds, namely isopropylamino 2-(4-chloroanilino)cinchoninic acid of the formula:

< / BR>
possessing anti-inflammatory and analgesic activity, suggesting the possibility of its use in medicine as a drug for the treatment of inflammatory processes

The invention relates to medicine, specifically to experimental physiology, pharmacology and pathophysiology related to the possibility of modeling violations of motor-evacuation function of the intestines - constipation

The invention relates to chemistry, medicine and pharmacology, new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to a derivative of xanthine f-ly I, their stereoisomers and the physiologically tolerated salts, and pharmaceutical compositions having reducing pathological hyperactivity eosinophilic granules activity

The invention relates to arylalkylamines formula I, where R1and R2each, independently of one another, denote H or A; R3and R4each, independently of one another, denote OR10R5is phenyl residue substituted R6Q - alkylene with 1-6 C-atoms, R6denotes - NH2, -NR8R9, -NO2; R8is hydrogen, R9- alkanoyl with 2-8 C-atoms which may be substituted by 1 to 5 fluorine atoms, -cooa or-SO2A; And - alkyl with 1-6 C-atoms, R10- Or cycloalkyl with 3-7 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them

The invention relates to therapeutic tools, specifically setidentityproviderid N-substituted nitrogenous heterocyclic compounds and methods of producing such compounds, intermediate products used in obtaining, compositions containing such compounds and the use of such heterocycles

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof

The invention relates to new derivatives of propiophenone having hypoglycemic activity, and method of production thereof

The invention relates to compounds that should be applied in the pharmaceutical industry as biologically active substances to obtain drugs

The invention relates to chemical-pharmaceutical industry and relates to a liquid composition for oral administration

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

Up!