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WO1997036589A1 - Utilisation de 1-benzyl-1,2,3,4-tetrahydroisoquinoleine pour la fabrication d'un medicament ameliorant la fonction cerebrale - Google Patents

Utilisation de 1-benzyl-1,2,3,4-tetrahydroisoquinoleine pour la fabrication d'un medicament ameliorant la fonction cerebrale Download PDF

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Publication number
WO1997036589A1
WO1997036589A1 PCT/JP1997/001063 JP9701063W WO9736589A1 WO 1997036589 A1 WO1997036589 A1 WO 1997036589A1 JP 9701063 W JP9701063 W JP 9701063W WO 9736589 A1 WO9736589 A1 WO 9736589A1
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WO
WIPO (PCT)
Prior art keywords
benzyl
compound
memory
effect
cerebral function
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/001063
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English (en)
Other versions
WO1997036589A9 (fr
Inventor
Masaaki Hirobe
Shigeru Ohta
Yoshikazu Masukawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Japan Inc
Original Assignee
Lederle Japan Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lederle Japan Ltd filed Critical Lederle Japan Ltd
Priority to AU20438/97A priority Critical patent/AU2043897A/en
Priority to JP9535126A priority patent/JP2000507570A/ja
Publication of WO1997036589A1 publication Critical patent/WO1997036589A1/fr
Publication of WO1997036589A9 publication Critical patent/WO1997036589A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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 (-)l-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.
  • (+/-)Com(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).
  • 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.

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Abstract

L'invention se rapporte à des agents améliorant la fonction cérébrale, agents contenant comme principe actif de la 1-benzyl-1,2,3,4-tétrahydroisoquinoléine de formule (I), ou à des sels pharmaceutiquement acceptables de cette dernière. Le composé de formule (I) atténue les troubles de la mémoire et améliore la mémorisation grâce à son effet cholinergique central. Il ne crée pas dépendance du type dépendance de la morphine et n'a pas d'effet ulcérogène.
PCT/JP1997/001063 1996-03-29 1997-03-28 Utilisation de 1-benzyl-1,2,3,4-tetrahydroisoquinoleine pour la fabrication d'un medicament ameliorant la fonction cerebrale Ceased WO1997036589A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
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
JP9535126A JP2000507570A (ja) 1996-03-29 1997-03-28 脳機能改善薬を製造するための１―ベンジル―１，２，３，４―テトラヒドロイソキノリンの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/99667 1996-03-29
JP9966796 1996-03-29

Publications (2)

Publication Number Publication Date
WO1997036589A1 true WO1997036589A1 (fr) 1997-10-09
WO1997036589A9 WO1997036589A9 (fr) 1997-12-31

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PCT/JP1997/001063 Ceased WO1997036589A1 (fr) 1996-03-29 1997-03-28 Utilisation de 1-benzyl-1,2,3,4-tetrahydroisoquinoleine pour la fabrication d'un medicament ameliorant la fonction cerebrale

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WO (1) WO1997036589A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419247A2 (fr) * 1989-09-20 1991-03-27 JOHN WYETH & BROTHER LIMITED Antagonistes sÀ©lectifs GABA, particulièrement dérivés d'isoquinoléine, et leur utilisation pour le traitement de désordres du système nerveux central

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419247A2 (fr) * 1989-09-20 1991-03-27 JOHN WYETH & BROTHER LIMITED Antagonistes sÀ©lectifs GABA, particulièrement dérivés d'isoquinoléine, et leur utilisation pour le traitement de désordres du système nerveux central

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI CHEN ET AL.: "Comparison of the electrophysiological effects of S49, CSH087 and CSH068 in rat ventricular cells", PROC NATL SCI COUNC REPUB CHINA B, vol. 17, no. 2, 1993, pages 48 - 56, XP000654526 *
NANCY M. GRAY ET AL.: "Phencyclidine-like effects of tetrahydroisoquinolines and related compounds", J.MED.CHEM., vol. 32, no. 36, 1989, pages 1242 - 1248, XP000652263 *

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JP2000507570A (ja) 2000-06-20
AU2043897A (en) 1997-10-22

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