JP3022959B2 - Acetylcholinesterase inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

SUMMARY OF THE INVENTION The present invention relates to compounds of the formula (I) 1,2,3,3
tetrahydroisoquinolinyl carbamate of a, 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indole:

[0002]

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Wherein R is hydrogen or lower alkyl; and X is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy, wherein the compound is a memory dysfunction characterized by a cholinergic defect. For example, it is useful for alleviating Alzheimer's disease.

[0004]

DETAILED DESCRIPTION Unless stated otherwise, the following definitions will apply throughout the specification and the appended claims.
The term lower alkyl refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms. Examples of said lower alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and straight and branched chain pentyl and hexyl. The term halogen means fluorine, chlorine, bromine or iodine. The compounds of the present invention
It is prepared by using the synthetic steps described below. Throughout the description of the synthesis steps, unless otherwise stated or indicated, the symbols R and X have the respective meanings given above.

In the structural formulas depicting the compounds of the present invention, the 1,2,3,3a, 8,8a-hexahydropyrrolo [2,3-b] indole ring system is derived from the 3a-carbon and the 8a-carbon. A bold line indicates that two substituents are above the average plane of the tricyclic system, while a dotted line indicates that two substituents are below the average plane of the tricyclic system, and a wavy line. Represents that two substituents may be both above the average plane or below the average plane. Due to conformational constraints, the two substituents at positions 3a and 8a must both be above the average plane or both be below the average plane. Thus, in formula (I), the substituents at the 3a- and 8a-carbons are cis as long as they are on the same side of the tricyclic system. When both said substituents are above the average plane of the tricyclic system, the configuration is 3a
When referred to as S-cis, and both substituents are below the average plane of the ring, the configuration will be referred to as 3aR-cis. The two configurations are shown below.

[0006]

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For each given compound name or structural formula containing the above wavy line, the cis isomer, ie, 3aS
It is an object of the present inventors to claim both -cis and 3aR-cis isomers. Racemic mixture (3aS-
Cis: 3aR-cis in a 1: 1 ratio).
It is also an object of the present invention to claim any mixture of aS-cis and 3aR-cis isomers.

Step A Starting with a compound of formula II, and Julian et al.
J. Chem. Soc. , 1935 , 563-566 and 755-757 can be used to prepare compounds of formulas IV and V. This synthesis scheme is outlined below; see the original document for details. For details of other optical resolution methods not described in the Julian et al.
Nenberger et al. Med. Chem. , 19
86 , Vol. 29, 2268-2273; and Scho
Nenberger et al., Helv. Chim. Act
a, 1986 , Vol. 69, 283-287 and 148
See 6-1497.

[0009]

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[0010]

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In the above synthetic scheme, compound III
If the conversion from to the compound IV is performed without using the optical resolution step, a racemic compound is obtained. The racemate is a 50:50 mixture of compound IV and its 3aR-cis isomer, which can be used to prepare a racemic mixture containing compound V.

Step B Compound Va obtained from Step A is reacted with 1,1'-carbonyldiimidazole, and the resulting product is reacted with an amine of formula VI to give compound I.

[0013]

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The reaction of compound Va with 1,1'-carbonyldiimidazole typically involves preparing a degassed solution of compound Va in a suitable solvent, for example dichloromethane, and adding 1,1 'to this solution. The reaction is carried out by adding carbonyldiimidazole and stirring at room temperature for a suitable period of time, for example 1 hour. The carbamidation reaction is typically performed by adding an amine to the solution obtained above and stirring the solution for several hours at room temperature. The compounds of Formula I of the present invention are useful for treating various memory dysfunctions characterized by reduced cholinergic function, such as Alzheimer's disease. This utility is demonstrated by the ability of the compound to inhibit the acetylcholinesterase enzyme and thereby increase acetylcholine levels in the brain.

Ratio of the compound of the present invention to physostigmine
Although comparative physostigmine is a potent acetylcholinesterase inhibitor, its low therapeutic and oral bioavailability, short duration of action and potent acute toxicity limit its therapeutic use. We have (3aS-cis)-as a representative example of compounds within the scope of the present invention.
1,2,3,3a, 8,8a-Hexahydro-1,3
a, 8-Trimethylpyrrolo [2,3-b] indole-
A 5-ol (1,2,3,4-tetrahydroisoquinolinyl) carbamate (hereinafter referred to as Compound A) was selected and the effects of this compound and physostigmine were compared in various in vitro and in vivo tests. The test results demonstrated that Compound A shows several therapeutic advantages over physostigmine.

Stability Compound A was significantly more stable than physostigmine when incubated at 37 ° C. with human plasma. 4
After time, about 70% of Compound A remained, but physostigmine was completely destroyed under those conditions. Compound A was about 1/34 more potent than physostigmine as an inhibitor of butyrylcholinesterase. This low affinity for the enzyme can be attributed to the plasma stability of Compound A.

Oral Bioavailability An oral bioavailability study on Compound A showed that it was rapidly orally absorbed (C _{max in} 30 minutes) and distributed well across the blood-brain barrier (C brain: plasma at _max was 4.55: 1). In contrast, physostigmine had poor bioavailability by the oral route and no pharmacokinetic data was available. The brain: plasma ratio of physostigmine after intravenous administration was only about 1.5: 1 (Somani and Khalique, Drug Metabolism ann.
d Disposition, Vol. 15, 627-633, 198
7). In vitro acetylcholinesterase (AChE)
Oral bioavailability and activity was also demonstrated in the inhibition test, where rat AChE was administered after oral administration of Compound A.
Significant inhibition was demonstrated. (See below for details of the test method used to measure inhibition of rat brain AChE).

Duration of action The duration of action of Compound A was compared to that of physostigmine in the in vitro AChE test. Compound A (20 mg
/ Kg) is equivalent to rat brain A at 4 and 6 hours after oral administration.
ChE was significantly inhibited, but the effect at 24 hours was not statistically significant. The time course of physostigmine action did not show any significant inhibition 2 hours after intraperitoneal administration. Repeated administration of Compound A at 20 mg / kg for 4 days in rats showed no cumulative effect.

Efficacy and Acute Mortality Compound A and physostigmine were tested in vitro for AChE.
As effective as an inhibitor. In this assay, Compound A had an IC ₅₀ value of 0.036 μM and physostigmine had an IC ₅₀ value of 0.034 μM. However, there is considerable difference in acute toxicity between the two compounds. Intraperitoneal administration of physostigmine to rats killed 50% of test animals at doses of 1.0-2.5 mg / kg. On the other hand, the dose of Compound A causing 50% mortality was 40-80 mg / kg.

There is also a substantial difference in cardiovascular effects between Compound A and physostigmine, apparently due to the noradrenergic action of Compound A. Compound A (100 μM) stimulated [ ³ H] -norepinephrine release in vitro, whereas physostigmine had no such effect.
^([3 H] - see below for details of the test method used to measure norepinephrine release).

Cholinesterase Inhibition Assay Cholinesterase is detected throughout the body, both in the brain and in serum. However, only brain acetylcholinesterase (AChE) distribution correlates with central cholinergic innervation. This innervation is said to be attenuated in Alzheimer's patients. We measured the in vitro inhibition of acetylcholinesterase in rat striatum.

Acetylcholine es in rat striatum
In Vitro Inhibition of Terase Acetylcholinesterase (AChE), which may be referred to as authentic or special cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AChE can be distinguished from other cholinesterases by substrate and inhibitor specificities and by localized distribution. Its distribution in the brain is roughly correlated with cholinergic innervation, with subfractions showing the highest levels at nerve endings.

It is generally recognized that the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. AChE inhibitors show significant cholinergic effects in cholinergic innervated effector organs and have been used therapeutically in the treatment of glaucoma, myasthenia gravis and paralytic ileus. However, recent studies suggest that AChE inhibitors may also be useful in treating Alzheimer's disease. In the present invention, the method described below was used to assay cholinesterase activity. This is Ellman et al., Bioche
m. Pharmacol. 7, 98 (1961).

Procedure: A. Reagent 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) 13.40g Na 2 HPO 4} · 7H 2 O / 10
0 ml distilled water (c) Add (a) to (b) until pH reaches 7.2 (d) Dilute 1:10 Substrate in buffer (a) 198 mg of acetylthiocholine chloride (10 mM) (b) 0.05 M phosphate buffer, pH 7.2 (reagent 1) is added to an appropriate volume to make 100 ml.

3. DTNB in buffer (a) 19.8 mg of 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM) (b) 0.05 M phosphate buffer, pH 7.2 (reagent 1) in an appropriate amount To 100 ml. Make a 2 mM stock solution of the test drug in an appropriate solvent and adjust the dose with an appropriate amount of 0.5 mM DTNB (Reagent 3). Drugs are serially diluted to a final concentration (in cuvette) of 10 ^-4 M and screened for activity. If active, the IC ₅₀ value is determined from the subsequent concentration of inhibitory activity.

B. Tissue preparation Male Wistar rats were decapitated, brains were immediately removed,
The striatum was excised, weighed, and purified in 19 volumes (about 7 mg protein / ml) of 0.05 M phosphate buffer, pH 7.2.
Homogenize using an otter-Elvehjem homogenizer. A 25 μl aliquot of this homogenate is added to vehicle or 1.0 ml of test agent at various concentrations and pre-incubated at 37 ° C. for 10 minutes.

C. Assay Enzyme activity is measured using a Beckman DU-50 spectrophotometer. This method can be used to measure IC ₅₀ and rate constants. Instrument Setting Kinetics Soft Pack Module (Kinetic
s Soft-Pac Module) # 59827
3 (10) Program # 6 Kindata: Light Source-Vis Wavelength-412 nm Shipper-None Cuvette-2 ml cuvette blank with automatic 6 sampler-1 interval time for each substrate concentration-15 seconds (15 or 30 for kinetics)
Seconds) Total time-5 minutes (5 or 10 minutes for kinetics) Plot-YES Scale width-Automatic scale Slope-Increase Result-YES (given slope) Factor -1

Add reagent to blank and sample cuvette as follows: blank : 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 drug : 0.8 ml phosphate buffer / DTNB / drug / enzyme 0.8 ml phosphate buffer / substrate Measure blank value for each measurement to control for non-enzymatic hydrolysis of substrate Then, those blank values are automatically subtracted by the Kin Data program available to the Kinetics Soft Pack module. This program also calculates the change in absorbance for each cuvette.

For IC ₅₀ determination: substrate concentration is 10 mM,
The assay gives a 1: 2 dilution to give a final concentration of 5 mM.
The DTNB concentration is 0.5 mM, giving a final concentration of 0.25 mM.

[0030]

(Equation 1) IC ₅₀ values are calculated from log-probit analysis.

Rat whole brain or hypothalamic synaptosome
The assay ³ H- norepinephrine uptake in the use as a biochemical sieve (screen) for compounds that block norepinephrine uptake. The norepinephrine (NE) neuronal reuptake mechanism is the most important physiological means for inactivating NE by removing transmitters from the synaptic cleft.

NE incorporation is saturable and stereospecific.
With high affinity (K_m= 10^-7-10 ^-6M)
This is achieved by a system-dependent, active transport system, which
Slices, homogenates and purified synaptosome preparations
Is present in tissues of both the peripheral and central nervous systems
It has been shown. NE uptake is cocaine and fene
Potentially inhibited by tylamine and tricyclic antidepressants
You. It is ouabain, a metabolic inhibitor and phenoxybe
Inhibited by Ndamine. Clinically effective tricyclic
Inhibition of NE uptake by antidepressants is a category of affective disorders.
There is significant relevance in the Kohlamine hypothesis.

NE uptake, which is related to the endogenous level of NE, has large site variations. The hypothalamus shows the highest level and maximum uptake of NE. This area is used to further test compounds that are active in whole brain preparations. ³ H-NE uptake by synaptosomes is a useful marker of the integrity of noradrenergic neurons after damaging experiments and furthermore for compounds that enhance the action of NE by blocking the reuptake mechanism. It is a useful marker for the assay.

Procedure: A. Animals: Male CR Wistar rats (100-125
g) B. Reagent 1. Krebs-Henseleit bicarbonate buffer, pH
7.4 (KHBB). Make a 11 batch containing the following salts: g / l mM NaCl 6.92 118.4 KCl 0.35 4.7 MgSO 4 · 7H 2 O 0.29 1.2 KH 2 PO 4 0.16 2.2 NaHCO 3 2.10 24.9 CaCl 2 0.14 1.3 What to add before use: Glucose 2 mg / ml 11.1 Iproniazid phosphate 0.30 mg / ml 0.1 95% O ₂ /5% CO ₂ aerated for 60 minutes,
Check the pH (7.4 ± 0.1).

2.0.32M sucrose: Adjust 21.9 g of sucrose to 200 ml. 3. Purchase L-(-)-norepinephrine bitartrate from a commercial source. Make a 0.1 mM stock solution in 0.01 N HCl. Use this solution to dilute the specific activity of the radiolabeled NE. 4. Rebo from commercial sources [ring-2,5,6 ³ H] - buy norepinephrine (40 to 50 Ci / mmol). The final desired concentration of ³ H-NE in the assay is 50
nM. The dilution is 0.8; therefore, 62.5 nM
KHBB is prepared so as to contain [ ³ H] -NE. 1
Add the following to 00 ml of KHBB: B. 0.1 mM NE 59.4 μl = 59.4 nM 0.31 nmole of ³ H-NE = 3.1 nM 62.5 nM

5. For most assays, a 1 mM stock solution of the test compound is made in a suitable solvent and serially diluted to give a final concentration in the assay of 2 × 10 ⁻⁸ to 2 × 10 ⁻⁵ M. Seven concentrations are used for each assay.
Higher or lower concentrations may be used depending on the potency of the test compound.

C. Tissue Preparation Male Wistar rats are decapitated and brains are immediately removed.
Weigh either the whole brain from which the cerebellum was taken or the hypothalamus and place Potter- in 9 volumes of ice cold 0.35M sucrose.
Homogenize using an Elvehjem homogenizer. Homogenization should be performed 4-5 up and down reciprocations at medium speed to minimize lysis of synaptosomes. The homogenate is centrifuged at 1000 g for 10 minutes at 0-4 ° C. The supernatant (S ₁ ) is decanted and used for the uptake experiment.

D. Assay 800 μl KHBB with [ ³ H] -NE 20 μl Excipient or appropriate drug concentration 200 μl Tissue suspension Incubate the tubes for 5 minutes at 37 ° C. under an atmosphere of 95% O ₂ /5% CO ₂ . For each assay, incubate 3 tubes at 0 ° C. in an ice bath with 20 μl of vehicle. After incubation, immediately transfer all tubes to 4
Centrifuge at 000 g for 10 minutes.

Aspirate the supernatant and dissolve the pellet by adding 1 ml of solubilizer. The tubes are vortexed vigorously, decanted into scintillation vials, and counted in 10 ml of Liquiscint scintillation counting cocktail. The effective uptake is the difference in cpm between 37 ° C and 0 ° C. The percent inhibition at each drug concentration is the average of three measurements. I
C ₅₀ values are logarithmic - is derived from the probit analysis.

Cardiovascular Pharmacology Purpose : The purpose of the studies described below was to characterize the cardiovascular profile of Compound A and compare it to that of the standard acetylcholinesterase inhibitor physostigmine. (Details of the test method used to measure acute cardiovascular hemodynamic effects are provided in the Conclusions section below).

Summary of Results : Compound A (0.01 mg / kg / min) instilled intravenously into anesthetized dogs caused significant cardiovascular depression as observed with physostigmine infusion at the same rate. None (see Table 1). In fact, high doses of Compound A (0.1 mg / kg / min, iv)
Increased the measured cardiovascular and peripheral vascular parameters significantly (Table 1). This hemodynamic profile is quantitatively similar to that observed for the intravenous injection of the endogenous catecholamine norepinephrine. Therefore,
The cardiovascular response to Compound A is also consistent with in vitro results showing that Compound A enhances spontaneous release of norepinephrine from sympathetic nerve endings.

Compound A (0.1 mg / d) during blockade of a combination of α and β adrenergic receptors in anesthetized dogs.
kg / min, i. v. ) And physostigmine (0.01 mg /
kg / min, i. v. Supplementary experiments comparing the cardiovascular effects of Infusion of physostigmine during alpha and beta adrenergic receptor blockade caused severe cardiovascular depression and death within 17-29 minutes in three of three dogs. No mortality was observed at this dose of physostigmine at intact α and β adrenergic receptors. In contrast, α- and β-adrenergic receptor blockade abolished the positive cardiac and hemodynamic effects of Compound A, which caused a moderate decrease in blood pressure and cardiac output.

The use of higher doses of physostigmine in these experiments caused a block in the conduction of action potentials from the atria to the ventricles (AV block; Table 1). 0.01 ~
Compound A at 0.1 mg / kg / min (iv) produced no drug-related changes in the electrocardiogram (ECG). Right arterial pressure (RA) observed during physostigmine instillation
P) and a significant increase in left ventricular end-diastolic blood pressure (LVEDP), which indicates a decrease in cardiac contractility, was compound A
Was not observed during instillation.

Conclusion : The results summarized above suggest that Compound A exhibits potent acetylcholinesterase inhibition in dogs, but has the unique property of attenuating cardiovascular suppression as observed with standard physostigmine. . In addition, those data point to the importance of a functional adrenergic compensatory mechanism in attenuating the severe cardiovascular depression caused by acetylcholinesterase.

Method used for evaluation of acute cardiovascular hemodynamics Beagle of either male or female was treated with sodium thiopental 1
5 mg / kg + sodium barbital 200 mg / kg + sodium pentobarbital 60 mg / kg i. v. Anesthetize. Intratracheal intubation with cuff is intubated into the trachea, and it is 20 ml /
Beats and Harvard R set at 10 beats / minute
Connect to the espirator Pump. The right femoral artery and vein were exposed and used to measure arterial pressure and drug i. v. Cannulate the polyethylene tube for administration. The duration of these experiments was based on i.p. v. The time of administration is 2 hours after drug administration, i. d. The time of administration is 3 hours.

An arterial cannula was inserted into a Statham P23.
Connect to Gb converter. Catheter insertion into the left ventricle is performed by introducing a Millar microtip pressure transducer into the left carotid artery and advancing it toward the left ventricle.
Connect the cannula to a Millar TC-100 converter suppressor connected to a Beckman volts / pressure pulse coupler. By wiring the signal output from the ventricular pressure tracking to the differentiator, the ventricular pressure and its first derivative dP / dt are measured simultaneously.

Introduced into the right external jugular vein and into the superior aorta,
4 or lumen 7F through right artery, right ventricle and pulmonary artery
Cardiac output (CO) is measured using a thermodilution technique using a Swan-Ganz flow-directed catheter. The proximal lumen of the catheter is in the right lumen when the distal lumen and the thermistor are properly positioned in the pulmonary artery. The signal output from the proximal and distal sites is Statham P23B
B transducer and connect right arterial pressure (RAP) and pulmonary artery pressure (P
AP) is measured. Cardiac output is measured by injecting 5 ml of ice-cold 5% aqueous glucose solution into the proximal site (right artery) and then measuring the change in temperature in the pulmonary artery.

Using the Stewart-Hamilton equation, an Edwards cardiac output calculator (model 9520)
By integrating the area under the thermodilution curve, the cardiac output can be determined. The heart rate is calculated by adding the pressure wave from the pulse pressure curve of the arterial pressure to
Measure using a diotach. Record the lead IIEKG. All of those signal outputs are converted to Beckmam R-6
Display on 11 records. The measurement of those parameters provides information so that the following can be measured or calculated directly:

1. 1. Mean arterial blood pressure-MAP (mmHg) Heart rate-HR3. 3. Cardiac output-CO (1 / min) 4. Total peripheral resistance-TPR Cardiac index -CI (CO / m ²⁾ 6.1 Stroke Volume -SV (ml / beat) 7. 7. Pulse work-SW (gm-m / pulse) Central venous pressure -CVP; right arterial pressure (RAP) measured as mmHg or cm H ₂ O.

9. Left ventricular end diastolic blood pressure-LVEDP (mm
Hg) 10. Rate of rise of ventricular pressure (dP / dt / Pmax) This parameter is a better estimate of the contraction state of the myocardium than dP / dt alone, since it is relatively independent of cardiac loading (sec ^-1 ). . 11. Pulmonary artery pressure-PAP (mmHg) 12. Electrocardiogram-EKG The results of the acute cardiovascular hemodynamic evaluation for compound A and physostigmine are given in Table 1.

[0051]

[Table 1]

An effective amount of a compound of the present invention may be administered in any of a variety of ways, for example orally, in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases, sterile solutions. Can be administered intravenously to patients. The free base end products, while effective in themselves, are formulated and administered in the form of their pharmaceutically acceptable acid addition salts for the purpose of stability, ease of crystallization, increased solubility, etc. Can be. Acids useful for preparing the pharmaceutically acceptable acid addition salts of the present invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, and organic acids such as tartaric acid. , Citric acid, acetic acid, succinic acid, maleic acid, fumaric acid and oxalic acid.

The active compounds of the present invention can be administered orally, for example, with an inert diluent or an edible carrier, or enclosed in gelatin capsules, or compressed into tablets. it can. For the purpose of oral therapeutic administration, the active compound of the present invention can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These formulations will contain at least 0.5% of the active ingredient, but can vary depending on the particular form, and may conveniently be from 4% to about 70% of the weight of the dosage unit. . The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations of the present invention are those wherein the oral dosage unit form is 1.
It is prepared to contain 0-300 mg of the active compound.

Tablets, pills, capsules, troches and the like may additionally contain the following ingredients: binders, such as microcrystalline cellulose, gum tragacanth or gelatin;
Disintegrants such as alginic acid, primogel, corn starch and the like; lubricants such as magnesium stearate or sterotex (S
lubricants, such as colloidal silicon dioxide; and sweeteners, such as sugar or saccharin, or flavoring agents, such as peppermint, methyl salicylate or orange flavors. When the dosage unit form is a capsule,
In addition to materials of the above type, a liquid carrier such as a fatty oil may be included.

Other dosage unit forms can contain other various materials which modify the physical form of the dosage unit, for example, coatings. Tablets or pills can be coated with sugar, shellac or other enteric coatings. A syrup may contain, in addition to the active compounds, sugar as a sweetening agent and certain preservatives, dyes, colorings and flavors. The materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the active compounds of the invention can be formulated in solutions or suspensions. These formulations will contain at least 0.1% of the active ingredient, but can vary between 0.5 and about 30% of the weight of the formulation. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention have parenteral dosage units of between 0.5 and 100.
It is prepared to contain mg of active compound.

The solutions or suspensions may also contain the following ingredients: sterile diluents such as distilled water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate or phosphate; and osmotic agents, such as sodium chloride Or glucose. Parenteral preparations can be enclosed in disposable syringes or multiple dose vials made of glass or plastic.
Examples of the compounds of the present invention include the compounds listed below and their 3aR-cis isomers, and mixtures of 3aS-cis and 3aR-cis isomers (including racemic mixtures).

(3aS-cis) -1,2,3,3a,
The (1,1) of 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol
2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8a-
Hexahydro-1,3a, 8-trimethylpyrrolo [2,
3-b] (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's (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 of (1-propyl-
(1,2,3,4-tetrahydroisoquinolinyl) carbamate; (3aS-cis) -1,2,3,3a, 8,8
(1-butyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol;

(3aS-cis) -1,2,3,3a,
(6-Chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) of 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol Carbamate; (3aS-cis) -1,
2,3,3a, 8,8a-Hexahydro-1,3a, 8
(7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of -trimethylpyrrolo [2,3-b] indol-5-ol; (3aS-
Cis) -1,2,3,3a, 8,8a-Hexahydro-
(6-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate of 1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol; (3aS-
Cis) -1,2,3,3a, 8,8a-Hexahydro-
(7-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate of 1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol; (3aS-
Cis) -1,2,3,3a, 8,8a-Hexahydro-
(6-hydroxy-1,2,3,4) of 1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol
-Tetrahydroisoquinolinyl) carbamate;

(3aS-cis) -1,2,3,3a,
(7-hydroxy-1,2,3,4-tetrahydroisoquinolinyl) carbamate of 8,8a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol; (3aS -Cis) -1,2,3,3
a, 8,8a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol (6
-Hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate; and (3aS-
Cis) -1,2,3,3a, 8,8a-Hexahydro-
(7-Hydroxy-1-methyl-) of 1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol
1,2,3,4-tetrahydroisoquinolinyl) carbamate. The following examples are provided to illustrate the present invention.

Example 1 (3aS-cis) -1,2,3,3a, 8,8a-hex
Sahydro-1,3a, 8-trimethylpyrrolo [2,3-
b] Indole-5-ol of (1,2,3,4-tetra
Lahydroisoquinolinyl ) carbamate Eseroline (3.0 g) in 80 ml of dry dichloromethane
Was treated once with 1,1'-carbonyldiimidazole (2.7 g) and stirred at room temperature. After 1 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 by flash chromatography to give 2.8 g of pale oil, which was crystallized from ether to give 2.4 g of white crystals. mp
83-85 ° C.

Analysis : Calculated for C ₂₃ H ₂₇ N ₃ O ₂ : 73.18% C 7.20% H 11.3% N Found: 72.98% C 7.22% H 11.0 9% N

Example 2 (3aS-cis) -1,2,3,3a, 8,8a-hex
Sahydro-1,3a, 8-trimethylpyrrolo [2,3-
b] Indole-5-ol's (1-methyl-1,2,2,
Eseroline (2.3 g) in 60 ml of dry dichloromethane ( 3,4-tetrahydroisoquinolinyl) carbamate
And a degassed solution of 1,1'-carbonyldiimidazole (2.1 g) were stirred at room temperature for 1 hour. This solution was treated with 1-methyl-1,2,3,4-tetrahydroisoquinoline (1.
5 g) and stirred at 40 ° C. for 2 hours, then an equal amount of isoquinoline derivative was added, and the solution was stirred under reflux for 3 hours. The solution was concentrated and the residue was purified by column chromatography on alumina to give 2.0 g pale oil. This oil was crystallized from 50 ml of a 10: 1 pentane / ether solution to give 1.6 g of white crystals. mp 105-108 ° C.

Analysis : Calculated for C ₂₄ H ₂₉ N ₃ O ₂ : 73.62% C 7.46% H 10.73% N Found: 73.86% C 7.48% H 10.6 5% N

──────────────────────────────────────────────────の Continued on the front page (72) Inventor Helsley, Grover Cleveland United States, New Jersey 07978, Plakemin, P.E. Oh. Box 94 (72) Inventor Grand Korski, Edward Joseph United States of America, New Jersey 07060, Warren, Owens Drive 7 (72) Inventor Cian, Yulin United States of America, New Jersey 07961, Convent Station, Bon Agin Drive 24 (72) Invention Fryd, Brian Scott United States, New Jersey 08873, Somerset, Easton Avenue 112 Gee (72) Inventor Currys, Barbara Elaine United States, New Jersey 07407, Elmwood Park, Feng Kusak Avenue 69 (58) Fields studied (Int. Cl . ^7, DB name) A61K 31/4725 A61P 25 / 02,25 / 28 C07D 487/04 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. The following formula (I): Wherein R is hydrogen or lower alkyl; and X is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy, or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition for alleviating memory dysfunction characterized by a cholinergic deficiency. Wherein R is Ru hydrogen or a methyl group der pharmaceutical composition according to 請 Motomeko 1. (3) X is hydrogen or halogen.
2. The pharmaceutical composition according to 1. (4) R is hydrogen or methyl, and X
The pharmaceutical composition according to claim 1, wherein is a hydrogen or a halogen.
Adult. 5. The following compound: (1) (3aS-cis) -1,2,3,3a, 8,8a
(1,2,2-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol)
3,4-tetrahydroisoquinolinyl) carbamate or its (3aR-cis) isomer or a mixture of two isomers; (2) (3aS-cis) -1,2,3,3a, 8,8a
-(1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of two isomers; (3) (3aS-cis) -1,2,3,3a, 8,8a
-(1-ethyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (4) (3aS-cis) -1,2,3,3a, 8,8a
-(1-propyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (5) (3aS-cis) -1,2,3,3a, 8,8a
-(1-butyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of -hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (6) (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 its (3aR-cis )) Isomers or mixtures of the two isomers; (7) (3aS-cis) -1,2,3,3a, 8,8a
-(7-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (8) (3aS-cis) -1,2,3,3a, 8,8a
-(6-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or a salt thereof (3aR-cis) isomer or a mixture of two isomers thereof; (9) (3aS-cis) -1,2,3,3a, 8,8a
-(7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or a salt thereof (3aR-cis) isomer or a mixture of two isomers thereof; (10) (3aS-cis) -1,2,3,3a, 8,8
a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol of (6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl)
Carbamate or its (3aR-cis) isomer or a mixture of the two isomers; (11) (3aS-cis) -1,2,3,3a, 8,8
(7-Hydroxy-1,2,3,4-tetrahydroisoquinolinyl) of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol
Carbamate or its (3aR-cis) isomer or a mixture of the two isomers; (12) (3aS-cis) -1,2,3,3a, 8,8
(6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or The (3aR-cis) isomer, or a mixture of the two isomers; or (13) (3aS-cis) -1,2,3,3a, 8,8
(7-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or For alleviating memory dysfunction characterized by a cholinergic deficiency comprising a (3aR-cis) isomer, or a mixture of the two isomers thereof; or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition. 6. The pharmaceutical composition according to any one of claims 1 to 5 , for treating Alzheimer's disease. 7. The following formula (I): Wherein R is hydrogen or lower alkyl; and X is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy, or a pharmaceutically acceptable acid addition salt thereof. An acetylcholinesterase inhibitor. 8. R is Ru hydrogen or methyl der,請 Motomeko 7
The acetylcholinesterase inhibitor according to the above. 9. X is hydrogen or halogen.
8. The acetylcholinesterase inhibitor according to 7. 10. R is hydrogen or methyl, and
The ace according to claim 7, wherein X is hydrogen or halogen.
Tilcholinesterase inhibitors. 11. The following compound: (1) (3aS-cis) -1,2,3,3a, 8,8a
(1,2,2-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol)
3,4-tetrahydroisoquinolinyl) carbamate or its (3aR-cis) isomer or a mixture of two isomers; (2) (3aS-cis) -1,2,3,3a, 8,8a
-(1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of two isomers; (3) (3aS-cis) -1,2,3,3a, 8,8a
-(1-ethyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (4) (3aS-cis) -1,2,3,3a, 8,8a
-(1-propyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (5) (3aS-cis) -1,2,3,3a, 8,8a
-(1-butyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of -hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (6) (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 its (3aR-cis )) Isomers or mixtures of the two isomers; (7) (3aS-cis) -1,2,3,3a, 8,8a
-(7-chloro-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or its (3aR-cis ) Isomers or mixtures of the two isomers; (8) (3aS-cis) -1,2,3,3a, 8,8a
-(6-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or a salt thereof (3aR-cis) isomer or a mixture of two isomers thereof; (9) (3aS-cis) -1,2,3,3a, 8,8a
-(7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or a salt thereof (3aR-cis) isomer or a mixture of two isomers thereof; (10) (3aS-cis) -1,2,3,3a, 8,8
a-Hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol of (6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl)
Carbamate or its (3aR-cis) isomer or a mixture of the two isomers; (11) (3aS-cis) -1,2,3,3a, 8,8
(7-Hydroxy-1,2,3,4-tetrahydroisoquinolinyl) of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol
Carbamate or its (3aR-cis) isomer or a mixture of the two isomers; (12) (3aS-cis) -1,2,3,3a, 8,8
(6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or The (3aR-cis) isomer, or a mixture of the two isomers; or (13) (3aS-cis) -1,2,3,3a, 8,8
(7-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolinyl) carbamate of a-hexahydro-1,3a, 8-trimethylpyrrolo [2,3-b] indol-5-ol or An acetylcholinesterase inhibitor comprising the (3aR-cis) isomer, or a mixture of the two isomers; or a pharmaceutically acceptable acid addition salt thereof. 12. The acetylcholinesterase inhibitor according to any one of claims 7 to 11 , for treating Alzheimer's disease.