New derivatives of hinoklidina and medical compositions containing them

 

(57) Abstract:

Describes new derivatives of hinoklidina represented by the formula (I) in which ring a represents a phenyl group which may be optionally substituted by a halogen atom or a lower alkyl group, tsiklogeksilnogo group, pyridyloxy group, follow group or thienyl group; X represents a single bond or methylene group; l = 0 or 1; n = 1 or 2, or their salts with acids, or their Quaternary ammonium salts. Describes farbkomposition based on them. These compounds exhibit antagonistically effect on muscarinic M3receptors and are useful as preventive or therapeutic agents urological diseases, respiratory diseases, or diseases of the digestive system. 2 S. and 3 C.p. f-ly, 33 tab.

The invention relates to medicines, especially derivatives of hinoklidina or their salts, or Quaternary ammonium salts having antagonistic activity against muscarinic receptors, as well as to pharmaceutical compositions containing such compounds.

And conducted research muscarinic receptor the frames, cause the bronchi, the inhibition or suppression of gastrointestinal motor activity, suppression of acid secretion, dry mouth, mydriasis (pupil dilation), inhibition of bladder contractions, hypohidrosis, tachycardia or similar phenomena. It is known that muscarinic receptor includes at least three subtypes. The receptor for M1exists mainly in the brain or similar, the receptor for M2in the heart, or equivalent, and the receptor for M3in smooth muscle or gland tissues.

A number of such compounds having antagonistic activity against muscarinic receptors, is already known, and a typical example is, for example, atropine ("The Merck Index, 11-th edition, page 138). However, atropine antagonisitic M1-, M2and M3receptor selectivity, so it is difficult to use for treating a particular disease. In recent years, with progress in the study of subtypes of muscarinic receptors was studied compounds with selective antagonistic activity against M1-, M2or M3receptor (not passed examination, published patent application N 2249093 not held expertisea application (kokai) 3-133980). There is a need for compounds with selective antagonistic activity among the three subtypes against muscarinic M3-receptor and free of side-effects on the heart, which is the result of the action of M2-receptor.

In unexamined published Japanese patent application (kokai) 62-252764 describes the connection represented by the following General formula:

< / BR>
in which L is NH or O;

X and Y each independently represents a hydrogen atom or a C1-6with alkyl group, or they can be combined together to form the connection;

R1and R2each independently represents a hydrogen atom, a C1-6alkyl group...;

R3and R4each independently represents a hydrogen atom, halogen atom, CF3C1-6alkyl group..., phenyl group, amino group which may be optionally N - substituted by one or two groups selected from phenyl,1-6alkyl groups, or can be optionally N-disubstituted6-8polyethylene...;

Z represents a group

< / BR>
or similar;

p=1 or 2; and q=1-3.

The compound described in the above patev against muscarinic receptor. The above connection, it is clear that different from the compounds according to the present invention by the pharmacological action.

The inventors of this application conducted an extensive study of compounds with antagonistic activity against the above muscarinic M3- receptor. In the result, the inventors have created a new derivative of hinoklidina having a basic skeleton, non-skeletal conventional compounds, and found that these compounds exhibit excellent selective antagonistic activity against muscarinic M3-receptor, ending in the present invention.

Thus, the present invention relates to a derivative Innoclean represented by the following General formula (I), their salts or Quaternary ammonium salts; and to pharmaceutical compositions comprising these compounds and their salts and pharmaceutically acceptable carriers, especially for antagonists of muscarinic M3-receptor.

< / BR>
(symbols in the formula have the following meanings: Ring A (indicated in the structural formula as "Ring A"); aryl group, cycloalkyl group, cycloalkenyl group, Getli 5- - 7-membered saturated heterocyclic group, where the specified ring may be substituted by an optional Deputy;

X: single bond or methylene group;

R: halogen atom, hydroxyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, a lower acyl group, mercapto group, lower allylthiourea, sulfonylurea group, lower alkylsulfonyl group, sulfonylurea group, lower alkylsulfonyl group, sulfonamide group, a lower alkanesulfonyl group, carnemolla group, thiocarbamoyl group, mono - or di-lower alkylcarboxylic group, nitro group, cyano group, amino group, mono - or di-lower alkylamino group, methylenedioxy group, Ethylenedioxy group or a lower alkyl group which may be substituted by halogen atom, hydroxyl group, lower alkoxy group, amino group or mono - or denissa alkylamino group;

l= 0 or 1,

m= 0 or 1,2,3,

n= 1 or 2, further specified here above are applicable in the same way).

Among the compounds (1) of the present invention particularly preferred compounds are derivatives of hinoklidina, in which ring a is aryl which the R group, consisting of atoms of oxygen, nitrogen and sulfur, or a 5 - to 7 - membered saturated heterocyclic group in which the ring may be substituted by substituents selected from the group consisting of halogen atoms, hydroxyl groups, lower alkoxy groups, carboxyl groups, lower alkoxy-carbonyl groups, lower acyl groups, mercapto groups, lower alkylthio groups, sulfanilic groups, lower alkyl-sulfanilic groups, sulfinyl, lower alkylsulfonyl, sulfonamide groups, lower alkanesulfonyl groups, carbamoyl groups, thiocarbamoyl groups, mono - or di-lower alkylcarboxylic groups, nitro groups, cyano groups, amino groups, mono - or di-lower alkylamino groups, methylendioxy, Ethylenedioxy, and lower alkyl groups which may be substituted by halogen atoms, hydroxyl, lower alkoxy, amino groups or mono - or di-lower alkylamino groups, and their salts or Quaternary ammonium salts;

derivatives of hinoklidina, in which m represents a halogen atom, a lower alkyl group, hydroxyl group, lower alkoxy group, nitro group, cyano group, amino group or mono - or di-lower alkylamino group, and ring a represents aryl group, cycloalkyl the Ohm, selected from the group consisting of atoms of oxygen, nitrogen and sulfur, or a 5 - to 7-membered saturated heterocyclic group, in which such a ring may be substituted by substituents selected from a halogen atom, a lower alkyl group, hydroxyl group, lower alkoxy group, nitro group, cyano group, amino group or mono - or di-lower alkylamino group, and their salts or Quaternary ammonium salts;

derivatives of hinoklidina, in which m is O, ring a is aryl group, cycloalkyl group or cycloalkenyl group which may be substituted by halogen atoms, lower alkyl groups, hydroxyl groups or lower alkoxy groups, or a 5 - or 6-membered monocyclic heteroaryl group having 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, and their salts or Quaternary ammonium salts;

derivatives of hinoklidina, in which ring a represents a phenyl group which may be substituted by a halogen atom or a lower alkyl group, cycloalkyl group, pyridyloxy group, follow group or thienyl group, and their salts or Quaternary ammonium salts;

derivatives of hinoklidina, the cat is and, in which n is 2 and their salts or Quaternary ammonium salt.

The present invention also provides antagonists of muscarinic M3receptors, which include derivatives of hinoklidina (I) or their salts or Quaternary ammonium salts, that is, the compound (I) of the present invention and pharmaceutically acceptable carriers, preferably, agents for prevention (prophylaxis and/or treatment of urinary diseases (e.g., demyelinating pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospaz and chronic cystitis), or respiratory diseases (e.g. chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis).

Below the compound (I) of the present invention will be described in detail.

Unlike conventional antagonist muscarinic M3receptor, the compound (I) of the present invention is structurally characterized in that it has as a main skeleton tetrahydroisoquinoline skeleton (Ia) or isoindoline skeleton (Ib), having hinoklidilkarbinola group, etc. related to the nitrogen atom in the ring, as shown below.

< / BR>
In addition to what the SCP, selected from aryl groups, cycloalkyl group, cycloalkenyl group, heteroaryl group having 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, or a 5 - to 7-membered saturated heterocyclic group in the 1 position tetrahydroisoquinoline or isoindoline attached through X.

If not noted otherwise, the term "lower" used in the definition of the General formula herein, denotes a linear or branched carbon chain having 1-6 carbon atoms. Accordingly, the "lower alkyl group" denotes a linear or branched alkyl group having 1-6 carbon atoms. Candy examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert - boutelou, pentelow, isopentanol, neopentyl, tert - pentelow, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropylene, hexeline, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 - dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3 - dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2 - trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1 - methylpr carbon such as methyl, ethyl, sawn, ISO-propyl and bucilina group, and more preferred is methyl group.

"Aryl group" means an aromatic hydrocarbon group, and preferably aryl groups having 6-14 carbon atoms. Specific examples include phenyl, naftalina, indenolol, untilnow and phenanthroline group, and more preferred is a phenyl group.

Examples of "cycloalkyl group" include groups having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Among these groups, preferred cyclopropyl, cyclobutyl, cyclopentolate and tsiklogeksilnogo group, and more preferred tsiklogeksilnogo group.

Examples of "cycloalkenyl group" include groups having 3-8 carbon atoms, such as 1-cyclopropyl, 2-cyclopropyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cyclo-heptenyl, 3-cycloheptenyl, 4-cycloheptenyl, 1-cyclooctene, 2-cyclooctene, 3-cyclooctene, 4-cyclooctene, 2,4-cyclopentadienyl, 2,5-cyclohexadienyl, 2,4-cyclohepta, consisting of atoms of oxygen, nitrogen and sulfur" means 5 - or 6-membered heteroaryl group which may be condensed with a benzene ring. Specific examples include 5 - or 6-membered monocyclic heteroaryl group containing 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, such as furilla, thienyl, pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, tetrataenia, isothiazolinone, isoxazolidine, perederina, piratininga, pyrimidinamine and pyridazinyl group; and 5 - or 6-membered heteroaryl group condensed with a benzene ring, such as indayla, indazolinone, indolizinyl, kinolinna, chinadaily, hyalinella, khinoksalinona, indolenine, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzisoxazole, benzoxazole, benzothiazolinone and benzothiazoline group.

Among these groups, preferred are 5 - or 6-membered monocyclic heteroaryl group containing 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, and more preferred furilla, thienyl and Peregrina group.

the th group, containing 1-2 oxygen atom, nitrogen and/or sulfur. Specific examples include pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinilnom and morpholinyl group.

"Aryl group", "cycloalkyl group", "cycloalkenyl group, heteroaryl group containing 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur", "5 - or 6-membered monocyclic heteroaryl group containing 1-4 hetero atoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, or a 5 - to 7-membered saturated heterocyclic group" as a group And may be substituted by the optional substituents. The number of substituents is not limited to one and may be large. Any group that may be substituted for such a ring, can be used as an optional substituent. Preferred examples include a halogen atom, hydroxyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, a lower acyl group, mercapto group, lower alkylthio group, sulfonyloxy group, lower alkylsulfonyl group, sulfonyloxy, lower alkylsulfonyl, sulfonamide group, a lower alkanesulfonyl group, cyano group, amino group, mono - or di - lower alkylamino group, methylendioxy, Ethylenedioxy, and the lower alkyl group which may be substituted by halogen atom, hydroxyl, lower CNS group, amino group or mono - or di-lower alkylamino group; more preferred are a halogen atom, a lower alkyl group, hydroxyl group, lower alkoxy group, nitro group, cyano group and mono - or di-lower alkylamino group; even more preferred halogen atom, a lower alkyl group, hydroxyl group and lower alkoxy group; and particularly preferred are a halogen atom and a lower alkyl group.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine. When a Deputy is a halogen atom, the number of substituents does not have special restrictions. When the substituents are two or more halogen atoms, there can be any combination of the above atoms. Examples of substituted by the halogen atom of the lower alkyl groups include vermeil, chloromethyl, methyl bromide, iodomethyl, 1-foretel, 1-chloroethyl, 1-bromacil, 2 - chloroethyl, 2-bromacil, dichloromethyl, trifluoromethyl, trichloromethyl, tribromoethyl, triodetic and dichloromethyl. Among these groups of predpochitau isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentylamine, tert-pentyloxy, neopentylene, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1 ethylpropoxy, hexyloxy. Among these groups, preferred lower alkoxy groups containing alkyl group having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and more preferred are methoxy, ethoxy group.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second - butoxycarbonyl, tert-butoxycarbonyl, pentyloxy (amyloxy) carbonyl, isopentylamine, tert-pentyloxybenzoyl, neopentylglycol, 2-methylbutadiene, 1,2-dimethylpropanolamine, 1-ethylpropoxy and hexyloxybenzoyl.

Examples of "lower acyl group" include formyl, acetyl, propionyl, butyryl, valeryl and pivaloyl, and preferred are formyl, acetyl and propionyl.

"Lower alkylthio group" means a mercapto group in which the hydrogen atom is substituted above as an example, alkyl group, such as methylthio, ethylthio, propylthio, isopropylthio, butylphenyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, intercultural and Vexillology.

Examples of "lower alkylsulfonyl group" include methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, pentasulfide and exisulind.

Examples of "lower alkanesulfonyl group" include methanesulfonamido, econsultation, propanesulfinamide, isopropanolamide, butanesulfinamide, pentanesulfonate, hexanesulfonate.

"Mono - or di-lower alkylcarboxylic group" means karbamoilnuyu group in which one or two hydrogen atoms substituted above as examples of the lower alkyl group (or groups), such as methylcarbamoyl, ethylcarbazole, profilirovannaja and dimethylcarbamoyl group.

"Mono - or di-lower alkylamino group" means amino group in which one or two hydrogen atoms substituted above as an example, alkyl groups such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino group.

The term "lower alkyl group which may be substituted by a halogen atom, hydroxyl alkyl group, in which at least one hydrogen atom optionally substituted by halogen atom, hydroxyl group, lower alkoxy group, amino group or mono - or di-lower alkylamino group. Lower alkyl group substituted by a halogen atom, is the same as described in the above description, taking into account the above halogen atoms.

The compound (I) of the present invention contains hinkleyville group. The nitrogen atom hinkleyville group may form oxide or Quaternary ammonium salt. When a Quaternary ammonium salt, specific examples of the groups attached to the nitrogen atom, include lower alkyl, lower alkenyl and lower quinil.

The term "lower alkenyl", as used here, denotes a linear or branched alkenylphenol group having 2-6 carbon atoms, such as vinyl, propenyl, butenyl, methylpropenyl, dimethylvinyl, pentenyl, methylbutanal, dimethylpropyl, ethylpropyl, hexenyl, dimethylbutanol and methylpentene. Among these groups, preferred protanilla group.

"Lower Alchemilla group" denotes a linear or branched alkylamino group having 2-6 carbon atoms, such as etinilnoy, proponila, are respectful alkyline group, having 2-3 carbon atoms, such as ethinyl and PROPYNYL.

The anion to the Quaternary ammonium salt has no particular restrictions, and examples of it include ions of atoms of halogen, triflate (triftormetilfullerenov), toilet (toluensulfonate) and mesilate (methylsulfonate), preferably ions of atoms of halogen, i.e., halide ions (such as chloride ion, brainy ion, iodide ion and triiodide ion). Examples of other anions include anions such as nitrate ion, sulfate, phosphate and carbonate ions, carboxylates, such as formate (HCOO-), acetate (CH3COO-), propionate, oxalate and malonate, and amino acid anions, such as glutamate. Among the halide ions are preferred brainy and iodide ions. Incidentally, the anion can turn into a preferred anion depending on the necessity of using a conventional ion-exchange reactions.

The compound (I) of the present invention contains an asymmetric carbon atom, so because of this there are optical isomers. In addition, some of the compounds of the invention are stereoisomers or tautomers. The present invention also covers the diastereomers and enantiomers, obtained with the help section is there to form salts with acids, as well as the above-described Quaternary ammonium salt with hinkleyville group. Examples of such salts include acid additive salts with a mineral acid, such as hydrochloric acid, Hydrobromic, itestosterone, sulphuric, nitric or phosphoric acid; and salts with organic acids such as formic acid, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, citric, tartaric, coal, picric acid, methanesulfonate acid, econsultancy (or econsult) acid or glutamic acid. The compound (I) of the present invention also cover a hydrate, a solvate with ethanol or similar, and substances in the form of any polymorphic crystals.

(The process of Obtaining)

The compound (I) of the present invention can be obtained in accordance with various processes. Typical processes are explained below.

The first method of obtaining

< / BR>
(in the above formula Q1represents a leaving group, which is favorable for this reaction, and ring A, R, X, m and n have the same values as defined above. Further below in this description similarly applies the same formula (II), and hinokitiol represented by the General formula (III), in the number corresponding to this reaction, in an inert solvent at room temperature or when heated.

Leaving group Q1includes, for example, halogen atom, lower alkoxy group, phenoxy group and imidazolidinyl group.

Examples of inert solvents include dimethylformamide (DMF or DMF), dimethylacetamide, tetrahydrofuran (TGF or THF), dioxane, dimethoxyethane, diethoxyethane, benzene, toluene and xylene and mixtures of these solvents.

It is preferable to add a base (such as sodium, sodium hydride, sodium methylate and sodium ethylate), in order to accelerate this reaction.

The second way of obtaining

< / BR>
(where the ring A, R, X, m, n and Q1have the same values as defined above).

This reaction is carried out by mixing the compound represented by the General formula (IV) and compounds represented by the General formula (V) described above in an inert solvent, at room temperature or when heated.

It is preferable to add a base (such as sodium, sodium hydride, sodium methylate, sodium ethylate, triethylamine and pyridine), chtenia, in which the nitrogen atom hinkleyville group forms an oxide or oxide or Quaternary ammonium salt can be obtained through education N-oxide or N-alkylation of the tertiary compounds of the compounds of the present invention.

The reaction of formation of N-oxide can be carried out using the oxidation of the conventional method, more specifically, by mixing the tertiary amine compounds of the compounds of the present invention and the corresponding amount or excess amount of oxidizing agent in an inert solvent, such as chloroform, dichloromethane or dichloroethane, an alcohol, such as methanol or ethanol, or water, or in mixtures of these solvents, under cooling or at room temperature, or in some cases, when heated. Examples of oxidizing agents include organic nagkalat, such as m-chlormadinone acid, periodate sodium and hydrogen peroxide.

The reaction of N-alkylation may be carried out in accordance with the usual reaction of N - alkylation, more specifically, by mixing the tertiary amine compounds of the compounds of the present invention and the corresponding number of alkylating agent in ri cooling or at room temperature, or, in some cases, when heated.

Examples of alkylating agents include lower alkylhalogenide, lower alkylarylsulfonate, lower alkyl p - toluensulfonate and lower alkyl-methansulfonate, preferably, the lower alkylhalogenide.

To obtain the compounds of the present invention is sometimes necessary to protect functional groups. In this case, additionally accepted way introduction of an appropriate protective group, and the operation for removing the protection.

The compound of the present invention, thus obtained, is provided, as it is, in free form or after it is processed for the formation of salts accepted way, is allocated and cleared in the form of its salt. Isolation and purification are carried out using a conventional chemical techniques, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization or the various chromatography techniques.

The compound of the present invention has affinity and selectivity for muscarinic M3- receptors and as an antagonist M3- receptor, it is useful as a means to prevent or profile is aka as incontinence or pollakiuriya when demyelinating pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospaz or chronic cystitis; respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma or rhinitis; or digestive diseases such as irritable bowel syndrome, spastic colitis or diverticulitis.

In particular, the compound of the present invention has a high selectivity to M3-receptor, existing in the smooth muscle or gland tissues, compared with M2receptor, existing in the heart, or similar bodies, so it is highly useful as an antagonist of M3- receptor, showing fewer side effects on the heart or other, especially as an agent or means for the prevention or treatment of matenadarani, pollakiuria, chronic obstructive pulmonary diseases, chronic bronchitis, asthma or rhinitis.

Affinity and antagonism of the compounds of the present invention in relation to a specific muscarinic receptor was confirmed by the following tests.

Test the binding of the muscarinic receptor (in vitro)

A. Preparation of membranes

SAC with 20 mm HEPES buffer (pH 7.5, which hereinafter will be abbreviated to be called "HEPES buffer" containing a 5-fold volume of 100 mm sodium chloride, and added 10 mm magnesium chloride, followed by homogenization in ice cooling. The resulting mixture was filtered through cheesecloth, followed by ultracentrifugation at 50000 x g and 4oC for 10 minutes. The precipitate was suspenderbelt in HEPES buffer. The resulting suspension was stored at -80oC and provided for testing after melting during use.

b. Test the binding of the muscarinic M2receptor

The test was conducted in accordance with the method of Doods et al. (J. PharmacoL Exp Ther. , 242, 257-262, 1987) with some modifications. A sample of the cardiac membrane, [3H] - hinkleyville and the test compound were incubated in 0.5 ml HEPES buffer at 25oC for 45 minutes followed by filtration with suction through a glass filter (Whatman GF/B). The filter was washed three times with 5 ml portions of HEPES buffer. The radioactivity of [3H]- khinuklidinilbenzilata adsorbed on the filter was measured using a liquid scintillation counter. In this case, the addition of 1 μm atropine was measured nonspecific binding of the receptor. the first dissociation constant (Kiaccording to the method of Chen u Prusoff (Biochem. Pharmacol. 22, 3099, 1973), based on the concentration (IC50) of the test compounds, which inhibited 50% of the binding of [3H]-khinuklidinilbenzilata, i.e., the labeled ligand.

c. Test the binding of the muscarinic M3receptor

Test the binding of the muscarinic M3- receptor was carried out by the method similar to that described above to test the binding of the muscarinic M2- receptor, except that as the sample membrane was used submandibular salivary gland, and as the labeled ligand was used [3H]-N-methylscopolamine.

Results: Compound (1) of the present invention showed a value of Kifrom 10-8up to 10-10in the case of M3- receptor, suggesting that the affinity for M3the receptor is at least 10 times higher than for M2the receptor.

Test for antagonism to muscarinic receptors (in vivo)

A. Test on rhythmic bladder contraction in rats.

Female Wistar rats (130-200 g) were subjected to anesthesia with urethane (1.0 g/kg subcutaneously (SC)) followed by bandaging of the ureter from the kidney. Uretral the ü approximately 1.0 ml of physiological solution for to cause rhythmic bladder contraction. Was measured vnutrishkolnoe pressure using a pressure sensor. After the rhythmic contraction continued to remain stable for at least 5 minutes, the test compound cumulative introduced from the external jugular vein. After 5-10 minutes was measured vnutrishkolnoe pressure. The degree of inhibition of bladder contractions was determined in comparison with a reduction in urinary bladder before the introduction of the test compound, and the dose of the test compound required for 30% inhibition of bladder contractions prior to the introduction, it was designated as ED30.

As a result of this test, the compound of the invention showed good value ED30.

b. Test saliva in rats

Male Wistar rats (160 - 190 g) were subjected to anesthesia with urethane (0.8 g/kg intraperitoneal I. p.), and were administered the test compound (control group: solvent). After 15 minutes was introduced 0.8 mmol/kg oxotremorine. In each case, the drug was administered through the femoral artery. Saliva, allocated within 5 minutes after administration oxotremorine, were collected and weighed. The degree of inhibition was determined in the Finance salivation in the control group, it was designated as ID50.

In the test result value: ID50in the test with atropine as a comparative compound was essentially the same as the value of the ED30obtained above when tested on rhythmic bladder contraction in rats, the value of the ID50compounds according to the invention was at least 5 times higher, as described above, the value of the ED30that talked about the fact that the compound of the present invention had a relatively weak effect on salivation.

c. Test bradycardia in rats

The test was conducted in accordance with the method of Doods et al. (J. Pharmacol. Exp. Ther., 242, 257-262, 1987). Male Wistar rats (250-350 g) were subjected to anesthesia pentobarbital-sodium (50 mg/kg I. p.). The neck was escalas, followed by separation of the right and left vagi. After the trachea cannula was inserted to ensure the passage of air, inserted the wand stainless steel, and the spinal cord was destroyed. In conditions of artificial respiration (10 cm3/kg and 50 times/min) rectal temperature was maintained at 37.5oC, and monitored the heart rate in the part of the carotid artery. In the femoral artery was noted for the ability to stay within a 15 minutes to reach equilibrium, followed by the introduction of atenolol (10 mg/kg). After the establishment of equilibrium for an additional 15 minutes was administered the test compound. Fifteen minutes later introduced cumulative oxotremorine, what was measured decrease in heart rate. The number of the test compounds required for a 10-fold shift to the right of the curve dose-response in the control group, was designated as d10.

Results: the Compound (I) of the present invention showed low activity against bradycardia, and there wasn't any bradycardia when the introduction amount of the order of several mg/kg

In the above test (in vitro) on the binding of muscarinic receptors was found that the compound (I) of the present invention showed selectivity and high affinity in respect of M3- receptor. Even when tested (in vivo) on the antagonism against muscarinic receptors compound of the present invention showed good activity against muscarinic M3- receptor and low activity in relation to aetiology, which is associated with muscarinic M2- a receptor. Accordingly, it was found that the compound (I) of the present invention has a selective antago the effects such as dry mouth, compared with the conventional anti-cholinergic agent.

Pharmaceutical composition containing one or more compounds of the present invention and their salts are prepared using conventional pharmaceutically acceptable carrier.

According to the present invention the introduction of the pharmaceutical composition can be performed either orally or parenterally in the form of injections, medical suppositories, transdermal agents, inhalants or vnutrikapilliarnuu injection.

The dose is determined in each case arbitrarily based on the status, age, sex and other factors of the patient, which introduces a therapeutic agent. By oral administration, the daily dose can typically be in the range of from about 0.01 mg/kg to 100 mg/kg for adults. It is injected once or 2-4 servings. When considering the condition of the patient is used intravenous administration, the daily dose can usually be varied from about 0.001 mg/kg to 10 mg/kg for an adult patient, in a single or multiple servings a day.

Examples of pharmaceutical carriers include non-toxic solid or liquid pharmaceutical substances.

Examples of liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs that contain a generally used inert diluent such as purified water or ethanol. In addition to such inert diluents, the composition can also contain a wetting agent, podcentral introduction or purpose according to the present invention include sterile aqueous or non-aqueous solution, the suspension or emulsion. Examples of aqueous solutions and suspensions include distilled water and saline solution for injection. The examples are not soluble in water solutions or suspensions include ethylene glycol, polypropyleneglycol, polyethylene glycol, vegetable oils such as cocoa butter, olive oil or sesame oil, alcohols such as ethanol, Arabian gum and Polysorbate 80" (trade name). Such a composition may further contain an isotonicity agent, an antiseptic agent, a wetting agent, emulsifying, dispersing agent, a stabilizer (e.g., lactose) and/or an agent that promotes solubilization (for example, glutamic acid, aspartic acid). Compositions are sterilized, for example, by filtration through inhibiting bacteria filter, switching regulator or irradiation. Alternatively, a sterile solid composition, which is obtained in advance, dissolved in sterile water or sterile injecting the solvent for use.

The best ways of carrying out the invention

The present invention will be further described herein with further detail using the following examples. However, the compounds of the present is to see all the connections, represented by the above formula (I), and salts, hydrates, solvate, geometric and optical isomers and any polymorphic forms of compound (I).

By the way, the source compounds for the compounds of the present invention include novel compounds, and examples of the preparation of such starting compounds are described below as reference examples.

Reference example 1

To a solution of 130 ml of dichloromethane containing 6.28 g of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 3.34 g of triethylamine under ice cooling is added dropwise 3.1 ml ethylchloride, followed by stirring over night at room temperature. The reaction solution is washed successively with water, 1 norms. hydrochloric acid, water and brine, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, whereby is obtained 10.58 g of ethyl 1-phenyl-1,2,3, 4-tetrahydro-2 - ethanolinduced in the form of a pale yellow oil. Spectrum infrared absorption max(net ) cm-1: 1700, 1430, 1296, 1230, 1122.

Spectrum of nuclear magnetic resonance (CDCl3TMS (TMC)) internal standard)

: 1.29 (3H, T. , J= 7.3 Hz), 2.75-3.45 (3H, m), 3.90-4.40 (1H, m), 4.21 (2H, KB.,J= 7.3 Hz), 6.38 (1H, s), 6.95-7.45 (9H, m).

Reference example 2

Methyl 1-phenyl-2-isoindolines

Starting compound: 1-Penelitian, methylchloroform

Spectrum infrared absorptionmax(KBr) cm-2: 1708, 1460, 1376, 1100.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 3.60, 3.72 (3H, s × 2), 4.89, 4.96 (2H, s x 2), 5.94, 6.03 (IH, c.x 2), 6.95-7.10 (1H, m), 7.15-7.35 (8H, m).

Reference example 3

Ethyl 1- (4-pyridyl)-1, 2, 3, 4-tetrahydro-2-isoquinoline carboxylate

Source connection: 1-(4-pyridyl)-1, 2,3,4-tetrahydroisoquinoline

Properties: pale yellow oil

Mass analysis (m/z. El): 282 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.29 (3H, T., J= 7.1 Hz), 2.60-3.45 (3H, m), 3.85 - 4.20 (1H, m), 4.22 (2H, square , J= 7.1 Hz), 6.31 (1H, s), 7.14 (2H, DD., J= 4.4, 1.5 Hz), 7.17-7.26 (4H, m), 8.51 (2H, DD., J= 4.4, 1.5 Hz).

Reference example 4

Ethyl 1,2,3,4-tetrahydro-1-(2-thienyl)-2-ethanolammonium

Source connection: 1,2,3,4-tetrahydro-1-(2-thienyl) isoquinoline

Properties: pale yellow oil

Mass analysis (m/z. El): 287 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.32 (3H, T. , J= 7.3 Hz), 2.65-3.60 (3H, m), 4.00-4.30 (1H, m), 4.23 (2H, square, J= 7.3 Hz), 6.53 (1H, s), 6.70-6.95 (2H, m), 7.15-7.30 (Noe connection: 1,2,3,4-tetrahydro-1-(3-thienyl)isoquinoline

Properties: orange oil

Mass analysis (m/z, FAB): 288 - (M++ 1)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.23-1.3 (3H, m), 2.7-2.8 (1H, m), 2.9-3.0 (1H, m), 3.1-3.3 (1H, m), 3.9-4.2 (3H, m), 6.2-6.4 (1H, m), 6.83 (1H, s), 6.95-7.26 (6H, m).

Reference example 6

Ethyl 1- (2-furyl)-1,2,3,4-tetrahydro-2-ethanolammonium

Source connection: 1- (2-furyl)-1,2,3,4-tetrahydroisoquinoline

Mass analysis (m/z, E1): 271 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.30 (3H, T. , J=6.5 Hz), 2.75-2.85 (1H, m), 2.90 - 3.10 (1H, m), 3.20-3.50 (1H, m), 4.05-4.35 (4H, m), 6.00 (1H, s), 6.20-6.45 (2H, m), 7.15-7.25 (4H, m), 7.33 (1H, s).

Reference example 7

(1S)-Ethyl 1-phenyl-1,2,3,4-tetrahydro - 2-ethanolammonium

Source connection: (1S)-1-phenyl - 1,2,3,4-tetrahydroisoquinoline

Elemental analysis (for C18H19NO2)

Calculated: C (%) 76.84 H (%) 6.81 N (%) 4.98

Found: C (%) 76.53 H (%) 6.82 N (%) 4.93

Specific optical rotation []2D5: 199.2 (C = 1.03, CHCl3)

Mass analysis (m/z, FAB): 282 (M++ 1)

Reference example 8

(1R)-Ethyl 1-phenyl-1,2,3,4-tetrahydro-2 - ethanolammonium

Parent compound: (1R)-1-phenyl-1,2,3,4 - tetrahydroisoquinoline

Elemental analysis (DL-Christ.

Specific optical rotation []2D5: -200.9 (C = 1.09, CHCl3)

Mass analysis (m/z. El): 281 (M+)

Reference example 9

Ethyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-ethanolammonium

Source connection: 1-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline

Properties: pale yellow oil

Mass analysis (m/z, E1): 315 (M+)

Spectrum of nuclear magnetic resonance (CDClC3, TMS internal standard)

: 1.29 (3H, T., J=7.0 Hz), 2.70-3.52 (3H,m), 4.00 - 4.30 (1H, m), 4.20 (2H, square, J=7.0 Hz), 6.35 (1H, s), 7.05 - 7.35 (8H, m)

Reference example 10

Ethyl 1-(4-forfinal)-1,2,3,4 - tetrahydro-2-ethanolammonium

Source connection: 1-(4-forfinal)-1,2,3,4-tetrahydroisoquinoline

Properties: pale yellow oil

Mass analysis (m/z, FAB): 300 (M++ 1)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.30 (3H, T., J=8.9 Hz), 2.75(1H, DD), J=12.5, 3.4 Hz), 2.9-3.1 (1H, m), 3.1-3.3 (1H, m), 4.0-4.3 (3H, m), 6.2-6.4 (1H, m), 6.93-7.03 (3H, m ), 7.16-7.24 (5H, m).

Reference example 11

Ethyl 1,2,3,4-tetrahydro-1-(4-tolyl)-2-ethanolammonium

Source connection: 1,2,3,4-tetrahydro-1-(4 - tolyl)isoquinoline,

Mass analysis (m/z. El): 295 (M+)

Spectrum of nuclear magnetic resonance (CDCI3, TMS internal standard)

:2">

Reference example 12

Ethyl 1-benzyl-1,2,3,4-tetrahydro-2 - ethanolammonium

Source connection: 1-benzyl-1,2,3,4 - tetrahydroisoquinoline

Properties: pale yellow oil

Mass analysis (m/z, FAB): 296 (M++ 1)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.02, 1.23 (3H, so x 2, J= 7.1 Hz), 2.63-3.20 (4H, m), 3.30-3.50 (1H, m ), 3.75-4.25 (3H, m), 5.27, 5.38 (1H, so x 2, J= 6.8 Hz), 6.85-7.28 (9H, m).

Reference example 13

Ethyl 1-cyclohexyl-1,2,3,4-tetrahydro-2-ethanolammonium

Source connection: 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline

Properties: yellow oil

Mass analysis (m/z, FAB): 288 (M++ 1)

Spectrum of nuclear magnetic resonance (CDCl3TMS internal standard)

: 0.70-2.00 (11,m), 1.26 (3H, T., J=7.3 Hz), 2.89 (2H, T., J - 7.1 Hz), 3.25-4.20 (2H, m), 4.14 (2H, square, J =7.1 Hz), 4.65-4.95 (1H, m), 7.00-7.30 (4H, m).

Reference example 14

Ethyl 1-(3-furyl)-1,2,3,4 - tetrahydro-2-ethanolammonium

Source connection: 1-(3-furyl)-1,2,3,4-tetrahydroisoquinoline

Properties: yellow oil

Mass analysis (m/z. El): 271 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.31 (3H, T., J=7.0 Hz), 2.55 - 3.40 (3H, m), 3.90 - 4.30 (1H, m), 4.22 (2H, square, J=7,0 Hz), 6.20-6.45 (2H, m), 6.95-7.40 (6H, m).

Example 1. To a solution of 30 ml of toluene containing 0.70 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2 - carboxylate and 0.41 g of 3-hinokitiol, was added 0.03 g of sodium hydride (60%). The resulting mixture was mixed at 140oC for 2 hours while removing the formed ethanol. The reaction mixture was cooled to room temperature, was added to the salt solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified using chromatography on silicagel column (chloroform: methanol = 10:1 ---> chloroform:methanol:28% aqueous ammonia = 10:1: 0.1) to give 0.11 g of 3-hinokitiol 1-phenyl-1,2,3,4-tetrahydro-2 - ethanolinduced in the form of a yellow oil. The resulting oil was dissolved in 10 ml of ethanol followed by the addition of 27 mg of oxalic acid. Then the solvent was removed under reduced pressure. The resulting solid was precrystallization of isopropanol and isopropyl ether, whereby was obtained 0.08 g of monoacetate 3-hinokitiol 1 - phenyl-1,2,3,4-tetrahydro-2-ethanolinduced in the form of colorless crystals.

Melting point: 122-124oC (i-D-:- H(%) 6.38, N(%) 6.01

Found: C(%) 64.25; H(%) 6.15, N(%) 5.88,

According to the method similar to example 1, was obtained the compound of example 2.

Example 2. (Monohydrochloride 3-hinokitiol 1-phenyl-2 - isoindolines

The original connection methyl-1-phenyl-2 - isoindolines

Melting point: 164-165oC (EtOH-Et2O)

Elemental analysis (for C22H25N2O2Cl1.3H2O)

Calculated: (%) 57.32; H(%) 5.98; N(%) 5.81; S(%) 6.65.

Found: C(%) 57.62; H(%) 6.00; N(%) 5.84; S(%) 6.27.

Mass analysis (m/z, FAB): 369 (M++ 1)

Example 5. (RS, 3'R)-3'-hinokitiol 1,2,3,4 - tetrahydro-1-(3-thienyl)-2-ethanolammonium

Starting compound: ethyl 1,2,3,4-tetrahydro-1-(3-thienyl)-2 - ethanolammonium, (3R)-3-hinokitiol

Properties: Brown butter

Elemental analysis (for C21H24N2O2S0.3H2O)

Calculated: (%) 67.46; H(%) 6.63; N(%) 7.49; S(%) 8.58;

Found: C(%) 67.35; H(%) 6.76; N(%) 7.21; S(%) 8.46.

Mass analysis (m/z, FAB): 369 (M++ 1)

Example 6

3-Hinokitiol 1-(2-furyl) -1,2,3,4-tetrahydro-2-ethanolammonium

Source connection: ethyl 1-(2-furyl)-1,2,3,4-tetrahydro-2 - ethanolammonium

Properties: Pale yellow oil

Elemental analysis (for C21H24N2++ 1)

Example 7. To 30 ml of pyridine solution containing 2.09 g of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, was added and 2.26 g of monohydrochloride 3-giocodigitale at room temperature, followed by stirring at 80oC for 4 hours. Then was added 0.12 g of monohydrochloride 3 - giocodigitale, followed by stirring at 80oC for 4 hours. Then was added 1.01 g of monohydrochloride 3 - giocodigitale, and the mixture was mixed at 80oC for 25 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water, followed by rinsing twice with ethyl acetate. The resulting aqueous layer was brought to pH 9 with saturated aqueous sodium bicarbonate solution followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, whereby was obtained 3.02 g of (1S, 3'RS)-3'-hinokitiol 1-phenyl-1,2,3,4-tetrahydro-2-ethanolinduced in the form of a yellow oil.

Mass analysis (m/z, FAB): 363 (M++ 1)

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 1.20-2.00 (5H, m), 2.40-2.95 (nsii, containing 12.0 g of (1S)-ethyl-1-phenyl-1,2,3,4-tetrahydro-2 - ethanolinduced and 16.27 g of (3R)-3-hinokitiol, was added at room temperature 1,69 g of sodium hydride (60%). The resulting mixture was heated for 3 hours while the resulting ethanol was removed with toluene. The reaction mixture was cooled to room temperature, and was added to 50 ml of saline solution, followed by extraction with ethyl acetate. The organic layer was rinsed with water and then was extracted with 20% hydrochloric acid. The resulting aqueous layer was brought to pH 9-10 by the addition of 1 norms. an aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in 140 ml of ethanol, and the resulting solution was added 10 ml of 4 standards. hydrogen chloride in an ethyl acetate solution. The solvent was then removed under reduced pressure. To the residue was added acetonitrile and ether, and the resulting crude or crude crystals were precrystallization from acetonitrile and ether, the resulting 10.1 monohydrochloride (1S, 3'R)-3'-hinokitiol 1-phenyl-1,2,3,4 - tetrahydro-2-Ishino the BR>
Elemental analysis (for C23H27N2O2Cl)

Calculated: (%) 69.25; H(%) 6.82; N(%) 7.02, Cl(%) 8.89,

Found: C(%) 69.24; H(%) 6.89; N(%) 7.03; Cl(%) 8.97.

Specific optical rotation []2D5: 98.1 (C = 1.00, EtOH)

According to the method similar to the method of example 8, were obtained the following compounds of examples 9-16.

Example 9. Monohydrochloride (1R, 3'S)-3'-hinokitiol 1-phenyl-1,2,3,4 - tetrahydro-2-ethanolinduced

Starting compound: (1R)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-ethanolammonium, (3S)-3 - hinokitiol

Melting point: 211-212oC (EtOH-Et2O)

Elemental analysis (for C23H27N2O2Cl]2D5. -97.4 (C=0.50, EtOH)

Example 10. Monohydrochloride (1R, 3'R)-3-'-hinokitiol 1-phenyl-1,2,3,4-tetrahydro-2-ethanolinduced

Starting compound: (1R)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2 - ethanolammonium, (3R) -3-hinokitiol

Melting point: 195-196oC (EtOH-Et2O)

Elemental analysis (for C23H27N2O2Cl]2D5: -151.2 (C =0.50, EtOH)

Example 11. Monohydrochloride (1S, 3'S)-3'-hinokitiol 1 - phenyl-1,2,3,4-tetrahydro-2-ethanolinduced

Starting compound: (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2 - ithin analysis (for C23H27N2O2Cl)

Calculated: (%) 69.25; H(%) 6.82; N(%) 7.02; Cl(%) 8.89;

Found: C(%) 69.08; H(%) 6.71; N(%) 6.99; Cl(%) 8.91.

Specific optical rotation []2D5163.2 (C = 0.50, EtOH)

Example 12. Monopolar 3-hinokitiol 1-(4-chlorophenyl)- 1,2,3,4-tetrahydro-2-ethanolinduced

Starting compound: 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-ethanolammonium

Melting point: 164-166oC (EtOH-Et2O)

Elemental analysis (for C27H29N2O6Cl0.1H2O)

Calculated: (%) 72.27; H(%) 6.64; N(%) 7.33; F (%) 4.97;

Found: C(%) 72.05, H(%) 6,63; N(%) 7.15; F (%) 4.99.

Mass analysis (m/z, FAB): 381 (M++ 1)

Example 14. 3-hinokitiol 1, 2, 3, 4-tetrahydro-1- (4 - tolyl)-2-ethanolammonium

Starting compound: ethyl 1, 2,3, 4-tetrahydro-1- (4-tolyl) -2-ethanolammonium

Properties: colorless oil

Elemental analysis (for C24H28N2O20.8 H2O)

Calculated: (%) 73.74; H(%) 7.63, N(%) 7.17;

Found: C(%) 73.96; H(%) 77.50; N(%) 6.95.

Mass analysis (m/z, FAB): 377 (M++ 1)

Example 15. 3-Hinokitiol 1-benzyl-1, 2, 3, 4 - tetrahydro-2-ethanolammonium

Source connection: ethyl 1-benzyl-1,2,3,4-tetrahydro-2 - ethanolammonium

Properties: blen 74.78;, H (%) 7.58; N(%) 7.26;

Found: C (%) 74.95; H (%) 7.83; N(%) 7.18.

Mass analysis (m/z, FAB): 377 (M++ 1)

Example 16. 3 Hinokitiol 1-cyclohexyl-1, 2, 3, 4-tetrahydro-2 - ethanolammonium

Starting compound: ethyl 1-cyclohexyl-1,2,3,4-tetrahydro-2 - ethanolammonium

Properties: pale yellow amorphous substance

Elemental analysis (for C23H32N2O30.3 H2O)

Calculated: (%) 73.88; H (%) 8.79; N(%) 7.49;

Found: C (%) 73.76; H (%) 8.75; N(%) 7.37.

Mass analysis (m/z, FAB): 369 (M++ 1)

Example 17. In 12 ml of dichloromethane was dissolved 1.20 g of (1S, 3'R)-3'-hinokitiol 1-phenyl-1, 2, 3, 4-tetrahydro-2 - ethanolinduced under ice cooling was added 0.33 g of sodium bicarbonate and 0.79 g m-chlormadinone acid (80%), followed by stirring at room temperature for one hour. To the reaction mixture, water was added and then the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous solution of sodium thiosulfate solution, and then dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure, and the residue was purified using chromatography on silicagel column (chloroform: methanol = 20:1), whereby was obtained 0.43 g of (1'S,3R)-3-[[(1'-Veneto

Mass analysis (m/z, FAB): 379 (M++ 1)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1.85-2.15 (3H, m), 2.15-2.35 (2H, m), 2.75-2.90 (1H, m), 2.90-2.95 (1H, m), 3.20 - 3.50 (6H, m), 3.70-3.80 (1H, m), 3.85 - 4.10 (1H, m), 5.14 (1H, Tyr.C.), 6.14, 6.43 (1H, Shir. with x 2), 7.05 - 7.40 (9H, m).

Example 18. To 8 ml of 2-betononasos solution containing 1.04 g of (1S, 3'r)-3'-hinokitiol 1-phenyl-1, 2, 3, 4 - tetrahydro-2-ethanolinduced, was added 0.18 ml under the conditions, followed by stirring at 55oC for 40 minutes. After air cooling precipitated precipitated crystals were collected by filtration, and then washed sequentially with 2 - butanone and diethyl ether, whereby was obtained as colorless crystals 0.93 g of iodide (1'S, 3R)-1-methyl-3-[[(1'- phenyl-1', 2', 3', 4' - tetrahydro-2'-ethanolic)carbonyl] oxy]chinoline.

Melting point: 202-203oC (2-butanone)

Elemental analysis (for C24H29N2O2I)

Calculated: (%) 57.15; H (%) 5.79; N(%) 5.55; I (%) 25.16;

Found: C(%) 57.17; H (%) 5.71; N(%) 5.51; I(%) 25.15.

According to the method similar to the method of example 8, was the connection the following example 19.

Example 19. (1RS, 3'R)-3'-Hinokitiol 1-(3-furyl)-1,2,3,4-tetrahydro-2 - ethanolammonium

Isodontia analysis (for C21H24N2O30.3 H2O)

Calculated: (%) 70.49; H (%) 6.93; N(%) 7.83;

Found: C(%) 70.35; H(%) 6,83; N(%) 7.63.

Mass analysis (m/z. El): 362 (M+)

The chemical structural formulas of the compounds obtained in examples 1-19, shown below in Tables 3-5.

Each of the above compounds in examples 3-6, 12-14, 16 and 19 can be obtained in an optical split form, as shown in the following tables 6-8, using optically split intermediate product according to the method similar to the methods of examples 8-11.

Other compounds covered by this invention, are shown in table 9-33. They can be synthesized by any of the above methods of preparation, methods described in the examples or by methods known to experts in the art and does not require the presentation of any experiments. Incidentally, these compounds are described in the form of racemic compounds but also includes optically active substances due to the presence of asymmetric carbon.

1. Derivatives of hinoklidina formula (I)

< / BR>
in which ring a represents a phenyl group which may be optionally substituted by a halogen atom or NISS is/BR> X represents a single bond or methylene group;

l = 0 or 1;

n = 1 or 2

or their salts with acids, or their Quaternary ammonium salt.

2. Derivatives of hinoklidina, or their salts with acids, or their Quaternary ammonium salt under item 1, in which X represents a single bond.

3. Derivatives of hinoklidina, or their salts with acids, or their Quaternary ammonium salt on the PP. 1 and 2, selected from the group consisting of the following compounds:

3-hinokitiol 1-phenyl-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol 1,2,3,4-tetrahydro-1-(2-thienyl)-2-ethanolammonium,

3-hinokitiol 1,2,3,4-tetrahydro-1-(3-thienyl)-2-ethanolammonium,

3-hinokitiol (2-furyl)-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol (4-chlorophenyl)-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol 1-(4-forfinal)-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol 1,2,3,4-tetrahydro-1-(4-tolyl)-2-ethanolammonium,

3-hinokitiol 1-cyclohexyl-1,2,3,4-tetrahydro-2-ethanolammonium,

3-hinokitiol 1-(3-furyl)-1,2,3,4-tetrahydro-2-ethanolammonium,

and E ammonium salt under item 1 or 2, in which n = 2.

5. Pharmaceutical composition, which is an antagonist of muscarinic M3-receptor and includes derived hinoklidina formula (I)

< / BR>
in which ring a represents a phenyl group which may be optionally substituted by a halogen atom or a lower alkyl group, tsiklogeksilnogo group, pyridyloxy group, follow group or thienyl group;

X represents a single bond or methylene group;

e = 0 or 1;

n = 1 or 2

or its salt with the acid, or its Quaternary ammonium salt and a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to a method for separating 1 - azabicyclo[2.2.2]Octan-3-amine, 2- (diphenylmethyl) -N- [[2-methoxy - 5-(1-methylethyl)phenyl]methyl]

The invention relates to derivatives of 3-genocidally esters of the formula I or their pharmaceutically acceptable acid additive salts, where X is phenyl, Y is the group - (CH2)A- CR1R2- (CH2)BS(O)Z-R3where A and B are independently 0, 1 or 2, Z is 0, 1 or 2, R1and R2independently a hydrogen atom, (C1-C4)-alkyl, R3- (C1-C4)-alkyl or phenyl

The invention relates to new derivatives of hinoklidina, pharmaceutical compositions containing such compounds and to the use of such compounds for the treatment and prevention of inflammatory disorders and disorders of the Central nervous system, as well as some other disorders

The invention relates to new and useful derivatives of hinoklidina that are of interest in the field of medicinal chemistry

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to new compounds with pharmacological activity, in particular bicyclic 1-Aza-cycloalkanes General formula

(I) where R is lower alkyl, unsubstituted or substituted furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; quinil with 3-6 carbon atoms; phenyl, unsubstituted or substituted lower alkyl, alkoxygroup or by halogen; benzyl, unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;

A, b and C independently of one another denote-CH2or a simple bond;

n is 0 or 1, mixtures of isomers, or individual isomers and their pharmacologically tolerable acid additive salts exhibiting holinoliticheskoy properties

The invention relates to pharmaceutical industry
The invention relates to medicine, neurology

The invention relates to pharmacology, specifically to new tools for the treatment of sea-sickness, vomiting, or nausea during movement, and to pharmaceutical compositions on the basis of this tool

The invention relates to medicine, namely to synthetic biologically active compounds derived class 1 detoxi-1-N - methylaminoethanol and N-greenexpo acid

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

Up!