HU211951A9 - Tetrahydroisoquinolinylcarbamates of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo(2,3-b)indole - Google Patents

Description

The present invention relates to 1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indole-tetrahydroisoquinolinylcarbamate derivatives.

The 1,2,3,3a, 8,8a-hexahydrol, 3a.8-trimethylpyrrolo [2,3-b] indole tetrahydroisoquinolinylcarbamates of the invention are represented by the formula (I):

R is hydrogen or lower alkyl, and

X is hydrogen, lower alkyl, lower alkoxy, or hydroxy, or halogen.

The compounds of formula (I) are useful in the alleviation of memory disorders, such as those useful in cholinergic disorders such as Alzheimer's disease.

As used herein, references to substituents on compounds of Formula I, unless otherwise indicated, are to be understood as meaning above.

The lower alkyl group may be straight or branched C 1-6 alkyl such as methyl, ethyl, η-propyl, isopropyl, n-butyl. isobutyl, sec-butyl, tert-butyl, and straight or branched pentyl or hexyl.

Halogen is fluorine, chlorine, bromine or iodine.

Compounds of formula (I) are prepared according to the procedure set forth below, wherever X and R are as described above, unless otherwise indicated.

In the structural formulas describing the compounds of the present invention, the thick line (-) is the

] .2.3,3a.8.8a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indole ring system appears at 3a and 8a carbon atoms, meaning that these two substituents are the three ring system. above its average plane. The dashed line (- «) indicates that the two substituents are below the average plane. while the wavy line (-) indicates that each of the two substituents is below or above the plane. Due to structural constraints, the two substituents in the 3a and 8a positions must each be located below or above the plane. Thus, the 3a and 8a carbon atoms in the formula (I) are in the cis configuration when they are on the same side of the three membered ring system. When the two substituents are each located above the plane of the three-membered ring system, the configuration is designated as the 3aS-cis configuration, and where the substituents are below the plane, the configuration is designated as 3aR-cis. The two configuration structures are represented by the formulas (Γ) and (T).

Accordingly, the invention encompasses both of the two cis isomers of the compounds of the general formula containing the above wavy lines. that is, both the 3aS-cis and the 3aR-cis isomers. Also included within the scope of the invention are all mixtures of the 3aS-cis and 3aR-cis isomers, including the racemic mixture (3aScis: 3aR-cis = 1: 1).

The step

Using the method of Julien et al., J. Chem. Soc., 1935, 563-566 and 755-757, compounds of formula (IV) and (V) are prepared. This reaction is illustrated in Scheme A, but details are given in the aforementioned article. Other resolution steps not described in this article are known, for example, from Schonenberger et al., J. Med. Chem., 1986, Vol. 29, pp. 2268-2273; Schonenberger et al., Helv. Chim. Acta, 1986, Volume 69, pp. 283-287 and 1486-1497.

When the process of Scheme A above is carried out without converting the compound of formula (ΙΠ) to the compound of formula (IV), the racemic mixture is obtained. This racemic mixture is a 50:50 mixture of the compound of formula IV and the 3a Rcis isomer and can be used to prepare a racemic mixture of the compound of formula V.

Step B.

The compound of formula (Va) from step A is reacted with 1,1'-carbonyldiimidazole and the resulting compound is reacted with an amine of formula (VI) to give compound of formula (I) (Scheme B).

The reaction between the compound (Va) and the 1,1'-carbonyldiimidazole is generally carried out by dissolving the compound (Va) in a suitable solvent such as dichloromethane and then degassing the solution, adding at room temperature with stirring at room temperature. l'-carbonyldiimidazole and the reaction mixture are stirred for a suitable period of time, for example 1 hour. The carbamate-forming step is generally carried out by adding the amine to the resulting solution and stirring the resulting mixture at room temperature for several hours.

The compounds of formula I are useful in the treatment of various memory disorders such as reduced cholinergic functions such as Alzheimer's disease.

This use is based on the ability of the compounds to inhibit the action of the acetylcholinesterase enzyme and thereby increase acetylcholine levels in the brain.

Comparison of Compounds of the Invention with Physostigmine

Although known physostigmine is an effective acetylcholinesterase inhibitor, its therapeutic use is limited due to its poor stability and oral bioavailability as well as its short duration of action and acute toxicity. Among the compounds of the invention, (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1,2,3,4-Tetrahydroisoquinolinyl) carbamate was selected and compared for its effect with physostigmine in various in vitro and in vivo assays. As

A9 test results show that Compound A has several therapeutic benefits over physostigmine.

Stability

Compound A is significantly more stable than physostigmine when incubated with human plasma at 37 ° C. After 4 hours approx. 70% of Compound A remains while physostigmine is completely degraded under these conditions. Compound A was ca. 34-fold less inhibition of butyrylcholinesterase than physostigmine. The reduced affinity for this enzyme is due to the stability of Compound A in plasma.

Oral bioavailability

A study of the bioavailability of Compound A has shown that it is rapidly absorbed (Cmax at 30 min) following oral administration and is well distributed in the blood brain barrier (brain: plasma = 4.55: 1 at C max). In contrast, the bioavailability of physostigmine following oral administration is such that pharmacokinetic data cannot be obtained. The brain to plasma ratio of physostigmine for intravenous administration is only 1.5: 1 (Somani and Khalique, Drug Metabolism and Disposition, Vol. 15, 627-633, 1987). Oral bioavailability as well as activity was also demonstrated in ex vivo acetylcholinesterase (AChE) inhibition assays, which showed significant inhibition of AChE in rat brain by oral administration of Compound A. (Details of the assay are described below.)

Duration of action

Compound A duration of action was compared with physostigmine ex vivo AChE assay. Compound A at 20 mg / kg significantly inhibited rat brain AChE at 4 and 6 hours after oral administration, whereas this effect was not statistically significant at 24 hours. No significant inhibition of physostigmine was observed 2 hours after intraperitoneal administration. No accumulation effect was observed in rats at Compound A at 20 mg / kg for 4 days.

Effectiveness and acute lethality

Compound A and physostigmine are equally effective in vitro as AChE inhibitors. Compound A has an IC ₅₀ in this assay of 0.036 μπιό] and physostigmine 0.034 μπιό. However, there is a significant difference between the two compounds in acute toxicity. Physostigmine exhibits 50% mortality in rats given intraperitoneal administration 1 and

At a dose of 2.5 mg / kg, the same mortality occurs for Compound A at a dose of 40 to 80 mg / kg. There is also a significant difference in the cardiovascular effect between Compound A and physostigmine, which may be due to the noradrenergic activity of Compound A. Compound A stimulates the release of [ ³ H] norepinephrine at a concentration of 100 μιη vitro in vitro, whereas physostigmine has no such effect (see below for details of the assay method for [ ³ H] norepinephrine release).

Cholinesterase Inhibition Cholinesterase is found throughout the body, both in the brain and in serum. However, only cerebral acetylcholinesterase (AChE) distribution is associated with central cholinergic innervation. This innervation is believed to be reduced in Alzheimer's disease. Acetylcholinesterase activity in rat striatum was determined in vitro.

Inhibition of acetylcholinesterase activity in vitro in rat striatum

Acetylcholinesterase (AChE), sometimes referred to as true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AChE can be distinguished from other cholinesterases by its substrate, as well as its inhibition specificity and area distribution. Spatial distribution in the brain is largely related to cholinergic innervation and is found to a large extent in nerve endings.

It is generally believed that the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. AChE inhibitors show significant cholinominetic activity in cholinergically innervated effector organs and therapeutically in glaucoma. used to treat myasthenia gravis and paralytic ileus. However, recent studies suggest that AChE inhibitors may also be effective in the treatment of Alzheimer's disease.

The following is a description of the method used to assay for cholinesterase activity, which is described by Ellman et al., Biochem. Pharmacol. 7.98 (1961)].

procedure:

A. Reagents

1. 0.05 M phosphate buffer, pH 7.2

(a) 6.85 g NaH ₂ PO ₄ · H ₂ O / 100 ml distilled water

b) 13.4 g Na ₂ HPO ₄ -7H ₂ O / 100 ml distilled water

(c) a mixture of (a) + (b) until the pH reaches 7.2,

d) dilution 1:10

2. Substrate in buffer

a) 198 mg acetylthiocholine chloride (10 mmol)

b) 0.05 mol phosphate buffer, pH, up to 100 ml

7.2 (Reagent 1)

3. In DTNB buffer

a) 19.8 mg of 5,5-dithiobis (nitrobenzoic acid) (DTNB 0.5 mmol)

b) 0.05 moles of phosphate buffer, pH, up to 100 ml

7.2 (Reagent 1)

4. Prepare a 2 mM stock solution of the test compound in a suitable solvent and make up to the desired volume with 0.5 mM DTNB (reagent 3). Prepare a serial dilution (1:10) by placing in the cuvette

The final volume of A9 should be 1CT ⁴ moles and assay for activity. For active substances, IC ₅₀ values are determined from the inhibitory activity of the following concentration.

B. Tissue preparation

Male Wistar rats are decapitated, the brain is rapidly removed, the copora striatum is released, weighed and homogenized in 19 volumes (about 7 mg protein / ml) in 0.05 ml phosphate buffer (pH 7.2) using a Potter-Elvehjem homogenizer. An aliquot of 25 ml of the homogenate is withdrawn and added to 1 ml of vehicle or test compound at various concentrations and preincubated for 10 minutes at 37 ° C.

C. Examination

Enzyme activity was determined on a Beckman DU-50 spectrophotometer. This method can be used to determine IC ₅₀ values and kinetic constants.

Instrument setting

Kinetics Soft-Pac Module # 598273 (10)

Program # 6 Kindata:

Light source - visible

Wavelength - 412 nm

Sipper - None

Cuvette - 2 mm cuvette, automatic 6-sample Blank - 1 for each substrate concentration Measurement time - 15 sec (15 or 30 sec for kinetic assay)

Total time - 5 minutes (5 or 10 minutes for kinetic assay)

Visualization - yes

Measuring range - automatic

Slope - Ascending

Result - Yes (there is a slope)

Factor - 1

Add the reagents to the blank and / or test cell as follows:

Blank test: 0.8 ml phosphate buffer / DTNB

0.8 ml buffer / substrate Control: 0.8 ml phosphate buffer / DTNB / enzyme

0.8 ml phosphate buffer / substrate Active ingredient: 0.8 ml phosphate buffer / DTNB / active substance / enzyme

0.8 ml of phosphate buffer / substrate

Blank values are determined for each assay to verify non-enzymatic hydrolysis of the substrate, and these values are automatically subtracted using the kindata program on the kinetics soft-pac module. This program also calculates the changes in absorbance in the cuvettes.

/ C ₅₀ Definitions:

The 10 mM substrate concentration was diluted 1: 2 to give a final assay concentration of 5 mM. The initial concentration of DTNB is 0.5 mmol and the final concentration is 0.25 mmol.

% Inhibition = control slope - active ingredient slope θθ control slope

IC ₅₀ values are calculated by log-probit analysis.

³ H-norepinephrine uptake in whole rat brain or in the hypothalamic synaptosome Using this assay, compounds that block norepinephrine uptake are determined biochemically.

The nerve cell reuptake mechanism of norepinephrine (NE) is one of the most important physiological tools for inactivating NE by removing the transmitter from the synaptic cleft. NE uptake was performed using a saturated, stereospecific, high affinity (K _m = 120 - 10 ^-6 moles) sodium-dependent active transport system, which was shown to be present in both peripheral and central nervous system tissues, in a thin, homogenized, purified synaptosome. preparations. NE uptake is effectively inhibited by cocaine, phenethylamines and tricyclic antidepressants. It is also inhibited by oubain, metabolic inhibitors, phenoxybenzamine. NE reuptake inhibited by clinically active tricyclic antidepressants is a significant factor in the catecholamine hypothesis for affective diseases.

There are very large spatial variations in NE uptake that are related to the endogenous level of NE. The hypothalamus shows the highest concentration of NE and the highest uptake. This area was used for further study of compounds that showed activity in whole brain preparations.

Synaptosomal ³ -NE uptake is an important indicator of the integrity of noradrenergic neurons after injury attempts, and can be used to identify compounds that enhance the NE effect by blocking the reuptake mechanism.

process

A. Experimental animals: male CR Wistar rats (100-125 g)

B. Reagents

1. A solution of Krebs-Henseleit bicarbonate buffer, pH 7.4 (KHBB), is prepared containing the following salts:

g / L mmol NaCl 6.92 118.4 KC1 0.35 4.7 MgSO ₄ 7H ₂ O 0.29 1.2 kh _{2 after 4} 0.16 2.2 NaHCO ₃ 2.10 24.9 CaCl ₂ 0.14 1.3 Before use, we add the following: dextrose 2 mg / ml 11.1 Iproniazid phosphate 0.30 mg / ml 0.1

Aeration is carried out with 95% O ₂ /5% CO _{2 for} 9 minutes and the pH is checked (7.4 ± 0.1).

2. 0.30 mol sucrose: 21.9 g sucrose, made up to 200 ml.

3. L-(-) - Norepinephrine bitartrate is commercially available. A 0.1 M stock solution was prepared with 0.01 N hydrochloric acid. This solution is used at dilution to determine the specific activity of radiolabeled NE.

4. deduction [Ring-2,5,6- ³ H] -norepinefrint (40-50

Ci / mmol). The final concentration is 50 nM. This was diluted 0.8 times so that the KHBB buffer solution contained 62.5 nm [ ³ H] -NE.

To 100 ml KHBB add the following:

A. 59.4 μ] 0.1 M NE = 59.4 nm

B. 0.31 nm ³ H-NE = 3.1 nm

62.5 nm

5. For most assays, a stock solution of 1 mM is prepared from the test compound in a suitable solvent and serially diluted to a final concentration range of 2 x 10 ^-8 to 2 x 10 ^-5 moles. For each assay, 7 concentration values are used. Lower and upper concentrations are selected based on the potency of the test compound.

C. Tissue preparation

Male Wistar rats are decapitated and the brain is rapidly removed. The total brain mass - cerebellum and hypothalamus - is weighed first and then homogenized with 9 volumes of ice-cold 32 M sucrose in a Potter-Elvejhem homogenizer. Homogenization is performed at 4-5 up-tap speeds at medium speed to minimize synaptosome lysis. The homogenates were then centrifuged at 1000 G for 10 minutes at 0-4 ° C. The supernatant (S1) is decanted and used for experiments.

D. Examination

KHBB μΐ carrier or equivalent concentration of 800 μ ható [ ³ H] -NE

200 μΐ tissue suspension

The test tubes were incubated at 32 ° C in 95% O ₂ /5% CO _{2 for} 5 minutes. For each assay, three tubes were incubated with 20 μΐ support at 0 ° in an ice bath. Immediately after incubation, the tubes are centrifuged at 400 G for 10 minutes. The supernatant liquid is aspirated, the pellets are dissolved in 1 ml of solvent, the tubes are vigorously shaken, then decanted into scintillation vials and counted using 10 ml of Liquiscin scintillation counter. Active recording is the difference between the incidence rate (CPM) at 37 'C and 0' C. The percentage inhibition at each drug concentration is the average of three measurements. 1C ₅₀ values were determined by log-probit analysis.

Cardiovascular pharmacology

Objective: The purpose of the assay is to characterize the cardiovascular profile of a compound of the invention compared to physostigmine, a known acetylcholinesterase inhibitor. The assay method used to determine the acute cardiovascular, hemodynamic effect will be described in the following section, Conclusions.

Summary of results: Intravenous administration of 0.01 mg / kg / min of Compound A did not induce prominent cardiovascular depression in anesthetized dogs as observed with similar amounts of physostigmine infusions (see Table 1). At higher doses, Compound A (0.1 mg / kg / min i.v.) showed a marked increase in measured cardiac and peripheral vascular parameters (Table 1). This hemodynamic profile is qualitatively similar to that observed with intravenous injections of endogenous catecholamine, norepinephrine. Thus, the cardiovascular responses to Compound A are consistent with the in vitro results, which show that Compound A increases the spontaneous release of norepinephrine from sympathetic nerve endings.

Additional studies were performed in anesthetized dogs comparing the cardiovascular effects of Compound A and physostigmine (0.1 mg / kg / min i.v. and 0.01 mg / kg / min i.v.) during blockade of alpha and beta adrenergic receptors, respectively. Physostigmine infusion during alpha and beta receptor blockade resulted in severe cardiovascular depression and death in three out of three dogs within 17 to 29 minutes. No deaths were observed with the same dose of physostigmine with intact alpha and beta adrenergic receptors. In contrast, alpha and beta adrenergic blockade abolishes the positive cardiac and hemodynamic effects of Compound A and results in a slight decrease in blood pressure and cardiac output.

The higher dose of physostigmine used in this study blocked the transfer of action potentials from the atria to the ventricles (A-V blocking Table 1). There was no drug-related change in the electrocardiogram (ECG) of 0.01 and 0.1 mg / kg / min i.v. dose for Compound A. No significant increase in right atrial pressure (RAP) and left ventricular end-diastolic pressure (LVEDP), which indicates depression of cardiac contractile force, was observed during physostigmine infusion.

Conclusion: Based on the above results, it can be stated that although Compound A is an effective acetylcholinesterase inhibitor in dogs, it is able to significantly reduce the cardiovascular depression observed with the known physostigmine. Furthermore, the results obtained demonstrate the importance of a functional adrenergic compensatory mechanism in the alleviation of severe cardiovascular depression, which is triggered by acetylcholinesterase inhibition.

Method for determining acute cardiovascular hemodynamics

Beagle dogs of both sexes 15 mg / kg sodium thiopental + 200 mg / kg sodium barbital + 60

A9 mg pentobarbital sodium i.v. was anesthetized. The trachea was intubated with a flanged endotracheal tube and connected to a Harvard respiratory pump set at 20 ml / stroke and 20 strokes / min. The right femoral artery and vein were dissected and cannulated with a polyethylene tube to measure arterial blood pressure, and i.v. dispensing. The duration of the experiment is 2 hours after drug administration if i.v. and 3 hours if i.d. We added.

The arterial cannula was connected to a Statham P23Gb pressure transducer. Left atrial catheterization was performed by inserting a Millar microtype pressure transducer into the left carotid artery and transferring it to the left ventricle. The cannula was connected to a Millard TC-100 pressure transducer control unit connected to a Beckman voltage / pressure pulse switch. At the same time, ventricular pressure and the first derivative of dP / dt were measured by applying the left ventricular pressure signal to a differentiator. Cardiac output (CO) was determined by a thermodilution technique using a quadruplett lumen 7F Swan-Ganz flow-guided catheter, introduced into the right outer vein jugular and through the upper vena cava, right atrium and right ventricle into the pulmonary artery. The proximal cavity of the catheter is located in the right atrium if the distal cavity and the thermistor are properly positioned in the pulmonary artery. The output signals from the proximal and distal sides were fed to a Statham P23BB pressure transducer to measure right ventricular pressure (RAP) and pulmonary arterial pressure (PAP). Cardiac output was determined by injecting 5 ml of ice-cold 5% aqueous dextrose solution on the proximal side (right atrium) and measuring the temperature change in the pulmonary artery. Using the Stewart-Hamilton equation, cardiac performance was determined by integrating the area under the thermodilution curve using Edwars Cardiac Output Computer (model 9520). The heart rate was determined using a Beckman Cardiotach, which summarizes the pressure waves of the arterial pressure pulse pressure curve. The ECG II curve was recorded. All of these signals were routed to the Beckman R-611 recorder. By measuring these parameters, information is obtained which can either directly measure or calculate:

1. Average Arterial Blood Pressure - MAP (mmHg)

2. Pulse - HR

3. Cardiac Power - CO (1 / min)

4. Split Peripheral Resistor - TPR

5. Cardiac index - Cl (CO / m ² )

6. Stroke volume - SV (ml / stroke)

7. Impact Work - SW (gm-m / impact)

8. Central venous pressure - CVP, measured as right atrial pressure (RAP) in mmHg or cmH ₂ 0.

9. Right ventricular end diastolic pressure - LVEDP (mmHg)

10. The degree of chamber pressure rise is dP / dt / Pmax

This parameter provides a better estimate of myocardial contractility than dP / dt alone, as this parameter is relatively independent of cardiac load conditions (sec ^_1 )

11. Pulmonary arterial pressure - PAP (mmHg)

12. Electrocardiogram - ECG

The results of the evaluation of acute cardiovascular hemodynamic effects for Compound A and physostigmine are summarized in Table 1 below.

Table 7

Comparison of hemodynamic effects in anesthetized dogs

Dose Dosage 0.01 mg / kg / min i.v. 0.01 mg / kg / min i.v. The compound Fizosztig- min The compound Fizosztig- min * MAP -12% -49% + 54% -78% HR -12% -49% -13% -82% CO + 20 / -17% -23% + 40% -79% TRP -18% -34% + 61% -48% dP / DTM + 37% -32% + 38% -80% Rapman NC +5mmHg NC +8mmHg LVEDP NC +5mmHg NC +8mmHg ECG NC NC NC A-V blocking inc. T. wave

* N - 2J2 dog; N = 1 dog within 30 minutes

An effective amount of the compounds of the invention may be administered to patients in any known manner, such as orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base end products, although effective in themselves, may be administered in the form of their pharmaceutically acceptable acid addition salts, since their stability, crystallization ability, and increased stability are superior. The acid addition salts may be prepared using any pharmaceutically acceptable inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, and tartaric acid, citric acid, acetic acid, succinic acid, maleic acid, fumaric acid, or oxalic acid.

For oral administration, the active ingredient may be mixed with an inert diluent or an edible carrier, or the active ingredient may be incorporated into gelatin capsules, or compressed into tablets. The composition may take the form of tablets, wafers, capsules, elixirs, suspensions, syrups, chewing gums, etc. The formulations will generally contain at least 0.5% of active ingredient, but may be in the range of 4% to 50%, depending on the particular form. The active ingredient content of the formulations is selected so as to obtain suitable dosage units. Preferred oral dosage units of the present invention contain from 1 to 300 mg of active ingredient.

HU 211 951 A9

Tablets, pills, capsules, wafers, etc. the compositions may contain the following additives: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; starch or lactose, such as alginic acid, primogel, corn starch, etc .; the lubricant is magnesium stearate or sterotex; colloidal silicon dioxide as glidane; as a sweetening agent, for example, sucrose or saccharin, and as a flavoring, fennel, methyl salicylate or orange flavoring. If the dosage unit form is a capsule, it may contain, in addition to a liquid carrier such as a fatty oil. Other dosage unit forms may also contain other various materials which, for example, may alter the physical appearance of the unit dosage form, for example, by coating. For coated tablets or pills, sugar, shellac or other enteric coatings are used. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. All materials used in the preparation of the compositions should be pharmaceutically pure and non-toxic in the amounts used.

In parenteral formulations, the active ingredient is formulated as a solution or suspension. These compositions contain at least 0.11% of the active ingredient, but may also be present in an amount of 0.5 to 30% by weight. The amount of active ingredient is always chosen in this way. to provide a dosage unit suitable for administration. Preferred parenteral formulations contain from 0.5 to 100 mg of active ingredient per unit dose.

The solutions and suspensions may also contain a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols. glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl baraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral formulations are formulated as disposable or multiple dose vials made of glass or plastic.

The following are some of the preferred compounds of the invention, as well as their 3aR-cis isomers and mixtures of 3aS-cis and 3aR-cis isomers, including racemic mixtures:

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1,2,3, 4-tetrahydroisoquinolinyl) carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-methyl-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis / 1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-ethyl-1,2, 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis / 1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-propyl-1,2, 3,4-tetrahidroizokinolinilj carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (1-butyl-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-chloro-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-chloro-1-methyl) 1,2,3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-chloro-1-methyl) tetrahidroizokinolinilj -1,2,3,4-carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-hydroxy-1,2 , 3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (6-hydroxy-1-methyl) 1,2,3,4-tetrahydroisoquinolinyl / carbamate;

(3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol, (7-hydroxy-1-methyl) 1,2,3,4-tetrahydroisoquinolinyl / carbamate;

The following examples further illustrate the invention.

Example 1 (3aS-cis) -1,2,3,3a.8,8a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol (1,2,3, 4-Tetrahydroisoquinolinyl) -carbamate g. Eseroline was dissolved in 80 ml. Of anhydrous dichloromethane. After 1 hour, 4 g of 1,2,3,4-tetrahydroisoquinoline was added and stirring continued overnight. The solution is then concentrated and the residue is purified by flash chromatography to give 2.8 g of a pale oil, which is recrystallized from ether, m.p.

2.4 g of white crystals are obtained, m.p. 83-85 °.

Analysis for C ₂₃ H 7 N ₂ O ₃ Calculated compound _2: Η C N Calculated: 73.18% 7.20% 11.13% Found 72.98% 7.22% 11.09%

Example 2 (3aS-cis) -1,2,3,3a, 8,8a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol,] -methyl- (1, 2,3,4-tetrahydroisoquinolinyl) carbamate

Ezeroline (2.3 g) and Ι, Γ-carbonyldiimidazole (2.1 g) were dissolved in dichloromethane (60 ml) and stirred at room temperature for 1 hour, followed by addition of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.5 g). and stirring was continued at 40 ° for 2 hours. Then, azo7

A isoquinoline is added in an amount of 9 N and the solution is refluxed for 3 hours. The solution is then concentrated and the residue is chromatographed on alumina to give 2 g of a pale oil, which is recrystallized from 50 ml of 10: 1 = pentane: ether to give 1.6 g of white crystals, m.p. 105-108 ° C.

Elemental analysis for C ₂₄ H ₂₉ N ₃ O ₂ :

Calculated for CΗ N: 73.62% 7.46% 10.73% Found: 73.86% 7.48% 10.65%

Claims (19)

PATENT CLAIMS A compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof R is hydrogen or lower alkyl, X is hydrogen, or halogen, lower alkyl, lower alkoxy, or hydroxy, which compounds can be used to ameliorate memory disorders associated with cholinergic damage. Compounds of formula I according to claim 1, wherein R is hydrogen or methyl. Compounds of formula (1) according to claim 1, wherein X is hydrogen or halogen. Compounds of formula I according to claim 1, wherein R is hydrogen or methyl and X is hydrogen or halogen. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ] indol-5-ol, (1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (1-ethyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula (I) according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3- b] indol-5-ol, (1-propyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula (I) according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8ahexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indole. -5-ol, (1-butyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (6-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] serine compound of formula I according to claim 1 ] indol-5-ol, (7-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (6-chloromethyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ] indol-5-ol, (6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ] indol-5-ol, (7-hydroxy-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. 16. A compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b ] indol-5-ol, (6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. 17. The compound of formula I according to claim 1, which is (3aS-cis) -1,2,3,3a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] ] indol-5-ol, (7-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate, or a 3aR-cis isomer thereof, or a mixture of the two isomers. 18. A pharmaceutical composition comprising, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, in admixture with a suitable carrier, to ameliorate memory disorders characterized by cholinergic deficiencies. 19. A method of treating patients with memory disorders characterized by cholinergic deficiencies, comprising administering to the patient an effective amount of a compound of formula (I) according to claim 1.