WO1997036589A9 - Use of 1-benzyl-1,2,3,4-tetrahyhydroisoquinoline for the manufacture of a medicament for improving cerebral function - Google Patents
Use of 1-benzyl-1,2,3,4-tetrahyhydroisoquinoline for the manufacture of a medicament for improving cerebral functionInfo
- Publication number
- WO1997036589A9 WO1997036589A9 PCT/JP1997/001063 JP9701063W WO9736589A9 WO 1997036589 A9 WO1997036589 A9 WO 1997036589A9 JP 9701063 W JP9701063 W JP 9701063W WO 9736589 A9 WO9736589 A9 WO 9736589A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzyl
- compound
- memory
- effect
- cerebral function
- Prior art date
Links
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Definitions
- the present invention relates to cerebral function improving agents, i.e., agents which employ the memory disturbance improving effect and memory retention en- hancing effect of 1-benzyl-l,2,3,4-tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, more spe ⁇ cifially, (-)1-benzyl-l,2,3,4-tetrahydroisoquinoline or pharmaceutically acceptable salts thereof.
- iso- quinoline derivatives have been found to have a peripheral vasodilatory effect, a sympathetic nerve stimulating effect, an analgesic effect, or an anticonvulsant effect, and a few of them have become clinically available.
- the present inventors have found that 1-benzyl- 1, 2, 3, 4-tetrahydroisoquinoline, which is an isoquinoline derivative having a simple chemical structure, can improve memory disturbance and enhance memory retention.
- this isoquinoline derivative may have a specific effect on memory function.
- the present invention provides cerebral function improving agents which act through the memory disturbance improving effect and memory retention enhancing effect of 1-benzyl-l ,2,3,4-tetrahydro- isoquinoline or pharmaceutically acceptable salts thereof.
- the cerebral function improving agents of the present invention contain as the active ingredient
- This isoquinoline derivative of formula (I) is a known compound, but has never been found to have any specific pharmacological effects, such as a memory dis- turbance improving effect or a memory retention enhancing effect.
- one aspect of the present invention provides cerebral function improving agents which act through the memory disturbance improving effect of 1- benzyl-1 , 2, 3, 4-tetrahydroisoquinoline of formula (I) or pharmaceutically acceptable salts thereof.
- Another aspect of the present invention provides cerebral function improving agents which act through the memory retention enhancing effect of 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline of formula (I) or pharmaceutically acceptable salts thereof.
- 1-Benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) is a known compound as mentioned above, and can be produced in a high yield according to the procedure described in J. Med. Chem., 32, 1242-1248, 1989.
- the final product obtained according to the procedure may contain an asymmetric carbon atom at the 1-position. Accordingly, theoretically there are two optical isomers, both of which as well as the isomeric mixture may be used for the purposes of the present invention.
- the present invention provides cerebral function improving agents containing as the active ingredient (- ) 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, which act through the memory disturbance improving effect of the compound.
- the present invention provides cerebral function improving agents containing as the active ingredient (- )1-benzyl-l, 2, 3,4- tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, which act through the memory retention en ⁇ hancing effect of the compound.
- the brain is susceptible to irreversible dysfunction even after short-term hypoxia or impaired perfusion.
- Agents now in use for the treatment of cerebral dysfunction of such an etiology include those which improve cerebral function by directly stimulating impaired cerebral energy metabolism and those which stimu ⁇ late cerebral energy turnover by an indirect mechanism, i.e., improving the cerebral circulation.
- Agents of the former type stimulate cerebral energy metabolism by acting directly on the brain tissue and cause a consequent in ⁇ crease in cerebral blood flow.
- These agents can be further classified into those which stimulate or improve cerebral energy metabolism and those which stimulate or modulate cerebral neurotransmission.
- 1-benzyl- 1, 2, 3,4-tetrahydroisoquinoline of formula (I) improves cerebral function by stimu ⁇ lating cerebral energy metabolism, primarily by activating and modulating cerebral neurotransmission through an increase of cholinergic activity.
- Patients with Alzheimer's disease or senile dementia show a selective decrease in the brain activity of choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine, and consequent suppres ⁇ sion of cholinergic activity that may result in memory disturbance.
- Compound (I) improves cerebral function by increasing cholinergic activity through its central cholinergic effect. It markedly stimulates cholinergic neurotransmission, which plays an important role in memory and learning, and thus has a high potential value for the treatment of memory deficits associated with conditions like Alzheimer's disease or senile dementia that are characterized by selective loss of memory.
- Compound (I) has been found to reverse the disturbance of acquired memory induced by cycloheximide, a protein synthesis inhibitor, and even to enhance normal memory.
- the memory improving and enhancing effects of the compound increase in a dose-dependent manner, indicating that an adequate response can probably be obtained by adjusting the dose according to the sever ⁇ ity of memory disturbance.
- the compound has been shown to have pharmacological characteristics similar to those of physostigmine, a compound having a central cholinergic effect, and dissimilar to those of neostigmine, a compound having a peripheral cholinergic effect.
- the chewing behavior induced by intraperitoneal administration of physostigmine or Compound (I) was completely abolished by pretreatment with scopolamine.
- the cholinergic effect of Compound (I) in this model was more sustained and had a higher selectivity for central effect than that of physostigmine.
- isoquinoline skeleton is derived from natural alkaloids which act on central nervous system
- clinical application of isoquinoline derivatives may be limited because of their addictive potential or gastro- intestinal ulcerogenic potential.
- Compound (I) has been found to cause no morphine-like dependence and to have no such ulcerogenic potential as that observed with indomethacin. Since Compound (I) can improve impairment of cerebral function induced by various organic diseases, it was presumed that the compound might induce endogenous parkinsonism similar to that seen in Perkinson's disease by causing damage to the substantia nigra. However, the compound has shown no adverse effects on spontaneous motor activity and are thought unlikely to induce parkinsonism.
- Figure 1 shows data obtained with physostigmine in Pharmacological Test 1.
- Figure 2 shows data obtained with the (+/-) Com ⁇ pound (I) hydrochloride in Pharmacological Test 1.
- Figure 3 shows the cumulative duration of chewing behavior induced by the (+/-) Compound (I) hydrochloride in Pharmacological Test 1.
- Figure 4 shows the cumulative duration of chewing behavior induced by physostigmine in Pharmacological Test 1.
- Figure 5 shows the improvement of memory distur ⁇ fleecee in a model of severe memory disturbance in Pharmaco ⁇ logical Test 2.
- Figure 6 shows the changes of spontaneous movement in a model of severe memory disturbance in Pharmacological Test 2.
- Figure 7 shows the improvement of memory distur ⁇ niethe in a model of memory disturbance induced by low-dose cyclohexidine in Pharmacological Test 2.
- Figure 8 shows enhancement of memory retention in Pharmacological Test 3.
- Figures 9 through 16 show enhancement of memory retention in Pharmacological Test 4.
- 1-Benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) can be used as the free base or pharmaceutically acceptable salts thereof for the purposes of the present invention.
- Such salts may be produced by treating the free base with an organic or inorganic acid.
- Suitable organic acids may include, for example, aliphatic acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid and the like; organic acids such as succinic acid, maleic acid, fumaric acid and the like; substituted or unsubstituted benzoic acid such as benzoic acid, p-nitrobenzoic acid and the like; lower (halo)alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and the like, substituted or unsubstituted arylsulfonic acids such as benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6- triisopropylbenzenesulfonic acid and the like; and organic phosphoric acids such as diphenylphosphoric acid
- salts thus produced most preferable ones include salts formed with organic acids such as succinates, maleates, fumarates, methansulfonates, as well as salts formed with inorganic acids such as hydro- chlorides, hydrobromides, sulfates, and phosphates.
- organic acids such as succinates, maleates, fumarates, methansulfonates
- salts formed with inorganic acids such as hydro- chlorides, hydrobromides, sulfates, and phosphates.
- the compound may be administered orally or parenterally.
- a usual recommended daily dose for oral administration is within the range of 0.002 - 100 mg/kg, preferably 0.01 - 50 mg/kg, and more preferably 0.02 - 30 mg/kg
- a usual recommended daily doses for parenteral administra ⁇ tion is within the range of 0.002 - 100 mg/kg, preferably 0.01 - 50 mg/kg and more preferably 0.02 - 30 mg/kg.
- the compound may be prepared into various oral formulations, including tablets, capsules, powders, granules, troches and liquid preparations.
- formula ⁇ tions may be formed by procedures known per se to those skilled in the art.
- the compound is mixed with a suitable excipient such as starch, mannitol, lactose, glucose, corn starch and so on; a binder such as sodium carboxymethylcellulose, hydroxypropylcellulose and so on; a lubricant such as talc, magnesium stearate and so on; a fluidizing agent such as light anhydrous silicic acid, to obtain tablets, capsules, powders, granules or troches.
- a suitable excipient such as starch, mannitol, lactose, glucose, corn starch and so on
- a binder such as sodium carboxymethylcellulose, hydroxypropylcellulose and so on
- a lubricant such as talc, magnesium stearate and so on
- a fluidizing agent such as light anhydrous silicic acid
- the compound may also be administered in the form of injectable formulations for parenteral route.
- injectable formulations may include, for example, injectable solu- tions made by dissolving or dispersing the compound in an aqueous vehicle such as physiological saline with the aid of surfactants, emulsifiers, and/or suspensory agents. Otherwise, the compound may be made into a crystalline or lyophilized form which can be dispersed or solubilized immediately prior to injection.
- Aqueous vehicles which can be used to prepare the injectable formulations may contain pH adjusting agents, stabilizers, as well as the above-mentioned or any other necessary inactive substances.
- the injectable formulations may be adminis- tered intravenously, intra-arterially, subcutaneously, intraperitoneally, or via any other appropriate route depending on the patient's pathophysiological state.
- Each dose may be administered as a bolus injection or by in ⁇ fusion over an appropriate time period.
- This compound was dissolved in 5 ml of methylene chloride, then 0.19 ml (1.34 mmol) of triethyl ⁇ amine and 0.14 ml (1.35 mmol) of phenyl isothiocyanate were added. The reaction mixture was stirred for 30 min ⁇ utes under ice-cooling and further 30 minutes at a room temperature. After the reaction, 10 ml of methylene chlo- ride was added and the organic layer was washed with water and dried over magnesium sulfate.
- (+/-)Com(I)-HCl (+/-)1-Benzyl-l,2,3,4-tetra- hydroisoquinoline hydrochloride
- (+/-)Com(I)-HCl (10 mg/kg and 30 mg/kg) was tested in comparison with physostigmine (0.1 mg/kg and 0.3 mg/ kg).
- (+/-) Com(I)-HCl or physostigmine rats were observed for chewing behavior for 30 minutes to determine the cumula- tive duration of the behavior.
- scopolamine (1 mg/kg) was administered subcutaneously 10 minutes before administration of (+/-)Com( I ) • HCl or physostigmine to determine whether the cholinergic activ ⁇ ity is antagonized by scopolamine.
- groups of untreated rats served as negative controls.
- (+/-)C ⁇ m(I)-HCl (10 mg/kg, 30 mg/kg, and 100 mg/ kg) was tested in comparison with physostigmine (0.1 mg/ kg, 0.3 mg/ kg, and 1 mg/kg) and neostigmine (0.1 mg/kg, 0.3mg/kg, and 1 mg/kg).
- Rat i.p.
- Mouse s .c.
- mice Groups of 10 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Each mouse was placed in a light compartment and trained for passive avoidance behavior in this system. Each mouse learned not to cross from the light compartment to another dark compartment in order to avoid a foot electric shock (100 V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with a subcutaneous dose (120 mg/kg) of cyclo- heximide, a protein synthesis inhibitor, followed by an intraperitoneal dose (10 or 30 mg/kg) of (+/- )Com( I ) • HCl . On the following day, each mouse was again placed in the light compartment and the latency to the first crossing was recorded.
- a subcutaneous dose 120 mg/kg
- cyclo- heximide a protein synthesis inhibitor
- Pharmacological Test 3 Effect on memory retention Method: Groups of 10 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Each mouse was placed in a light compartment and trained for passive avoidance behavior in this system. The animals learned not to cross from the light compart- ment to another dark compartment in order to avoid a foot electric shock (25 V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with an intraperitoneal dose (30 mg/kg) of (+/-) Com(I)-HCl.
- 1-benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) has a sustained and selective central cholinergic effect. It markedly improves memory disturbance and enhances normal memory retention.
- the memory retention enhancing effect is unique to this compound and this effect gives it an advantage over other agents currently in use.
- mice Groups of 12 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Mice was placed in a light compartment and trained for passive avoidance behavior in this system. The animals were required to learn not to cross from the light compartment to another dark compartment in order to avoid a foot electric shock (25V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with a subcutaneous dose (30 mg/kg) of cyclo ⁇ heximide, a protein synthesis inhibitor, followed by an oral dose of one of the test compounds described below.
- a subcutaneous dose (30 mg/kg) of cyclo ⁇ heximide, a protein synthesis inhibitor
- test compounds included (+/-)Com(I ) • HCl, (+)Com(I)- HCl, and (-)Com(I ) • HCl, all of which were pre ⁇ pared according to the procedures described above in Example 1. All the three compounds were tested at four doses (0.3, 1,3, and 10 mg/kg).
- Cycloheximide (30 mg/kg) significantly reduced the latency to the first crossing, i.e., induced memory dis ⁇ turbance.
- Subsequent treatment with (+/-)Com( I ) • HCl or (-)Com(I ) • HCl improved the memory disturbance induced by cycloheximide.
- the increase in latency produced by 3 mg/kg or 10 mg/kg of (-)Com(I ) • HCl was sta ⁇ tistically significant (p ⁇ 0.01) (Fig. 11) and was greater than that produced by the same dose of (+/-)Com(I)• HCl (Fig. 10 and Fig.11).
- the latency to the first crossing in mice treated with (+)Com(I ) ⁇ HCl was similar to that in the mice given vehicle after adminis ⁇ tration of cycloheximide (Fig. 12).
- the positive control tacrine also significantly improved memory at a dose of 30 mg/kg (Fig. 9).
- 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline of formula (I) is about 10 times more potent than tacrine.
- Pharmacological Test 5 Ulcerogenic potential Groups of 3 mice were treated with single sub ⁇ cutaneous doses of 30 and 100 mg/kg of (+/- )Com(I ) • HCl . At 5 hours after administration, the mice were sacrificed and their stomachs were removed to observe for ulcers under a stereomicroscope. A similar experiment was performed using 3 mice given a subcutaneous dose of 100 mg/kg of indomethacin.
- Acute toxicity test was performed for (+/-)Com(I)- HCl by using mice given a single subcutaneous dose of 100 mg/kg. The mice were observed for signs of toxicity for 3 days after the administration. No deaths occurred during the observation period.
- the present invention provides cere- bral function improving agents which act by improving memory disturbance and enhancing memory retention and thus would be of great therapeutic benefit.
- All the ingredients except for magnesium stearate were sieved and granulated by using a standard kneader and granulator.
- the granules thus prepared were air-dried and passed through a size selector. Then the granules were mixed with magnesium stearate and compressed into tablets each weighing 150 mg.
Abstract
Cerebral function improving agents containing as the active ingredient 1-benzyl-1,2,3,4-tetrahydroisoquinoline represented by formula (I) or pharmaceutically acceptable salts thereof. The compound of the above formula (I) exerts a memory disturbance improving effect and a memory retention enhancing effect through its central cholinergic effect. It causes no morphine-like dependence and has no ulcerogenic potential.
Description
OF 1 -BENZYL- 1,2,3,4-TETRAHYDROISOQUINOLINE FOR THE MANUFACTURE OF A MEDICAMENT FOR
IMPROVING CEREBRAL FUNCTION
TECHNICAL FIELD
The present invention relates to cerebral function improving agents, i.e., agents which employ the memory disturbance improving effect and memory retention en- hancing effect of 1-benzyl-l,2,3,4-tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, more spe¬ cifially, (-)1-benzyl-l,2,3,4-tetrahydroisoquinoline or pharmaceutically acceptable salts thereof.
BACKGROUND ART
Recent rapid socioeconomic changes have compli¬ cated the profile of many diseases which pose a serious challenge to physicians. With the continued increase in the elderly population, various organic brain diseases have become prevalent. Among them, senile dementia or Alzheimer's disease, which are characterized by selective loss of memory, have raised serious concern. For the treatment of these diseases, various agents, including those which stimulate cerebral energy metabolism, improve and modulate cerebral neurotransmission, or improve the cerebral circulation, have been developed, but none of them have shown any definite anti-dementia efficacy. Thus, no agents have yet become available that are truly effective for reversing these diseases or delaying their progression.
DISCLOSURE OF THE INVENTION
The present inventors actively examined many compounds for their therapeutic potential in various fields and noticed of the pharmacological activity of iso- quinoline derivatives. Some isoquinoline derivatives have been found to have a peripheral vasodilatory effect, a sympathetic nerve stimulating effect, an analgesic effect, or an anticonvulsant effect, and a few of them have become clinically available.
The present inventors have found that 1-benzyl- 1, 2, 3, 4-tetrahydroisoquinoline, which is an isoquinoline derivative having a simple chemical structure, can improve memory disturbance and enhance memory retention.
Several other compounds have been shown to improve memory disturbance, but no single compound having such an effect can also enhance memory retention. In this res¬ pect, this isoquinoline derivative may have a specific effect on memory function. Thus, the present invention provides cerebral function improving agents which act through the memory disturbance improving effect and memory retention enhancing effect of 1-benzyl-l ,2,3,4-tetrahydro- isoquinoline or pharmaceutically acceptable salts thereof.
Namely, the cerebral function improving agents of the present invention contain as the active ingredient
1-benzyl-l, 2, 3,4-tetrahydroisoquinoline represented by the following formula (I):
This isoquinoline derivative of formula (I) is a known compound, but has never been found to have any specific pharmacological effects, such as a memory dis- turbance improving effect or a memory retention enhancing effect.
Therefore, one aspect of the present invention provides cerebral function improving agents which act through the memory disturbance improving effect of 1- benzyl-1 , 2, 3, 4-tetrahydroisoquinoline of formula (I) or pharmaceutically acceptable salts thereof.
Another aspect of the present invention provides cerebral function improving agents which act through the memory retention enhancing effect of 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline of formula (I) or pharmaceutically acceptable salts thereof.
1-Benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) is a known compound as mentioned above, and can be produced in a high yield according to the procedure described in J. Med. Chem., 32, 1242-1248, 1989. The final product obtained according to the procedure may contain an asymmetric carbon atom at the 1-position. Accordingly, theoretically there are two optical isomers, both of which as well as the isomeric mixture may be used for the purposes of the present invention.
Among the isomers and their mixture, (-)l-benzyl- 1, 2, 3, 4-tetrahydroisoquinoline ((-) isomer) has proved to be especially potent in improving cerebral function.
Therefore, in a preferred embodiment the present invention provides cerebral function improving agents containing as the active ingredient (- ) 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, which act through the memory disturbance improving effect of the compound.
In another preferred embodiment the present invention provides cerebral function improving agents containing as the active ingredient (- )1-benzyl-l, 2, 3,4- tetrahydroisoquinoline or pharmaceutically acceptable salts thereof, which act through the memory retention en¬ hancing effect of the compound.
Unlike other organs, the brain is susceptible to irreversible dysfunction even after short-term hypoxia or impaired perfusion. Agents now in use for the treatment of cerebral dysfunction of such an etiology include those which improve cerebral function by directly stimulating impaired cerebral energy metabolism and those which stimu¬ late cerebral energy turnover by an indirect mechanism, i.e., improving the cerebral circulation. Agents of the former type stimulate cerebral energy metabolism by acting directly on the brain tissue and cause a consequent in¬ crease in cerebral blood flow. These agents can be further classified into those which stimulate or improve cerebral energy metabolism and those which stimulate or modulate cerebral neurotransmission.
The present inventors have found that 1-benzyl- 1, 2, 3,4-tetrahydroisoquinoline of formula (I) (including the (-) isomer and the mixture of the (-) and (+) isomers unless otherwise specified; hereinafter also referred to as "Compound (I)") improves cerebral function by stimu¬ lating cerebral energy metabolism, primarily by activating and modulating cerebral neurotransmission through an increase of cholinergic activity. Patients with Alzheimer's disease or senile dementia show a selective decrease in the brain activity of choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine, and consequent suppres¬ sion of cholinergic activity that may result in memory
disturbance. Compound (I) improves cerebral function by increasing cholinergic activity through its central cholinergic effect. It markedly stimulates cholinergic neurotransmission, which plays an important role in memory and learning, and thus has a high potential value for the treatment of memory deficits associated with conditions like Alzheimer's disease or senile dementia that are characterized by selective loss of memory.
For example, Compound (I) has been found to reverse the disturbance of acquired memory induced by cycloheximide, a protein synthesis inhibitor, and even to enhance normal memory. The memory improving and enhancing effects of the compound increase in a dose-dependent manner, indicating that an adequate response can probably be obtained by adjusting the dose according to the sever¬ ity of memory disturbance.
In addition, the compound has been shown to have pharmacological characteristics similar to those of physostigmine, a compound having a central cholinergic effect, and dissimilar to those of neostigmine, a compound having a peripheral cholinergic effect. In rats, the chewing behavior induced by intraperitoneal administration of physostigmine or Compound (I) (in the form of a pharma¬ ceutically acceptable salt) was completely abolished by pretreatment with scopolamine. The cholinergic effect of Compound (I) in this model was more sustained and had a higher selectivity for central effect than that of physostigmine. These findings indicate that the cere¬ bral function improving effect of Compound (I) is based on its central cholinergic effect.
Since isoquinoline skeleton is derived from natural alkaloids which act on central nervous system, clinical application of isoquinoline derivatives may be limited because of their addictive potential or gastro-
intestinal ulcerogenic potential. However, Compound (I) has been found to cause no morphine-like dependence and to have no such ulcerogenic potential as that observed with indomethacin. Since Compound (I) can improve impairment of cerebral function induced by various organic diseases, it was presumed that the compound might induce endogenous parkinsonism similar to that seen in Perkinson's disease by causing damage to the substantia nigra. However, the compound has shown no adverse effects on spontaneous motor activity and are thought unlikely to induce parkinsonism.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows data obtained with physostigmine in Pharmacological Test 1.
Figure 2 shows data obtained with the (+/-) Com¬ pound (I) hydrochloride in Pharmacological Test 1.
Figure 3 shows the cumulative duration of chewing behavior induced by the (+/-) Compound (I) hydrochloride in Pharmacological Test 1.
Figure 4 shows the cumulative duration of chewing behavior induced by physostigmine in Pharmacological Test 1. Figure 5 shows the improvement of memory distur¬ bance in a model of severe memory disturbance in Pharmaco¬ logical Test 2.
Figure 6 shows the changes of spontaneous movement in a model of severe memory disturbance in Pharmacological Test 2.
Figure 7 shows the improvement of memory distur¬ bance in a model of memory disturbance induced by low-dose cyclohexidine in Pharmacological Test 2.
Figure 8 shows enhancement of memory retention in
Pharmacological Test 3.
Figures 9 through 16 show enhancement of memory retention in Pharmacological Test 4.
BEST MODE FOR CARRYING OUT THE INVENTION
1-Benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) can be used as the free base or pharmaceutically acceptable salts thereof for the purposes of the present invention. Such salts may be produced by treating the free base with an organic or inorganic acid. Suitable organic acids may include, for example, aliphatic acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid and the like; organic acids such as succinic acid, maleic acid, fumaric acid and the like; substituted or unsubstituted benzoic acid such as benzoic acid, p-nitrobenzoic acid and the like; lower (halo)alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and the like, substituted or unsubstituted arylsulfonic acids such as benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6- triisopropylbenzenesulfonic acid and the like; and organic phosphoric acids such as diphenylphosphoric acid. Suit- able inorganic acids may include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodinic acid, hydroborofluoric acid, perchloric acid, nitric acid and the like.
Among the salts thus produced, most preferable ones include salts formed with organic acids such as succinates, maleates, fumarates, methansulfonates, as well as salts formed with inorganic acids such as hydro- chlorides, hydrobromides, sulfates, and phosphates.
The compound may be administered orally or
parenterally. Although the optimum daily dose may vary depending on the severity of the target disease as well as the patient's age, body weight, condition and so on, a usual recommended daily dose for oral administration is within the range of 0.002 - 100 mg/kg, preferably 0.01 - 50 mg/kg, and more preferably 0.02 - 30 mg/kg, while a usual recommended daily doses for parenteral administra¬ tion is within the range of 0.002 - 100 mg/kg, preferably 0.01 - 50 mg/kg and more preferably 0.02 - 30 mg/kg. The compound may be prepared into various oral formulations, including tablets, capsules, powders, granules, troches and liquid preparations. These formula¬ tions may be formed by procedures known per se to those skilled in the art. For instance, the compound is mixed with a suitable excipient such as starch, mannitol, lactose, glucose, corn starch and so on; a binder such as sodium carboxymethylcellulose, hydroxypropylcellulose and so on; a lubricant such as talc, magnesium stearate and so on; a fluidizing agent such as light anhydrous silicic acid, to obtain tablets, capsules, powders, granules or troches.
The compound may also be administered in the form of injectable formulations for parenteral route. Such formulations may include, for example, injectable solu- tions made by dissolving or dispersing the compound in an aqueous vehicle such as physiological saline with the aid of surfactants, emulsifiers, and/or suspensory agents. Otherwise, the compound may be made into a crystalline or lyophilized form which can be dispersed or solubilized immediately prior to injection. Aqueous vehicles which can be used to prepare the injectable formulations may contain pH adjusting agents, stabilizers, as well as the above-mentioned or any other necessary inactive substances. The injectable formulations may be adminis-
tered intravenously, intra-arterially, subcutaneously, intraperitoneally, or via any other appropriate route depending on the patient's pathophysiological state. Each dose may be administered as a bolus injection or by in¬ fusion over an appropriate time period.
The following Example and Pharmacological Tests are given for the purpose of illustrating the invention in more detail.
Example 1: Optical resolution of 1-benzyl-l, 2, 3,4-tetra- hydroisoquinoline
( 1 ) ( 2 )
( 3 )
( 4 ) ( 5 )
(a) To a suspension of 6.0 g (23.12 mmol) of (+/-)l-benzyl-l, 2, 3, 4-tetrahydroisoquinoline hydrochloride [Compound (1)] (The process to obtain this compound is described in J. Med. Chem., 3_2, 1242-1248, 1989.) in 100 ml of methylene chloride were added 3.85 ml (27.75 mmol) of triethylamine, 7.74 g (34.68 mmol) of Z-L-Ala-OH, 8.88 g (46.24 mmol) of l-(3-dimethylaminopropyl )-3-ethylcar- bodiimide hydrochloride and 100 mg of 4-dimethylamino- pyridine at 0°C under ice-cooling. The reaction mixture was stirred for 5 minutes at 0°C and further 30 minutes at a room temperature. After removal of the solvent under reduced pressure, the resulting residue was extracted with 200 ml of ethyl acetate. The extract layer was washed with 1N-HC1 solution, saturated sodium hydrocarbonate solution and saturated saline solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 5:1 to 3:1) to give two isomers, i.e., Isomer (A) and Isomer (B) of Com- pound (2) .
Isomer (A) of Compound (2) (as pale yellow oil): 'H-NMR (CDCl3 )δ : 1.09 (d, 3H, J=6.6Hz), 2.63-3.76 (m, 6H), 4.54-4.77 (m, 1H), 5.04 (s, 2H), 5.80-5.90 (m, 2H), 7.02-7.37 (m, 14H) . Isomer (B) of Compound (2) (as pale yellow oil):
' H-NMR (CDCl3 )δ : 1.19 (d, 3H, J=6.9Hz), 2.50-3.15 (m, 4H), 3.39-3.64 (m, 2H), 4.62 (m, 1H), 5.03 (s, 2H), 5.55 (m, 1H), 5.71 (d, 1H, J=7.8Hz), 6.70-7.28 (m, 14H).
(b) A mixture solution of 500 mg (1.17 mmol) of the above-obtained Isomer (A) of Compound (2) in 1.5 ml of 25 % HBr-AcOH was stirred for 5 minutes at 0°C and further 1 hour at a room temperature. Then 12 ml of ethyl ether was added, and the mixture was further stirred for 10 min-
utes under ice-cooling. The resulting precipitate was collected and washed with ethyl ether to give 419 mg (95.6 %) of Isomer (A) of Compound (3) in the form of a pale yellow solid. This compound was dissolved in 5 ml of methylene chloride, then 0.19 ml (1.34 mmol) of triethyl¬ amine and 0.14 ml (1.35 mmol) of phenyl isothiocyanate were added. The reaction mixture was stirred for 30 min¬ utes under ice-cooling and further 30 minutes at a room temperature. After the reaction, 10 ml of methylene chlo- ride was added and the organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane : ethylacetate = 2 : 1) to give 446 mg (93.1 %) of Isomer (A) of Compound (4) in the form of a white solid.
1 H-NMR (CDCl3 )δ : 1.18 (d, 3H, J=6.7Hz), 2.69-3.32 (m, 4H), 3.44 (m, 1H), 3.83 (m, 1H), 3.39 (m, 1H), 5.82 (m, 1H), 7.02-7.45 (m, 14H), 7.73 (s, 1H) .
Isomer (B) of Compound (4) was obtained from Iso¬ mer (B) of Compound (2) in substantially the same manner as above.
'H-NMR (CDCl3 )δ : 1.38 (d, 3H, J=6.9Hz), 2.77-3.18 (m, 4H), 3.66-3.85 (m, 2H), 5.46 (m, 1H), 5.62 (m, 1H), 6.81- 7.47 (m, 14H), 8.10 (s, 1H).
(c) A mixture solution of 429 mg (1 mmol) of the above-obtained Isomer (A) of Compound (4) in 2 ml of tri- fluoroacetic acid was stirred for 20 minutes under ice- cooling and under N2 gas atmosphere. After removal of the solvent under reduced pressure, the resulting residue was treated with 10 ml of water and the pH of the solution was adjusted to 10 by adding 3N-sodium hydroxide, then extraction was done with methylene chloride. The organic
layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was treated with 5 ml of acetonitrile and 0.1 ml of concen¬ trated hydrogen chloride, and then concentrated under reduced pressure. To the residue, 5 ml of ethyl acetate was added and the mixture was stirred for 10 minutes at a room temperature. The resulting precipitate was col¬ lected, washed with ethyl acetate, and dried in vacuum to give 201 mg (77.5 %) of (+)1-benzyl-l,2,3,4-tetrahydroiso- quinoline hydrochloride [(+) Compound (5)] in colorless needle-form crystals.
1 H-NMR (CDCl3)δ : 3.00-3.34 (m, 5H) , 3.63 (dd, 1H, J=4.6 & 13.9Hz), 4.81 (m, 1H), 6.73 (d, 1H, J=7.6Hz), 7.06-7.33 (m, 8H). [α ]D 25: +10.0"(c=1.0/ EtOH)
(-)1-Benzyl-1,2,3,4-tetrahydroisoquinoline hydro¬ chloride [(-) Compound (5)] was obtained from Isomer (B) of Compound (4) in substantially the same manner as above. 'H-NMR (CDCl3)δ : 2.99-3.34 (m, 5H), 3.63 (dd, 1H, J=4.6 & 13.9Hz), 4.81 (m, 1H), 6.73 (d, 1H, J=7.6Hz), 7.05-7.33 (m, 8H). [α 3D25 : -9.2°(c=1.0, EtOH)
The compounds obtained above were subjected to the pharmacological tests as shown below.
The following abbreviations are used to mean the respective test compounds:
(+/-)Com(I)-HCl : (+/-)1-Benzyl-l,2,3,4-tetra- hydroisoquinoline hydrochloride
(-)Com(I)-HCl : (-)1-Benzyl-l,2,3,4-tetrahydroiso- quinoline hydrochloride (+)Com(I)-HCl : (+)1-Benzyl-l, 2, 3,4-tetrahydroiso- quinoline hydrochloride
Study A: Pharmacological actions of (+/-)1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline
Cerebral function improving activity of the isomeric mixture of Compound (I), i.e., (+/-)1-Benzyl- 1, 2, 3, 4-tetrahydroisoquinoline, was studied as follows.
Pharmacological Test 1: Central cholinergic activity Method ( 1) :
(+/-)Com(I)-HCl (10 mg/kg and 30 mg/kg) was tested in comparison with physostigmine (0.1 mg/kg and 0.3 mg/ kg).
Following intraperitoneal administration of (+/-) Com(I)-HCl or physostigmine, rats were observed for chewing behavior for 30 minutes to determine the cumula- tive duration of the behavior. In another experiment, scopolamine (1 mg/kg) was administered subcutaneously 10 minutes before administration of (+/-)Com( I ) • HCl or physostigmine to determine whether the cholinergic activ¬ ity is antagonized by scopolamine. For each experiment, groups of untreated rats served as negative controls. Results:
The results are shown in Figs. 1 through 4. As shown in Figs. 1 and 2, both physostigmine (0.1 mg/kg) and (+/-)Com(I ) • HCl (10 mg/kg) induced chewing behavior, which was completely abolished by pretreatment with scopolamine.
As shown in Fig. 4, the cumulative duration of the chewing behavior induced by physostigmine reached a plateau at 20 minutes after administration, that is, the chewing behavior lasted for only 20 minutes. On the other hand, the behavior induced by (+/-)Com(I ) • HCl lasted for at least 30 minutes after intraperitoneal administration (Fig. 3).
These results clearly indicate that (+/-)Com(I)- HCl has a central cholinergic effect which is more sus¬ tained than that of physostigmine. Method (2) : (+/-)Cσm(I)-HCl (10 mg/kg, 30 mg/kg, and 100 mg/ kg) was tested in comparison with physostigmine (0.1 mg/ kg, 0.3 mg/ kg, and 1 mg/kg) and neostigmine (0.1 mg/kg, 0.3mg/kg, and 1 mg/kg).
Following intraperitoneal administration of one of the test agents described above, rats were observed for chewing behavior and salivation. The effects of (+/-) Com(I)-HCl and physostigmine were also assessed in mice treated subcutaneously at the same dose levels. Results: The results are shown in Table 1.
Table 1
Rat (i.p. ) Mouse (s .c. )
Dose Chewing Test agents (mg/kg) behavior Salivation Salivation
(+/-)Com(I)- HCl 10 O x x
30 O x x
100
Physostigmine 0 . 1 o X
0 . 3 o X
1 o •
Neostigmine 0.1 x x
0.3 x x
1 x •
O or # : Positive x : Negative - : Not tested
Chewing behavior can be an index of a central cholinergic effect and the salivation can be an index of a peripheral cholinergic effect. As shown in Table 1 above, the cholinergic effect of (+/-)Com(I ) • HCl had a greater selectivity for central effect than that of physostigmine.
Pharmacological Test 2: Effect on memory disturbance (1) Assessment using a model of severe memory disturbance Method:
Groups of 10 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Each mouse was placed in a light compartment and trained for passive avoidance behavior in this system. Each mouse learned not to cross from the light compartment to another dark compartment in order to avoid a foot electric shock (100 V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with a subcutaneous dose (120 mg/kg) of cyclo- heximide, a protein synthesis inhibitor, followed by an intraperitoneal dose (10 or 30 mg/kg) of (+/- )Com( I ) • HCl . On the following day, each mouse was again placed in the light compartment and the latency to the first crossing was recorded.
Untreated animals and animals treated with cyclo- heximide alone were used as controls.
To confirm normal spontaneous motor activity in the individual mice, the frequency of spontaneous movement was measured using an Animex apparatus immediately after completion of the passive avoidance test. Results:
The results are shown in Figs. 5 and 6. In each mouse, treatment with cycloheximide (120 mg/kg) signifi-
cantly reduced the latency to the first crossing, i.e., induced memory disturbance. Subsequent treatment with (+/-)Com( I ) • HCl improved this memory disturbance, and im¬ provement caused by a dose of 30 mg/kg was statistically significant (Fig. 5).
In addition, spontaneous motor activity was not impaired by (+/-)Com( I ) • HCl (Fig. 6). This confirmed that prolongation of the latency to the first crossing in the mice treated with (+/-)Com(I )• HCl was not due to suppres- sion of spontaneous motor activity such as sedation.
(2) Assessment in a model of memory disturbance induced by low-dose cycloheximide
Method: Assessment was done using the same method as above with the following changes. Groups of 5 mice were used, the shock intensity was 25 V, and memory disturbance was induced by a lower dose of cycloheximide (30 mg/kg, s.c). The dose of (+/-)Com(I ) • HCl was 10 mg/kg intra- peritoneally.
Untreated animals and animals treated with cyclo¬ heximide alone served as controls. Results:
The results are shown in Fig. 7. Even at a dose as low as 10 mg/kg, (+/-)Com( I ) • HCl significantly improved the severe memory disturbance induced by cycloheximide.
Pharmacological Test 3: Effect on memory retention Method: Groups of 10 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Each mouse was placed in a light compartment and trained for passive avoidance behavior in this system. The animals learned not to cross from the light compart-
ment to another dark compartment in order to avoid a foot electric shock (25 V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with an intraperitoneal dose (30 mg/kg) of (+/-) Com(I)-HCl.
On the following day, each mouse was again placed in the light compartment of the system and the latency to the first crossing was recorded. Untreated animals were used as controls.
Results:
The results are shown in Fig. 8. As shown in this figure, treatment with 30 mg/kg of (+/- )Com( I ) • HCl sig¬ nificantly prolonged the latency to the first crossing compared with the untreated controls. This indicates that the compound enhances memory retention in normal animals.
Based on the results of these pharmacological tests, 1-benzyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) has a sustained and selective central cholinergic effect. It markedly improves memory disturbance and enhances normal memory retention.
The memory retention enhancing effect is unique to this compound and this effect gives it an advantage over other agents currently in use.
Study B: Pharmacological actions of (+) or (-)l-benzyl- 1,2,3, 4-tetrahydroisoquinoline
The results of Study A indicated that (+/-)1- benzyl-1 , 2, 3, 4-tetrahydroisoquinoline markedly improves cerebral function. Next, the potency of the two optical isomers was assessed independently.
Pharmacological Test 4: Effect on memory disturbance
Method :
Groups of 12 mice were used after they had been acclimatized to a step-through passive avoidance test apparatus. Mice was placed in a light compartment and trained for passive avoidance behavior in this system. The animals were required to learn not to cross from the light compartment to another dark compartment in order to avoid a foot electric shock (25V) which was delivered via the grid floor of the dark compartment after a light beam was broken. Immediately after training, each mouse was treated with a subcutaneous dose (30 mg/kg) of cyclo¬ heximide, a protein synthesis inhibitor, followed by an oral dose of one of the test compounds described below.
On the following day, each mouse was again placed in the light compartment of the system and the latency to the first crossing was recorded.
The test compounds included (+/-)Com(I ) • HCl, (+)Com(I)- HCl, and (-)Com(I ) • HCl, all of which were pre¬ pared according to the procedures described above in Example 1. All the three compounds were tested at four doses (0.3, 1,3, and 10 mg/kg).
The positive control was mice treated in a similar way with a single oral dose of 1, 3, 10, or 30 mg/kg of tacrine, which is the only agent approved in the U.S.A. for the treatment of Alzheimer's disease.
Mice that received vehicle with or without admin¬ istration of cycloheximide served as negative controls.
To confirm the normal spontaneous motor activity of the individual mice, the frequency of spontaneous move- ments was measured using an Animex apparatus immediately after completion of the passive avoidance test. Results:
The results are shown in Figs. 9 through 16.
Cycloheximide (30 mg/kg) significantly reduced the
latency to the first crossing, i.e., induced memory dis¬ turbance. Subsequent treatment with (+/-)Com( I ) • HCl or (-)Com(I ) • HCl improved the memory disturbance induced by cycloheximide. In particular, the increase in latency produced by 3 mg/kg or 10 mg/kg of (-)Com(I ) • HCl was sta¬ tistically significant (p<0.01) (Fig. 11) and was greater than that produced by the same dose of (+/-)Com(I)• HCl (Fig. 10 and Fig.11). On the other hand, the latency to the first crossing in mice treated with (+)Com(I ) ■ HCl was similar to that in the mice given vehicle after adminis¬ tration of cycloheximide (Fig. 12).
These results indicate that the cerebral func¬ tion improving effect (more specifically, the memory disturbance improving effect) of 1-benzyl-l, 2, 3, 4-tetra- hydroisoquinoline of formula (I) is dependent on the marked pharmacological activity of the (-)isomer.
The positive control tacrine also significantly improved memory at a dose of 30 mg/kg (Fig. 9). In view of these findings, it can be said that 1-benzyl-l, 2, 3, 4- tetrahydroisoquinoline of formula (I) is about 10 times more potent than tacrine.
Spontaneous motor activity was not impaired by any of the active compounds (Figs. 13 through 16). This confirms that the prolongation of latency to the first crossing caused by 1-benzyl-l, 2, 3, 4-tetrahydroisoquinoline was not due to suppression of spontaneous motor activity such as sedation.
Pharmacological Test 5: Ulcerogenic potential Groups of 3 mice were treated with single sub¬ cutaneous doses of 30 and 100 mg/kg of (+/- )Com(I ) • HCl . At 5 hours after administration, the mice were sacrificed and their stomachs were removed to observe for ulcers under a stereomicroscope.
A similar experiment was performed using 3 mice given a subcutaneous dose of 100 mg/kg of indomethacin.
Gastric ulcers were noted in 2 of the 3 mice treated with indomethacin versus none of the mice treated with (+/-)Com(I)-HCl.
Pharmacological Test 6: Toxicity
Acute toxicity test was performed for (+/-)Com(I)- HCl by using mice given a single subcutaneous dose of 100 mg/kg. The mice were observed for signs of toxicity for 3 days after the administration. No deaths occurred during the observation period.
The results of the above-mentioned pharmacological tests confirmed that 1-benzyl-l, 2, 3, 4-tetrahydroisoquino- line of formula (I), especially the (-)isomer, acts to improve cerebral function, specifically improving memory disturbance, through its central cholinergic effect. It was also confirmed that this compound not only improves memory disturbance but also enhances memory retention, which provides a clear distinction between other agents or compounds previously found to have only a memory dis¬ turbance improving effect.
Therefore, the present invention provides cere- bral function improving agents which act by improving memory disturbance and enhancing memory retention and thus would be of great therapeutic benefit.
The following are typical and non-limiting for- mulation examples which can be used for the purposes of the present invention.
Formulation Example 1 (Tablets) Ingredients:
(+/-)1-benzyl-l, 2,3, 4-tetrahydroisoquinoline hydrochloride 30 g Lactose 105 g
Macrocrystalline cellulose 20 g Corn starch 20 g
5% aqueous solution of hydroxypropylcellulose 100 ml Magnesium stearate 2 g
All the ingredients except for magnesium stearate were sieved and granulated by using a standard kneader and granulator. The granules thus prepared were air-dried and passed through a size selector. Then the granules were mixed with magnesium stearate and compressed into tablets each weighing 150 mg.
Formulation Example 2 (Tablets) Ingredients:
(-) 1-benzyl-1, 2,3, 4-tetrahydroisoquinoline hydrochloride 15 g Lactose 120 g
Microcrystalline cellulose 20 g Corn starch 20 g
5% aqueous solution of hydroxypropylcellulose 100 ml Magnesium stearate 2 g
The ingredients were made into tablets each weighing 150 mg according to the procedure described in Formulation Example 1.
Formulation Example 3 (Capsules) Ingredients:
(+/-)1-benzyl-1, 2,3, 4-tetrahydroisoquinoline hydrochloride 30 g Lactose 105 g
Corn starch 48 g
Magnesium stearate 2 g
All the ingredients were pulverized and mixed well to make a homogenous mixture, which was filled in hard gelatin capsules. Each capsule was filled with 0.15 g of the mixture.
Formulation Example 4 (Capsules) Ingredients: (-) 1-benzyl-l,2,3, 4-tetrahydroisoquinoline hydrochloride 15 g Lactose 120 g
Corn starch 48 g
Magnesium stearate 2 g All the ingredients were pulverized and mixed well to make a homogenous mixture, which was filled in hard gelatin capsules. Each capsule was filled with 0.15 g of the mixture.
Claims
1. A cerebral function improving agent containing as the active ingredient 1-benzyl-l, 2,3, 4-tetrahydroiso- quinoline represented by the following formula (I):
or pharmaceutically acceptable salt thereof.
2. A cerebral function improving agent containing as the active ingredient the 1-benzyl-l, 2, 3, 4-tetrahydro- isoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof, which acts through the memory disturbance improving effect of the compound.
3. A cerebral function improving agent containing as the active ingredient the 1-benzyl-l, 2, 3, 4-tetrahydro- isoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof, which acts through the memory retention enhancing effect of the compound.
4. A cerebral function improving agent as in any one of Claims 1-3, in which the 1-benzyl-l, 2, 3,4-tetrahydro- isoquinoline of formula (I) set forth in Claim 1 is (-)l- benzyl-1, 2,3, 4-tetrahydroisoquinoline.
5. A cerebral function improving agent containing as the active ingredient (- )1-benzyl-l, 2, 3, 4-tetrahydro- isoquinoline or pharmaceutically acceptable salt thereof.
6. A cerebral function improving agent which acts through the memory disturbance improving effect of (-)l- benzyl-1, 2, 3,4-tetrahydroisoquinoline or pharmaceutically acceptable salt thereof.
7. A cerebral function improving agent which acts through the memory retention enhancing effect of (-)l- benzyl-1, 2, 3, 4-tetrahydroisoquinoline or pharmaceutically acceptable salt thereof.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9535126A JP2000507570A (en) | 1996-03-29 | 1997-03-28 | Use of 1-benzyl-1,2,3,4-tetrahydroisoquinoline for producing a brain function improving drug |
AU20438/97A AU2043897A (en) | 1996-03-29 | 1997-03-28 | Use of 1-benzyl-1,2,3,4-tetrahyhydroisoquinoline for the manufacture of a medicament for improving cerebral function |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9966796 | 1996-03-29 | ||
JP8/99667 | 1996-03-29 |
Publications (2)
Publication Number | Publication Date |
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WO1997036589A1 WO1997036589A1 (en) | 1997-10-09 |
WO1997036589A9 true WO1997036589A9 (en) | 1997-12-31 |
Family
ID=14253391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP1997/001063 WO1997036589A1 (en) | 1996-03-29 | 1997-03-28 | Use of 1-benzyl-1,2,3,4-tetrahyhydroisoquinoline for the manufacture of a medicament for improving cerebral function |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP2000507570A (en) |
AU (1) | AU2043897A (en) |
WO (1) | WO1997036589A1 (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8921304D0 (en) * | 1989-09-20 | 1989-11-08 | Wyeth John & Brother Ltd | New method of treatment and heterocyclic compounds used therein |
-
1997
- 1997-03-28 JP JP9535126A patent/JP2000507570A/en active Pending
- 1997-03-28 AU AU20438/97A patent/AU2043897A/en not_active Abandoned
- 1997-03-28 WO PCT/JP1997/001063 patent/WO1997036589A1/en active Application Filing
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