RU2040526C1 - Bicyclic 1-aza-cycloalkanes, mixture of their isomers or separate isomers, or their pharmacologically tolerated acid-additive salts - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: bicyclic 1-aza-cycloalkanes of the general formula -CH₂- where R lower alkyl, nonsubstituted or substituted with furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; alkynyl with 3-6 carbon atoms; nonsubstituted phenyl or substituted with lower alkyl, alkoxy-group or halide; nonsubstituted benzyl or substituted with halide; pyridyl; pyrimidinyl; A, B and C - independently each of other means

Description

(I) где R низший алкил, незамещенный или замещенный фураном, тиофеном или имидазолом; алкенил с 3-6 атомами углерода; алкинил с 3-6 атомами углерода; фенил, незамещенный или замещенный низшим алкилом, алкоксигруппой или галоидом; бензил, незамещенный или замещенный галоидом; пиридил; пиримидинил;
А, В и С независимо друг от друга означают -СН₂- или простую связь;
n 0 или 1, смесям из изомеров или индивидуальным изомерам и их фармакологически переносимым кислотно-аддитивным солям, проявляющим холинометические свойства.The invention relates to new compounds with pharmacological activity, in particular to bicyclic 1-aza-cycloalkanes of the general formula

(I) where R is lower alkyl unsubstituted or substituted with furan, thiophene or imidazole; alkenyl with 3-6 carbon atoms; alkynyl with 3-6 carbon atoms; phenyl unsubstituted or substituted by lower alkyl, alkoxy or halogen; benzyl unsubstituted or substituted by halogen; pyridyl; pyrimidinyl;
A, B and C, independently of one another, mean —CH ₂ — or a single bond;
n 0 or 1, mixtures of isomers or individual isomers and their pharmacologically tolerable acid additive salts exhibiting cholinometric properties.

(II) где А, В, С и n имеют вышеуказанные значения; Z защитная группа подвергают депротонированию с последующим взаимодействием с соединением общей формулы
Y-R₁ (III) где R₁ низший алкил, незамещенный или замещенный фураном, тиофеном или имидазолом, алкенил с 3-6 атомами углерода, алкинил с 3-6 атомами углерода, фенил, фенил, незамещенный или замещенный низшим алкилом, алкоксигруппой или галоидом; Y легко отщепляемая группа, и снятием защитной группы Z.New compounds can be obtained due to the fact that
a) a compound of the general formula

(II) where A, B, C and n have the above meanings; The Z protecting group is deprotonated followed by reaction with a compound of the general formula
YR ₁ (III) where R ₁ lower alkyl unsubstituted or substituted with furan, thiophene or imidazole, alkenyl with 3-6 carbon atoms, alkynyl with 3-6 carbon atoms, phenyl, phenyl unsubstituted or substituted with lower alkyl, alkoxy or halogen; Y is an easily cleavable group, and the removal of the protective group Z.

(IV) где А, В, С и n имеют вышеуказанные значения, подвергают взаимодействию с соединением общей формулы
HO-R₂ (V) где R₂ бензил, незамещенный или замещенный галоидом, пиридил, пиримидинил, в присутствии трифенилфосфина и сложного алкилового эфира азодикарбоновой кислоты.b) a compound of the general formula

(IV) where A, B, C and n have the above meanings, are reacted with a compound of the general formula
HO-R ₂ (V) where R _{2 is} benzyl, unsubstituted or substituted by halogen, pyridyl, pyrimidinyl, in the presence of triphenylphosphine and azodicarboxylic acid alkyl ester.

 Obtained according to (a) and (b), the target product is isolated in free form or as a racemate or enantiomer or diastereomeric mixture or diastereomers or as a pharmacologically tolerated acid addition salt, preferably in the form of a methiodide or methobromide.

 The reaction according to (a) is carried out in an environment of polar inert organic solvents, such as dimethylformamide, tetrahydrofuran, dioxane, etc. While deprotonation is preferably carried out at room temperature or slightly elevated temperature, subsequent alkylation is preferably carried out under ice cooling.

 Sodium hydride, sodium amide, alkali metal alcoholates, such as, for example, potassium tert-butylate, are preferably used as reagents for the implementation of deprotonation.

 The reaction according to (b) is usually carried out at room temperature in an inert organic solvent.

 The compounds of general formula (I) have valuable pharmacological properties. For example, in receptor-binding experiments, compounds exhibit an affinity for muscarinic receptors and muscarinic agonistic displacements of GTP.

 Research on receptor binding was carried out according to known methods.

 Receptor binding studies are listed below.

Radioligand: iodide L (+) cis- [2-methyl- ³ H] -N, N, N-trimethyl-1,3-dioxolane-4-methammonium (commercial product NET-647 of the foreign company NEN, GB).

Organ: Rat cerebral cortex Compound Factor Ki [nmol / 1]
for example 2 89 4 120 7 229 11 70 12 56 35 159
As muscarinic agonists (cholinomimetic substances), the new compounds are suitable for the treatment of diseases with insufficient cholinergic system function.

 As a result of pharmacological experiments, the new compounds are suitable, for example, for the treatment of the following diseases: Alzheimer's disease, senile dementia, cognitive disorders. In addition, they can also be used to improve the functional ability of the memory.

 The quaternary compounds of formula (I) are particularly suitable for peripheral use, such as, for example, for the treatment of glaucoma.

PRI me R 1. 3-Propargyloxy-1-azobicyclo [2.2.1] heptane. Under nitrogen atmosphere, 5.5 g (0.05 mol) of 1-azabicyclo [2.2.1] heptan-3-ol is dissolved in 150 ml of absolute tetrahydrofuran and mixed with 50 ml of 1M borane tetrahydrofuran complex at 0 ° ^C. After the end of the process of adding the indicated complex is stirred for 1 h at room temperature, concentrated to dryness, the residue is taken up in a saturated solution of sodium chloride and extracted with dichloromethane. The combined organic phases are dried and concentrated, the residue is dissolved in 120 ml of absolute tetrahydrofuran and, under nitrogen atmosphere, it is mixed with 2.08 g (0.052 mol) of sodium hydride in portions. After one hour, the reaction mixture was cooled ^to 0 ° C and at this temperature, dropwise added 17.55 g of propargyl bromide as a 50% solution in tetrahydrofuran. It is then stirred for 12 hours at room temperature, the excess hydride is decomposed with ethanol, concentrated, the residue is taken up in saturated sodium chloride solution and extracted with dichloromethane. After drying and thickening of the combined organic phases, an oil is obtained which is distilled in high vacuum (Tk _Lmbar 45-46 ^о С). To obtain fumarate, one equivalent of fumaric acid is used, recrystallized from a mixture of ethanol and ether, and dried in vacuum. Obtain 2.1 g of the above compounds in the form of colorless crystals with so pl. 121-123 ^about S.

¹ H-NMR (250 MHz, CD ₃ OD, TMS *): δ6.68 (2H, s, fumaric acid); 4.47 (1H, m, H-3); 4.21 (2H, m, CH ₂ -8); 3.73-2.86 (7H, m, CH ₂ -2.6.7; H-4); 2.95 (1H, t, J 3 Hz, H-9); 2.30; 1.96 (2H, m, CH ₂ -5).

*) tetramethyl sulfoxide
PRI me R 2. 3-Phenoxy-1-azabicyclo [2.2.1] octane. 3.82 g (0.03 mol) of 3-hydroxyquinuclidine, 2.82 g (0.03 mol) of phenol, 7.96 g (0.03 mol) of triphenylphosphine and 5.22 g (0.03 mol) of complex diethyl azodicarboxylic acid ester is dissolved in 150 ml of absolute tetrahydrofuran and stirred for two days at room temperature. It is concentrated to dryness, the residue is taken up in 20 ml of 6N hydrochloric acid and 50 ml of water and extracted with ether. The aqueous phase is made basic and extracted by shaking with ethyl acetate, the combined ethyl acetate phases are dried and concentrated. After distillation, 3.6g colorless oil Tc _0,1mbar 104-105 ° ^C).

¹Н-ЯМР (250 мГц, CDCl₃, ТМС): δ 7,26; 6,87 (5Н, м, арил-Н); 4,36 (1Н, м, Н-3); 3,34-2,63 (6Н, м, СН₂-2,6,7); 2,19-1,27 (5Н, м, СН-4; СН₂-5,8).

¹ H-NMR (250 MHz, CDCl ₃ , TMS): δ 7.26; 6.87 (5H, m, aryl-H); 4.36 (1H, m, H-3); 3.34-2.63 (6H, m, CH ₂ -2.6.7); 2.19-1.27 (5H, m, CH-4; CH ₂ -5.8).

The base is transferred in an ethanol solution to a fumarate, which is precipitated with ether and recrystallized from acetonitrile. Obtain 4.1 g of colorless crystals with so pl. 122-124 ^about S.

 PRI me R 3. (+) - and (-) - 3- (propargyloxymethyl) -1-azabicyclo- [2,2,2] octane.

 a) (+) - 3- (propargyloxymethyl) -1-azabicyclo [2.2.2] octane. 5.6 g of (+) - 3-quinuclidinemethanol hydrochloride, 1.32 g of sodium borane and 100 ml of tetrahydrofuran are stirred overnight. The solvent was removed from the filtrate, the residue was taken up in ethyl acetate and the resulting solution was washed with saturated sodium chloride solution. After drying and removal of the solvent, 3.4 g of the complex of (+) - 3-quinuclidinylmethanol and borane remain as a yellow oil.

3.4 g of this complex and 2.63 g of 60% sodium hydride are stirred in 100 ml of tetrahydrofuran for 30 minutes at room temperature, then the reaction product is reacted with 4.89 g of 80% propargyl bromide and stirred for further 6 hours. The reaction mixture is carefully decomposed with alcohol, the solvent is removed, the residue is taken up in 150 ml of ethyl acetate, the solution is washed with saturated sodium chloride solution and the solvent is removed again. To destroy the borane protecting group, the residue is taken up in 50 ml of acetone and mixed with 20 ml of 3 N hydrochloric acid overnight. After evaporation of the acetone, the aqueous phase is washed with ethyl acetate, alkalized with potash and extracted with ethyl acetate. The residue obtained as a result of extraction was flash chromatographed on silica gel using ethyl acetate, methanol and ammonia (85: 15: 1) as an eluent. Obtain 4.3 g of propargyl ether, which in alcohol is converted into fumaric salt by adding the calculated amount of fumaric acid. The salt is reprecipitated from a mixture of alcohol and diethyl ether. 3.9 g of m.p. 132-133 ^about C. [α] _D ²⁰ +28.47 ^about (s 1, methanol).

 b) (-) - 3- (propargyloxymethyl) -1-azabicyclo [2.2.2] octane.

Similarly to step (a), a protective borane group is introduced into (-) - 3-quinuclidinylmethanol, esterification with propargyl bromide is carried out, and after removal of the protective borane group, the free base is transferred to a fumarate having the like 132-133 ^about C. [α] _D ²⁰ -28,42 ^about (s 1, methanol).

 Similarly to examples 1-3, you can get even summarized in table. 1-4 compounds of General formula (I).

 PRI me R 36. 3- (2-Propynyloxy) -1-azabicyclo [2.2.2] octane.

14.1 g (0.1 mol) of 3-hydroxy-1-azabicyclo [2.2.2] octane is reacted with borane as a complex with 4 g of sodium hydride as a 60% dispersion in oil in 140 ml medium dimethylformamide at room temperature. Upon completion of the evolution of hydrogen, the reaction mixture was mixed with a solution of 14.28 g (0.12 mol) of propargyl bromide in 10 ml of toluene under ice-cooling, after which it was stirred at room temperature for 3 hours, 5 ml of ethanol was added and the mixture was concentrated under vacuum in a rotary evaporator . The residue was partitioned between 10% sodium chloride solution and diethyl ether. The organic phase is dried over anhydrous sodium sulfate and concentrated. The remaining dark brown oil is mixed with 75 ml of tetrahydrofuran and 15 ml of acetate. To the resulting solution, while cooling with ice, 30 ml of 4 N. of hydrochloric acid. The reaction mixture was left to stand for another hour at room temperature, after which the organic solvent was distilled off. The residue was diluted with a small amount of water and sequentially extracted with petroleum ether and diethyl ether. The aqueous phase is made basic with a 40% potassium carbonate solution and extracted with diethyl ether. The ethereal solution was dried over anhydrous sodium sulfate and concentrated. 6.9 g (41.8% of theory) of 3- (2-propionyloxy) -1-azabicyclo [2.2.2] octane are obtained in the form of a base, which is converted to fumarate by the addition of an equivalent of fumaric acid. Mp 138-140 ^about With (from a mixture of ethanol and diethyl ether).

Calculated, C 59.77; H 6.81; N 4.98
C ₁₀ H ₁₅ NO x C ₄ H ₄ O ₄ (281.31)
Found C, 59.86; H 6.76; N, 4.95.

PRI me R 37. Example 35 is repeated with the difference that n-propyl bromide is used instead of propargyl bromide. Get 3- (n-propyloxy) -1-azobicyclo [2.2.2] octane in the form of a fumarate with so pl. 120-121 ^C (from acetonitrile).

Calculated, C 55.97; H 7.34; N 4.08
C ₁₀ H ₁₉ NO x 1.5 C ₄ H ₄ O ₄ (343.38)
Found C 55.67; H 7.51; N, 4.09.

Claims (1)

Bicyclic 1-aza-cycloalkanes of the general formula

where R is lower alkyl unsubstituted or substituted by furan, thiophene or imidazole C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, phenyl unsubstituted or substituted by lower alkyl, alkoxy or halogen, benzyl unsubstituted or substituted by halogen, pyridyl, pyrimidinyl;
A, B and C are independently -CH ₂ - or a single bond;
n 0 or 1,
a mixture of their isomers or individual isomers, or their pharmacologically tolerable acid addition salts having cholinometric properties.

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