Tetrahydroisoquinolinium 1,2,3,3 and 8,8 and hexahydro-1.3 a - 8-trimethylpyrrole (2,3-b)indole, pharmaceutical composition and method of inhibiting acetylcholinesterase

 

(57) Abstract:

Describes tetrahydroisoquinolinium 1,2,3,, 8,8-hexahydro-1.3 a-8-trimethylpyrrole[2,3-b] indole of the formula I, in which R is hydrogen, lower alkyl, X is hydrogen, or acceptable acid additive salts, which are useful for the relief of memory dysfunction characterized by a cholinergic deficit. The proposed pharmaceutical composition and method of inhibiting acetylcholinesterase using the claimed compounds.

3 c. and 6 C.p. f-crystals, 2 tab.

This application is a partial continuation of the previous patent application, serial number 247826, registered on September 22, 1988, which is a continuation application under serial number 049894, registered on March 15, 1987, at present this patent 4791107, which is a continuation of a previous application under serial number 885991 registered on July 16, 1986, now abandoned.

The present invention relates to tetrahydroisoquinolinium 1,2,3,3 a,8,8 a-hexahydro-1.3 a,8-trimethylpyrrole[2,3-b]indole of the formula I

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in which R is hydrogen or lower alkyl; X is hydrogen, lower alkyl, halogen, lower alkoxyl or hydroxyl, which p is Alzheimer's.

If we are not talking about something different or not specified otherwise, the following definitions will be used throughout the specification and the attached claims.

The term lower alkyl denotes unbranched or branched alkyl group having 1-6 carbon atoms. To named examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.-butyl and branched and unbranched of pentyl and hexyl.

The term halogen means fluorine, chlorine, bromine or iodine.

Compounds of the present invention obtained using the stages of synthesis, which are described below. Throughout the description of stages of synthesis of the values of X and R have the meaning corresponding to the above, if not approved, or not indicated on anything else.

In the structural formulas, denoting the connection data of the present invention, the thick solid line ( _ _ _ ) emanating from 3a-carbon atom and 8a-carbon atom 1,2,3,3 a, 8,8 a-hexahydrofuro[2,3-b] indole ring system means that two deputies are above the median plane trehalase system, while the dashed line means that the two Vice-La are both above the median plane or below the median plan. Existing conformational constraints two of the substituent in position 3a and 8a should both be on this median plane, or both must be specified under the median plane. Thus, in the formula I the substituents in position 3a and 8a of the carbon atoms are in CIS position, as they are on the same side of the median plane trehalase system. When these substituents are both above the median plane trehalase system configuration must be assigned to 3a S-CIS configuration, and when both the Deputy located under the plane of the ring, then the configuration should be classified as 3a R-configuration. These two types of configuration of the molecule compounds indicated below.

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The purpose of the present invention is to declare both of these two isomers, namely, 3aS-CIS isomer and 3a-R-CIS isomer for each of the connection or structural formula, containing wavy lines mentioned above. The purpose of the present invention is to declare all of the mixture 3aR-CIS and 3aS-CIS isomers, including a racemic mixture (1:1 ratio 3aS-CIS:3aR-CIS).

Stage A

On the basis of the compounds of formula II and using the scheme of synthesis of razvedena below, but detailed information the reader can get in the original articles. The detailed procedure of the optical separation, is not described in the works of Julian et al. the reader may get the job Schonenberger et al., J. Med. Chem., 1986, vol. 29, 2268-2273; and Schonenberger et al. New Chim. Acta, 1986, volume 69, 283-287 and 1486-1497.

If the schema of the synthesis described above, the conversion of compound III to compound IV is carried out, bypassing the stage optical resolution, it turns out racemic mixture. Specified racemic mixture is a mixture consisting of compounds IV and 3aR-CIS isomer in the ratio of 50:50, and it can be used to obtain a racemic mixture containing the compound V.

Stage B

Connection Va obtained in stage A, left to interact with 1,1'-carbonyl diimidazol, and the resulting product is left to interact with the amine of formula VI

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in order to obtain the compound (VI).

The above reaction between the compound Va and 1,1'-carbonyl diimidazol usually carried out by preparing degassed solution of compound Va in a suitable solvent, such as dichloromethane, adding 1,1'-carbonyldiimidazole to the solution and stirring the solution at room temperature for a suitable period of time is the solution, obtained above and stirring the resulting solution for several hours.

The compounds of formula I of the present invention is suitable for treatment of various disorders of memory function, characterized by the weakening of cholinergic function, for example, for the treatment of Alzheimer's disease.

This utility is demonstrated by the ability of these compounds to inhibit the enzyme acetylcholinesterase and thus to improve the content of acetylcholine in the brain.

Comparison of the compounds of the present invention with physostigmine

Although physostigmine is a potent inhibitor acetylcholinesterase, its therapeutic use is limited because of low stability and oral bioavailability, short time steps and acute toxicity. We chose (3aS-CIS(-1,2,3,3 a,8,8 a-hexahydro-1.3 a,8-trimethylpyrrole[2,3-b] indol - 5-ol(1,2,3,4-tetrahydroisoquinoline)carbamate (denoted hereafter compound a) as an example of compounds included in the scope of the present invention, and compared its effects with the action of physostigmine in various in vitro and in vivo tests. The test results showed that the compound has A therapeutic advantage in the and physostigmine during incubation in human plasma at 37oC. After 4 hours of incubation, approximately 70% of A connection remains, whereas physostigmine completely destroyed under these conditions. As the inhibitor butyrylcholinesterase connection is A much less efficient (approximately 34 times) than physostigmine. Low affinity for this enzyme could be due to the stability of compound A in the plasma.

Oral bioavailability

The investigation of bioavailability of compound A showed that it can quickly be absorbed in the mouth (C Max. for 30 minutes) and easily pass through the blood brain barrier (brain: plasma C max is 4.55:1). In contrast to compound A physostigmine so poorly bioavailable when administered orally that the pharmacokinetic data were not available. The ratio of physostigmine in the brain and plasma after intravenous injection was equal to only about 1.5:1 (Somani and Khalique, Drug Metalolismand Disposition, vol 15, 627-633, 1987). Oral bioavailability and activity have also been demonstrated in trials of ex vivo inhibition of acetylcholinesterase, which was demonstrated significant inhibition of acetylcholinesterase (Ache) in the brain of rats after oral administration of compound A (see below for a detailed description of the test method used is the conduct of physostigmine in the test ex vivo was compared with the duration of A connection in this test. Compound a (20 mg/kg) significantly inhibited Ache rat brain after 4 and 6 hours after oral administration, at the same time its effect after 24 hours was statistically insignificant. Physostigmine no significant inhibitory effect already 2 hours after intraperitoneal introduction. Repeated administration of 20 mg/kg compound A for 4 days in rats did not show any effect of accumulation.

Activity in acute lethality

Compound a and physostigmine have equal silentauction as inhibitors of Ache in vitro. Value IR50for compound A in this experiment was equal to 0.036 M, and physostigmine is IR50was equal to 0.034 M. However, there is significant difference in acute toxicity between the two compounds. Intraperitoneal introduction of physostigmine in rats kill 50% of test animals at doses equal to 1.0, and 2.5 mg/kg, at the same time lethal dose causing death in 50% of animals, in the case of compound A is from 40 to 80 mg/kg there were also significant differences in the effect of compounds A and physostigmine on the cardiovascular system, the differences, which, apparently, caused noradrenergic action of compound A. Compound A (100 μm)I. (See below for a detailed description of this test method is used to highlight the definition of [3H] norepinephrine.

Experience in inhibition of cholinesterase

Cholinesterase is found in all parts of the body, brain and serum. However, only the distribution of brain acetylcholinesterase (Ache) is correlated with the Central cholinergic innervation. I think that the innervation weakened in patients with Alzheimer's disease. We determined the in vitro inhibition of acetylcholinesterase activity in neostriatal rats.

Inhibition of in vitro activity of acetylcholinesterase in neostriatum rats

The acetylcholinesterase (Ache), which is sometimes called the true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. Ache may differ from other cholinesterase specific action of the inhibitor and substrate and regional distribution. The distribution of acetylcholinesterase in rat brain roughly correlate with cholinergic innervation and subfractionated shows the highest level in the nervous system.

It is usually assumed that the physiological role of Ache conclusion the effect holinergiceski-innervated effector organs and are used for therapeutic purposes in the treatment of glaucoma, severe forms of myasthenia gravis and paralytic ileus. However, recent studies have shown that perhaps Ache inhibitors can also be used successfully in the treatment of dementia of Alzheimer's disease.

The method described here was used in the present invention for determining the activity of cholinesterase. He is a modification of the method of Ellman et al., Biochem. Pharmacol. 7, 98 (1961).

Procedure:

A. Reagents (reagents)

1. 0.05 M phosphate buffer, pH 7.2

(a) 6.85 g NaH2PO4H2O/100 ml of distilled water

(b) 13.40 g of Na2HPO47H2O/100 ml of distilled water

(c) add (a) to (b) up until the pH reaches 7.2

(d) dilute 1:10

2. The substrate in the buffer

(a) 198 mg acetylthiocholine chloride (10 mm)

(b) bring to 100 ml of 0.05 M phosphate buffer, pH 7.2 (reagent 1).

3. DTNB in the buffer

(a) 19.8 mg of 5,5-dithiobisnitrobenzoic acid (DTNB) (0.05 M)

(b) bring to 100 ml of 0.05 M phosphate buffer, pH 7.2 (reagent 2).

4. 2 mm of the original solution of the test drug is prepared in a suitable solvent and brought to a volume of 0.05 mm DTNB (reagent 3). The medicine is diluted serially (1:10) so that the final concentration in the blend is nsibirwa activity of a series of concentrations.

B. Preparation of tissue

Decapitate male Wistar rats, the brain quickly removed, striped body cut out, weighed and homogenized in 19 volumes (about 7 mg/ml) 0.05 mm phosphate buffer using a Potter homogenizer-Elvenhjem. The aliquot volume 25 microlitres homogenate is added to 1.0 ml of a solution containing various concentrations of test drug and pre-incubated for 10 minutes at 37oC.

C. Analysis

The enzyme activity is measured on a spectrophotometer Beckman D-50. This method can be used to determine IR50and for measurement of the kinetic constants.

Toolkit

The software package Soft-Pac Module 598273 (10)

Program 6 Kindata

Source - Vis

The wavelength of 412 nm

Sipper -

Cuvette 2 ml cuvette using auto-6-sampler

Blind experience (blank cuvette) 1 for each substrate concentration

The time interval is 15 seconds (15 or 30 seconds in the case of kinetic measurements)

Graphing - Yes

Interval - autographica

Tilt - growing

Results - Yes (give the slope)

Factor - 1

The reagents added in the blank cuvette and the cuvette with the sample as follows:

Drug: 0.8 ml phosphate buffer/DTNB/drug/enzyme, 0.8 ml phosphate buffer/substrate

The values in the idle experience determined for each experiment in order to control the nonenzymatic hydrolysis of the substrate, and these values will be automatically deducted using the kinetic data (Kindata program), which is available on the basis of the angular software package (Soft-pack module). This program also calculates the change rate of absorption for each cuvette. If IR50:

The substrate concentration is equal to 10 mm, in the process of analysis it is diluted in the ratio 1: 2, to obtain a final concentration of 5 mm. Concentration DTNB equal to 0.5 mm, final concentration 0.25 mm

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IR50values calculated on the basis of the logarithmic probability of the effect

[3H] -norepinephrine uptake of whole rat brain or hypothalamic-uptake by

This experience is used as a biochemical screening of compounds that block the uptake of norepinephrine.

Neuronal mechanism pe-uptake of norepinephrine (ne) is essential in fiziologicheskii saturated, stereospecific, high affinity (Km= 10-7- 10-6M) sodium-dependent active transport system, which, as shown, exists in the tissues of both peripheral and Central nervous system, when you use slice homogenate and purified synaptosomal preparations. Ne uptake significantly inhibited cocaine, phenylethylamine and tricyclic antidepressants. It is also inhibited by oubain, metabolic inhibitors and phenoxybenzamine. Inhibition of absorption ne clinically effective antidepressants tricyclic type represents an important link in the catecholamine hypothesis of mood disorders (disorders).

In absorption ne there are large variations in the regional plan that are correlated with the endogenous content of ne. The highest content found in the hypothalamus, and see the greatest absorption. This part of the brain selected for further testing compounds that are found activity in the whole brain preparations. Synaptosomal [3H]-ne uptake is a useful marker to determine the integrity of the noradrenergic neurons after termination of the experiment along with the fool:

A. Animals: Male rats CR Wistar (100 - 125g)

B. Reagents:

1. Bicarbonate buffered Krebs-Henseleit, pH 7.4 (KHBB)

Prepare a batch volume of 1 liter containing salts listed in table. 1.

Spend aerate the solution for 60 minutes with a mixture containing 95% O2and 5% CO2support pH equal 7.40.1.

2. 0.32 M sucrose: 21.9 g of sucrose was adjusted to 200 ml.

3. (-)-norepinephrine bitartrate obtained from a commercial source.

0.1 mm solution prepared in 0.01 M HCl. This solution is used for diluting ne, labeled with a radioactive label.

4. Levogyrate - [ring-2,5,6-3H] -norepinephrine/40 - 50 curies/mmol was obtained from a commercial source. The final desired concentration of [3H]-ne in the sample is equal to 50 nm. The dilution factor is equal to 0.8; therefore KBB prepared so that the content of [3H]-ne was equal to 62.5 nm.

Bring to 100 ml by adding CHBB:

A. 59.4 microliters of 0.1 mm ne = 59.4 nm

B. 0.31 nm [3H]-ne = 3.1 nm

Total: 62.5 nm

5. For most samples (assays) 1 mm ready solution of the test compound is prepared in a suitable solvent and serially diluted such that the final concentration in the sample varier is nishie concentration will be used - depends on how effectively test the connection.

C. fabric

Male Wistar rats were decapitated and quickly removed the brain. Either the whole brain excluding the cerebellum, or the hypothalamus weighed and homogenized in 9 volumes of cooled ice 0.32 M sucrose solution, using the homogenizer (Potter-Elvehjem. Homogenization should be performed when the fluid velocity is equal to 4-5 moves up and down to minimize lysis synaptosome. The homogenate cetrifugation at 1000 g for 10 minutes at 0-4oC. the Supernatant (I) is decanted and used in experiments to study absorption.

D. Analysis

800 microliters - KHB containing [3H]-NE

20 microlitres - Filler or the appropriate concentration of drug

200 microlitres - Suspension fabric

The tubes are incubated for five minutes at 37oC in an atmosphere of 95% O2/5% CO2. In each experiment 3 test tubes incubated with 20 Microlitre filler (solvent) at 0oC in an ice bath. After incubation all tubes are immediately centrifuged at 400 g for 10 minutes. Supernatant layer is sucked off, and the residue after centrifugation restoration vials and count the number of pulses in 10 ml hiquiscinr scintillation cocktail. Active uptake is the difference between the number of counts per minute at 37oC and 0oC. the Percent inhibition at each concentration of the drug is represented as the average of three measurements. Values IR50determined from the logarithmic dependence.

Cardiovascular pharmacology

Purpose. The objective of the study described below was to characterize the cardiovascular profile of Compound A and compare it with the profile of physostigmine, a standard inhibitor of acetylcholinesterase. (For a detailed description of test methods used to determine the acute cardiovascular hemodynamic effect later in the concluding section).

Conclusions on the basis of the obtained results: Intravenous infusion of compound A (0.01 mg/kg/min) shot the dogs did not lead to significant cardiovascular depression observed at equivalent speeds infusion of physostigmine (see tab. 2). Indeed, at higher doses of the compounds (0.1 mg/kg/min intravenously) measured cardiac and peripheral vascular parameters were significantly increased (table. 2). This hemodynamic profile is qualitatively similar profile, nabla response to compound A also correlates with the results in vitro and showing spontaneous secretion of norepinephrine endings of sympathetic nerves.

Additional research on shot the dogs were conducted by comparing the actions on the cardiovascular system Compound A (0.1 mg/kg/min) and physostigmine (0.01 mg/kg/min), and the other drugs were administered intravenously in the process of combined alpha and beta blockade adrenergicheskih receptors. Infusion of physostigmine in the process blockade of alpha and beta receptors has led to severe depression of the cardiovascular system and mortality during 17-29 minutes among 3 of the three dogs. In the case of intact alpha and beta adrenergic receptors with the same dose of physostigmine mortality was not observed. In contrast to physostigmine blockade of alpha and beta adrenergic receptors withdrew positive cardiac and hemodynamic effects of the compounds results in a moderate fall in blood pressure and cardiac output.

Higher doses of physostigmine, used in these studies were produced blockade of conduction potential impacts from the Atria to the ventricle (A-Y block) (table. 2). On the ECG there have been no changes, tie is reserve /RAP/ enddiastolic pressure in the left ventricle (VEDP), seen with infusion of physostigmine (indicating that the decrease in the contractile force of the heart muscle), was not observed during the infusion of compound A.

The conclusions. Summarized above results lead to the assumption that the connection A, despite a strong inhibitory effect on acetylcholinesterase, has an exceptional ability to reduce depression of the cardiovascular system observed in the case of the introduction of a standard preparation of physostigmine. In addition, our data indicate that functional adrenergichesky compensatory mechanism plays an important role in weakening severe forms of cardiovascular depression caused by inhibition of acetylcholinesterase.

The methods used to assess acute cardiovascular hemodynamics

Short-legged hounds dogs of both sexes were shot by intravenous injection of a mixture of sodium thiopental 15 mg/kg + sodium barbitala 100 mg/kg + sodium pentobarbital 60 mg/kg Trachea was intubated endotracheally tube with cuff and connected with respiratory pump Harward, giving 20 ml/pulse and 10 pulses/minute. The right femoral artery and vein were removed and Coulibaly with the aid of the drugs. The duration of these experiments was two hours after administration of a drug when administered intravenously preparation and three hours, when the drug was injected intradermally.

The arterial cannula was connected to a sensor am P23G. Catheterization of the left ventricle of the heart is accompanied by the introduction of miniature pressure sensor Millar in the left carotid (carotid) artery and advancing it into the left ventricle. The cannula is connected with the control device TC-100 sensor Millar, which is connected with the switching device Beckman linking stress and pressure. Ventricular pressure and its first derivative dp/dt is measured simultaneously by passing the output signal from the left ventricle in differentiating device. Cardiac volume (CO) is determined using techniques thermoresponsive using chetyrehsotletny 7FSwan-Ganz flow-controlled catheter inserted into the right external jugular vein and associated with Vena cava, right atrium, through the right ventricle and pulmonary artery. The proximal lumen of the catheter is in the right atrium, while the peripheral distal lumen and thermistor is firmly set in the pulmonary artery. The output signals of the proximal Oh artery (PPA). Cardiac volume was determined by injection of 5 ml ice dextrose 5% in water in the proximal site (right atrium) and the subsequent measurement of the temperature change in the pulmonary artery. Fundamentally volume (cardiac output) can be determined using equation Hewart-Hamilton by integrating the area under the curve of thermoresponsive on the computer Edwards (model 9520). Heart rate is determined using Beckman Cardiotach, which summarizes the pressure wave curve with pulse pressure blood pressure. Abstraction 11 electrocardiogram recording. All of these output signals appear on the recording device Beckman P-661. Measurement of these parameters provides information that can be used for either direct measurements or calculations.

1. Mean arterial blood pressure - MAP (mm RT. column)

2. Heart rate - HR

3. Cardiac output - CO (liter/minute)

4. Total peripheral resistance - TPR

5. Cardiac index (CI CO/m2)

6. Volume of discharge (ml/push)

7. Work release (g-m/jerk)

8. Central venous pressure CVP, measured as the pressure in preser. Art.

10. The frequency increase of the pressure in the ventricular dP/dt/Pmax. This parameter determines myocardial contractility than one derivative dP/dt, since it is relatively independent of the loading conditions of the heart (sec-1).

11. The pressure of the pulmonary artery - PAP (mm RT. Art.)

12. Electrocardiogram - ECG.

The results of the evaluation of acute cardiovascular hemodynamics are given for compounds A and physostigmine in the table. 2.

Effective amounts of compounds of the present invention can be introduced to the patient by various methods, including, for example, oral administration, in the form of capsules, tablets, parenteral - in the form of sterile solutions or suspensions, and in some cases intravenously in the form of a sterile solution. The final products in the form of a free base, being effective themselves, may be made in the form of compositions and introduced in the form of their pharmaceutically acceptable acid salts of accession with the aim of increasing stability, convenience of crystallization, higher solubility, and the like things.

Acids suitable for obtaining a pharmaceutically acceptable acid salts of the accession of the present invention, otesannoj acids, as well as organic acids such as wine, citric, acetic, succinic, fumaric and oxalic acids.

Active compounds of the present invention can be administered in a form suitable for oral administration, for example, with an inert diluent or edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic treatment they can be incorporated with excipients and used in the form of tablets, wafers, capsules, elixirs, suspensions, syrups, lozenges, chewing gum, etc., These preparations should contain at least 0.5% of active compound, but the content of the active compounds can vary depending on the specific form, can traditionally be from 4% to about 70% by weight. The number of active compound in such compositions is such that it should be provided with a suitable dose of a compound. Preferred compositions and preparations corresponding to the present invention are prepared so that the final form for oral administration contain from 1.0 to 300 mg of active compound.

Tablets, capsules, pills, lozenges, etc. manufactured forms can also SOA starch or lactose; cage mill type of alginic acid: Primogel, corn starch, etc.; lubricant type stearate or Startexe; a means of indicating the ability to glide, type colloidal silicon dioxide; sweetening tools like sucrose or saccharin, also can be added substances such as fragrances, such as peppermint, methylsalicylate or orange flavoring. In those cases where the final form is a capsule, it also can optionally contain, in addition to the substances, which were discussed above, the carrier liquid of the type of fatty oil. Other final dosage forms may also contain various materials which modify the physical form of the dosage unit, for example, coating. Thus, tablets or pills may be coated with sugar, Wellcom or other soluble in the stomach coating. A syrup may contain, in addition to active compound of sucrose as a sweetening means, and certain preservatives, dyes, color pigments, and perfumes. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

In those localista suspension or solution. These preparations should contain at least 0.1% of active compound, but may nevertheless vary from 0.5 to about 30% by weight. The number of active compounds in such compositions should be such as to achieve the appropriate dose. Preferred compositions and preparations corresponding to the present invention are prepared so that a dosage single form for parenteral introduction contained 0.5 to 100 milligrams of active compound.

The solutions or suspensions may also contain the following components: a sterile diluent type of water for injection, saline solution, certain solid oils, polyethylene glycol, glycerine, propylene glycol or other synthetic solvents; antibacterial (antimicrobial) type additives benzyl alcohol or methyl paraben, antioxidant type ascorbic acid or sodium bisulfite; hepatoblastoma tools like ethylenediaminetetraacetic acid; buffers, type, acetate buffer, citrate or phosphate buffer, and means for imparting restorative actions such as sodium chloride or dextrose. The parenteral preparation can be enclosed in syringes or ampoules for reusable dosiro the plants, including the 3aR-CIS isomer, and a mixture of 3aS-CIS and 3aR-CIS isomers, including racemic mixtures:

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (1,2,3,4-tetrahydroisoquinoline)carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (1-methyl-1,2,3,4-tetrahydroisoquinoline)carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (1-ethyl-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (1-propyl-1,2,3,4-tetrahydroisoquinoline)carbamate;

(3aS-CIS(1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol - 5-ol, (1-butyl-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (6-chloro-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (7-chloro-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (6-chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (6-guide-ol, (7-hydroxy-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, (6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline/carbamate;

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, /7-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline/carbamate.

With the purpose to illustrate the invention below, the following examples.

Example 1

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b]indol - 5-ol, /1,2,3,4-tetrahydroisoquinoline)carbamate.

Degassed solution eseroline (3.0 g) in 80 ml of dry dichloromethane was treated in one portion of 1,1'-carbonyldiimidazole (2.7 g) and mixed at room temperature. After one hour the solution was treated with 1,2,3,4-tetrahydroisoquinoline (4.0 g) and stirring continued overnight. The solution was concentrated and the residue was purified using flash chromatography, the obtained 2.8 g of pale oil, which was recrystallized from ether and obtained 2.4 g of white crystals. So pl. 83-85oC.

Analysis:

Calculated for C23H27N3O2: C 73.18%, H 7.20%, N 11.13%

Found: C, 72.97%, H 7.22%, N 11.09%.

Example 2

(3aS-CIS)-1,2,3,3 a, 8,8 a-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b 1,1'-carbonyldiimidazole (2.1 g) in 60 ml of dry dichloromethane was stirred at room temperature for one hour. This solution was treated with 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.5 g) and stirred at 40oC for 2 hours, then added the same number called isoquinoline derivative and the solution was stirred at reflux for three hours. The solution was concentrated, and the residue was purified using flash chromatography on aluminum oxide in the obtained 2.0 g of pale oil. This oil has recrystallize from 50 ml of a mixture of pentane and simple ether (10:1) and the obtained white crystals. So pl. 105-108oC.

Analysis:

Calculated for C24H29N3O2: C, 73.62%, H 7.46%, N 10.73%

Found: C, 73.86%, H 7.48%, N 10.65%.

1. Tetrahydroisoquinolinium 1,2,3,3 and 8,8 and hexahydro-1.3 a,8-trimethylpyrrole[2,3-b] indole of the formula I

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where R represents hydrogen or lower alkyl;

X represents hydrogen;

or their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which R represents hydrogen or methyl.

3. Connection on p. 1, which is (3A S-CIS) - 1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-ol (1,2,3,4-tetrahydroisoquinoline)carbamate, or (3R-CIS)isomer, or a mixture of two of the about[2,3-b] indol-5-ol (1-methyl-1,2,3,4-tetrahydroisoquinoline)carbamate, or (3R-CIS)isomer, or a mixture of two isomers.

5. Connection on p. 1, which is (3S-CIS) - 1,2,3,3 and 8,8 and hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-ol (1-ethyl-1,2,3,4-tetrahydroisoquinoline)carbamate, or (3R-CIS)isomer, or a mixture of two isomers.

6. Connection on p. 1, which is (3S-CIS) - 1,2,3,3 and 8,8 and hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-ol (1-propyl-1,2,3,4-tetrahydroisoquinoline)carbamate, or (3R-CIS)isomer, or a mixture of two isomers.

7. Connection on p. 1, which is (3S-CIS) - 1,2,3,3 and 8,8 and hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-ol (1-butyl-1,2,3,4-tetrahydroisoquinoline)carbamate, or (3R-CIS)isomer, or a mixture of two isomers.

8. Pharmaceutical composition having cholinergic activity and comprising an active agent and a carrier, wherein the active agent contains a compound of formula I under item 1 or its pharmaceutically acceptable acid additive salt in an amount effective to facilitate dysfunction of memory.

9. The method of inhibition of acetylcholinesterase in the treatment of functional disorders, characterized by a cholinergic deficit, including the introduction of anticholinesterases the th pharmaceutically acceptable acid additive salt.

 

Same patents:

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl

The invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, for example asthma, arthritis and allergies; fear; depression; fatigue syndrome; headache; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions

The invention relates to new derivatives of 1-piperazine-1,2-dihydroindeno and their acid additive salts which are active in relation to dopamine receptors in the Central nervous system, in particular are potential antagonists of dopamine receptors D, medicinal products containing these derivatives as active ingredients, and to the use of these derivatives in the treatment of diseases of the Central nervous system

The invention relates to new derivatives aminoquinolone

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose

The invention relates to tetraethylammonium compounds of the formula I

< / BR>
and their pharmaceutically acceptable salts,

where R1represents one or more substituents selected from H, halogen, hydroxy, alkyl with 1 to 3 carbon atoms (optionally substituted by hydroxyl), alkoxyl with 1 to 3 carbon atoms, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, nitro, cyano, Polygalaceae with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms), or R1is carbamoyl, optional alkilirovanny one or two alkyl groups, each independently from 1 to 3 carbon atoms;

R2represents an aliphatic group containing 1 to 3 carbon atoms, optionally substituted by hydroxy or alkoxy containing 1 to 3 carbon atoms;

E represents alkylenes chain containing 2 to 5 carbon atoms, optionally substituted by one or more alkyl groups containing 1 to 3 atom is dinasovymi or different and are independently an alkyl of 1 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, halogen, hydroxy, polyaluminum with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, cyano, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms or alkoxy with 1 to 3 carbon atoms), carbamoyl, optional alkilirovanny one or two alkyl groups, each of which is independently from 1 to 3 carbon atoms, or G represents a phenyl ring having condensed with him heterocyclic or aromatic carbocyclic ring,

and O-acylated derivatives
The invention relates to medicine, Nephrology

The invention relates to 6-[X-(2-hydroxyethyl)aminoalkyl]-5,11-dioxo-5,6,-dihydro-11H - indeno[1,2-C]isoquinolines of the General formula I

< / BR>
in which

X represents the number of carbon atoms equal to 0-5 in aminoalkyl group, located at the nitrogen atom in the 6 position of the canonical formulas indrosophila, to their salts with inorganic and organic acids and method of production thereof

The invention relates to water-soluble derivative of camptothecin described by formula (I)

< / BR>
where n = 1 or 2; 1) R1and R2taken separately, represent hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; 2) R1represents hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or lower alkoxy lower alkyl; R2is-COR3where R3represents hydrogen, lower alkyl, pergola-lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl, lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl; 3) R1and R2taken together with the connecting nitrogen atom form a saturated 3-7-atom heterocyclic group of formula 1A

< / BR>
where Y represents O, S, CH2, NR4where R4represents hydrogen, lower alkyl, pergola-lower alkyl, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyloxy lower alkyl, or COR5where R5represents hydrogen, lower alkyl, pergola-lower alkyl, lower alkoxy, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyl, pergola-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl; and their pharmaceutically acceptable salts, their use for the treatment of tumors and methods of preparation

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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