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WO1997036588A2 - Use of 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines for the manufacture of a medicament for the treatment of psychosis and pain - Google Patents

Use of 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines for the manufacture of a medicament for the treatment of psychosis and pain Download PDF

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Publication number
WO1997036588A2
WO1997036588A2 PCT/JP1997/001062 JP9701062W WO9736588A2 WO 1997036588 A2 WO1997036588 A2 WO 1997036588A2 JP 9701062 W JP9701062 W JP 9701062W WO 9736588 A2 WO9736588 A2 WO 9736588A2
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WO
WIPO (PCT)
Prior art keywords
tetrahydroisoquinoline
dialkyl
pharmaceutically acceptable
formula
acceptable salt
Prior art date
Application number
PCT/JP1997/001062
Other languages
French (fr)
Other versions
WO1997036588A3 (en
Inventor
Masaaki Hirobe
Shigeru Ohta
Yoshikazu Masukawa
Original Assignee
Lederle (Japan), Ltd.
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Priority to AU21765/97A priority Critical patent/AU2176597A/en
Priority to JP9535125A priority patent/JP2000507569A/en
Publication of WO1997036588A2 publication Critical patent/WO1997036588A2/en
Publication of WO1997036588A3 publication Critical patent/WO1997036588A3/en

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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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to novel antipsy ⁇ chotics and, more particularly, to antipsychotics which are based on the antidopaminergic effect of 1,1-dialkyl- 1,2,3,4-tetrahydroisoquinolines or pharmaceutically acceptable salts thereof, and also to analgesics.
  • Antipsychotic agents are used in psychiatric practice for the treatment of schizophrenia, atypical psychosis, mania, toxic psychosis, and psychosis due to organic disorders. Since antipsychotics have a specific efficacy against hallucinations, delusions, and psychomotor excitation, clinicians have recently reviewed their appraisal of the therapeutic role of these agents. Conventional antipsychotics have included phenothiazine, butyrophenone, thioxanthene, and benzamide derivatives, which are thought to act by blocking dopamine D 2 recep ⁇ tors. Antipsychotics are also referred to as neuroleptics because of their potent effects on both neurological and mental functions.
  • the present inventors have actively examined many compounds for their therapeutic potential in various fields and noted 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 available clinically.
  • the present inventors have found that 1,1-dialkyl- 1, 2, 3, 4-tetrahydroisoquinolines having a simple chemical structure, as well as pharmaceutically acceptable salts thereof, which have not previously been studied for pharmacological activity in detail, exert a potent anti- psychotic effect by blocking dopamine D 2 receptors, i.e., through antidopaminergic activity.
  • the inventors have also found that these compounds have a potent analgesic effect without causing any morphine-like dependence as commonly occurs with narcotics.
  • the present inven ⁇ tion provides antipsychotics which act through the antidopaminergic effect of 1 , 1-dialkyl-l, 2, 3, 4-tetrahydro- isoquinolines or pharmaceutically acceptable salts thereof, as well as analgesics.
  • one aspect of the present invention is to provide antipsychotics which contain as the active ingredient 1,1-dialkyl-l,2,3,4-tetrahydroisoquinolines represented by the following formula (I):
  • R 1 and R 2 are, independently each other, lower alkyl groups, or pharmaceutically acceptable salts thereof.
  • the present invention provides antipsychotics which contain as the active ingredient 1, 1-dialkyl-l,2,3,4-tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts there ⁇ of, and which act through the antidopaminergic effect (more specifically, the dopamine D 2 receptor-blocking effect) of these compounds.
  • Another aspect of the present invention is to provide analgesics which contain 1, 1-dialkyl-l,2,3,4- tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts therof, as the active ingredient.
  • Further aspect of the present invention is to provide drugs with the above-mentioned pharmacological effects, i.e., drugs which comprise 1, 1-dialkyl-l,2, 3,4- tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts thereof and, more specifically, drugs for treating schizophrenia which comprise 1, 1-dialkyl-l,2,3,4- tetrahydr ⁇ isoquinolines of formula (I) or pharmaceutically acceptable salts thereof.
  • Figure 1 shows the changes in body weight of individual mice used in Pharmacological Test 3.
  • drug(s) means drug(s) and quasi-drug(s) as defined in the Pharmaceutical Affairs Law which are intended for use in the treatment of diseases in humans.
  • lower means that the number of the carbon atom in a group or a compound to which this term is attached ranges from 1 to 7, preferably from 1 to 4. Therefore, the term “lower alkyl”, which is the definition of the R 1 or R 2 in formula (I) stands for a straight- chained or branched-chain alkyl group having 1 to 7 carbon atoms and may include, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n- hexyl, isohexyl, n-heptyl, isoheptyl and the like. Among them, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl are especial- ly preferable.
  • 1, 1-dialkyl-l, 2, 3, 4-tetra- hydroisoquinolines of formula (I) are the following: 1, 1-Dimethyl-l, 2,3, 4-tetrahydroisoquinoline; 1, 1-Diethyl-1,2,3, 4-tetrahydroisoquinoline; 1, 1-Dipropyl-l, 2,3, 4-tetrahydroisoquinoline;
  • the final product obtained according to the pro- cedure may contain an asymmetric carbon atom at the 1- position. Therefore, 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.
  • active compounds (I) exert an antipsychotic effect, more specifically, an antischizophrenic effect, through their antidopaminergic effect (more particularly, their dopamine D 2 receptor- blocking effect).
  • Antipsychotics are generally thought to act pri ⁇ marily through blocking dopamine receptors present in the frontal lobe, mesolimbic system, corpus striaum, and hypo- thalamus. Since schizophrenic patients show a remarkable increase of cerebral dopamine D 2 receptors and enhanced cerebral dopamine turnover, excessive dopaminergic activity has been implicated in the development of some symptoms of this psychosis. Based on these findings, many dopamine D 2 receptor-blocking agents have been assessed for their therapeutic potential. Among them, butyrophenone derivatives such as haloperidol, benzamide derivatives such as sulpride, dibenzoxazepine derivatives such as clozapine, and other agents have now become available clinically.
  • the active compounds (I) exert a dopamine D 2 re ⁇ ceptor-blocking effect without causing any of the side effects (e.g., catalepsy) produced by haloperidol and sulpiride, and show much less toxicity.
  • side effects e.g., catalepsy
  • 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquinoline hydrochloride is as effective as haloperidol, the most effective antipsychotic currently available, while it has no such side effects as the induction of catalepsy. Thus, this compound has been found to have a very wide safety margin.
  • the present invention provides antipsychotics containing as the active ingredient 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquinolines or pharmaceutically acceptable salts thereof, which act through the dopamine D 2 receptor-blocking activity of these compounds, as well as drugs especially for treating schizophrenia which act through said activity.
  • the active compounds (I) have also been found to have a potent analgesic effect in addition to dopamine D 2 receptor-blocking activity.
  • the active compounds (I) When tested using Haffner's method, the active compounds (I) exhibited an analgesic effect more potent than that of aminopyrine and about three times less potent than that of morphine, the most potent analgesic.
  • the compounds caused no addiction such as caused by morphine, i.e., there was no morphine-like dependence potential.
  • the compounds had no adverse gastrointestinal effects such as an ulcerogenic effect. Because of its potent analgesic effect, morphine is used for the relief of severe cancer pain, but its clinical use is more or less limited by its addictive potential.
  • the active com ⁇ pounds (I) may be used as morphine substitutes for achieving analgesia.
  • 1, 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride exhibited the most potent analgesic effect.
  • the present invention provides analgesics which contain as the active ingredient 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquino- lines of formula (I) or pharmaceutically acceptable salts thereof.
  • 1, 1-Dialkyl-l, 2,3, 4-tetrahydroisoquinolines of formula (I) may be used in the form of free base or in the form of pharmaceutically acceptable salts thereof for the purposes of the present invention.
  • the compounds of formula (I) may be converted to such salts with organic or inorganic acids.
  • salts thus produced, most desirable 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.
  • 1, 1-Dialkyl-l, 2,3, 4-tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts thereof may be administered orally or parenterally to human being in the form of a pharmaceutically acceptable composition containing an effective amount thereof.
  • the dose to be administered may vary in a wide range according to the age, weight and condition of patients, physicians' diag ⁇ noses and so on; however, 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 dose for parenteral route is within the range of 0.0005 - 100 mg/kg, preferably 0.002 - 50 mg/kg and more preferably 0.005 - 30 mg/kg.
  • These compounds may be prepared as various oral formulations, including tablets, capsules, powders, troches, and liquid preparations. These formulations may be formed by procedures known per se to those skilled in the art in the field of pharmaceutical formulations. 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.
  • 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
  • the compounds may also be administered in the form of injectable formulations for parenteral route.
  • injectable formulations may include, for example, injectable solutions 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, they 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, and any other necessary inactive substances.
  • the injectable formula- tions may be administered intravenously, intra-arterially, subcutaneously, intraperitoneally, or via other appro ⁇ priate route depending on the patient's pathophysiological state. Each dose may be administered as a bolus injection or by infusion over an appropriate time period.
  • 1, 1-Dialkyl-l, 2, 3, 4-tetrahydroisoquinolines of formula (I) and pharmaceutically accetable salts thereof have potent dopamine D 2 receptor-blocking activity and are effective as antipsychotics, especially for the treat ⁇ ment of schizophrenia.
  • These compounds also exert a potent analgesic effect without causing morphine-like addiction such as dependence or any other side effects, including an ulcero- genic effect. In this respect, these compounds may have a unique mechanism of action. Therefore, the present invention provides excellent antipsychotics and analgesics and is of a high therapeutic benefit.
  • 1, 1-Dimethyl-l, 2, 3, 4-tetrahydroisoquinoline hydro ⁇ chloride was used as the test compound.
  • the antipsychotic effect was assessed by comparison with haloperidol and sulpiride.
  • mice Following a single subcutaneous dose of each com ⁇ pound, the individual mice were allowed to hang from a horizontal wire by their forelimbs and were observed for catalepsy (defined as immobility for at least 30 seconds) for up to 5 hours. For each compound, the minimum dose which induced catalepsy was determined. Groups of 3 mice were used in this experiment.
  • Table 1-2 shows the following safety parameters calculated for each compound:
  • the minimum effective (antipsychotic) dose of the test compound was lower than that of sulpiride and comparable to that of haloperidol, which has the most potent dopamine D 2 receptor-blocking activity among the antipsychotics currently available.
  • test compound did not induce catalepsy, a typical undesirable side effect of antipsychotics, even at doses as high as 100 mg/kg and its minimum lethal dose was also above 100 mg/kg. These values were much higher than the corresponding values for haloperidol and sulpiride. Thus, as shown in Table 1-2), the test compound was found to have a very wide safety margin (as indicated by ratio A: minimum cataleptogenic dose relative to minimum effective dose and ratio B: minimum lethal dose relative to minimum effective dose) . These results indicate that 1, 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride has a potent dopamine D 2 receptor-blocking activity and an excellent safety profile.
  • Pharmacological Test 2 Analgesic effect and ulcerogenic potential Methods:
  • 1, 1-dimethyl-l, 2,3, 4-tetrahydroisoqinoline hydro ⁇ chloride was used as the test compound. It was tested at doses of 30 and 100 mg/kg.
  • morphine hydrochloride (30 mg/kg), indomethacin (100 mg/ kg), and aminopyrine (100 mg/kg) were used.
  • mice which appeared to have a normal pain sensa ⁇ tion were treated with a subcutaneous dose of the test compound or the control compounds.
  • the animals were tested at various time intervals for 5 hours after administration to assess the degree of analgesia using the Haffner's method (tail pinching).
  • Mice receiving the vehicle alone served as negative controls.
  • the mice were sacrificed. Their stomachs were removed and observed for ulcers under a stereomicroscope.
  • mice were used to assess the test compound, morphine hydrochloride and indomethacin, while 2 mice were given aminopyrine. Results:
  • the analgesic effect of 1 , 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride was less potent than that of morphine, but more potent than that of indomethacin or aminopyrine.
  • the test com ⁇ pound showed no ulcerogenic potential, while gastric ulcers were detected in mice treated with indomethacin or aminopyrine and mild gastric mucosal bleeding was also noted in both of the 2 mice given aminopyrine.
  • mice were subcutaneously given the test compound or morphine hydrochloride at escalating daily doses of 10, 20, 40, 60, 80, and 100 mg/kg (b.i.d.) for the first 6 days followed by a maintenance dose of 100 mg/kg for an additional 3 days. On each of these 9 treatment days, the doses were given at 9:00 and 18:00. Then, an additional dose of 100 mg/kg was administered subcutaneously at 9:00 on day 10. At 2 hours after the last dose, each mouse was given a subcutaneous dose of 3 mg/kg of naloxone and then observed for 60 minutes for the naloxone-induced with ⁇ drawal signs. Each mouse was also weighed serially after administration of naloxone and changes in body weight were calculated.
  • mice Groups of 9 mice were used for the two active treatments and the negative control group consisted of 20 mice. Results:
  • mice showed various signs of withdrawal, including diarrhea, ptosis, jumping, body shaking, and writhing behaviors. No such signs were induced by naloxone in the mice previously given increasing doses of 1, 1-dimethyl-l,2,3,4-tetrahydro- isoquinoline hydrochloride.
  • mice treated with morphine also showed significant weight loss, while the mice treated with the test compound had a body weight similar to that of the negative control mice (Fig. 1).
  • the above components (other than magnesium stearate) were mixed, sieved and granulated using a stan ⁇ dard 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 punched into tablets each weighing 150 mg.

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Abstract

Antipsychotics and analgesics containing 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines represented by formula (I) wherein R?1 and R2¿ are, independently each other, lower alkyl groups, or pharmaceutically acceptable salts thereof, which exert a potent antipsychotic effect by blocking dopamine D¿2? receptors and also a potent analgesic effect without causing any morphine-like dependence.

Description

DESCRIPTION
USE OF 1.1 -DIALKYL- 1.2.3.4-TETRAHYDROISOQUINOLINES FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF PSYCHOSIS AND PAIN
TECHNICAL FIELD
The present invention relates to novel antipsy¬ chotics and, more particularly, to antipsychotics which are based on the antidopaminergic effect of 1,1-dialkyl- 1,2,3,4-tetrahydroisoquinolines or pharmaceutically acceptable salts thereof, and also to analgesics.
BACKGROUND ART
Recent marked changes in the socioeconomic environment have altered the profile of diseases which pose a serious challenge to physicians. In particular, the dynamically changing social and economic environment increases mental stress and thus the prevalence of psy- chogenic diseases, including mania, depression, and schizophrenia, in the modern world.
Antipsychotic agents (antipsychotics) are used in psychiatric practice for the treatment of schizophrenia, atypical psychosis, mania, toxic psychosis, and psychosis due to organic disorders. Since antipsychotics have a specific efficacy against hallucinations, delusions, and psychomotor excitation, clinicians have recently reviewed their appraisal of the therapeutic role of these agents. Conventional antipsychotics have included phenothiazine, butyrophenone, thioxanthene, and benzamide derivatives, which are thought to act by blocking dopamine D2 recep¬ tors. Antipsychotics are also referred to as neuroleptics because of their potent effects on both neurological and mental functions. Their potent sedative effect has also endowed them with another name, which is "major tranquil- izers" . Many antipsychotics have now become available, while the recent attention paid to complicated psychoses due to extrinsic factors typical of the modern world has urged the active development of more effective antipsycho¬ tics. New agents which can be used to treat the above¬ mentioned psychoses need to have a higher efficacy while causing fewer adverse reactions compared with conventional antipsychotics.
DISCLOSURE OF THE INVENTION
The present inventors have actively examined many compounds for their therapeutic potential in various fields and noted 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 available clinically.
The present inventors have found that 1,1-dialkyl- 1, 2, 3, 4-tetrahydroisoquinolines having a simple chemical structure, as well as pharmaceutically acceptable salts thereof, which have not previously been studied for pharmacological activity in detail, exert a potent anti- psychotic effect by blocking dopamine D2 receptors, i.e., through antidopaminergic activity. The inventors have also found that these compounds have a potent analgesic effect without causing any morphine-like dependence as commonly occurs with narcotics. Thus, the present inven¬ tion provides antipsychotics which act through the antidopaminergic effect of 1 , 1-dialkyl-l, 2, 3, 4-tetrahydro- isoquinolines or pharmaceutically acceptable salts thereof, as well as analgesics. Accordingly, one aspect of the present invention is to provide antipsychotics which contain as the active ingredient 1,1-dialkyl-l,2,3,4-tetrahydroisoquinolines represented by the following formula (I):
Figure imgf000005_0001
wherein R1 and R2 are, independently each other, lower alkyl groups, or pharmaceutically acceptable salts thereof.
Some of the compounds of formula (I) have already been known, but have never been found to have dopamine D2 receptor-blocking activity.
Therefore, in more detail, the present invention provides antipsychotics which contain as the active ingredient 1, 1-dialkyl-l,2,3,4-tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts there¬ of, and which act through the antidopaminergic effect (more specifically, the dopamine D2 receptor-blocking effect) of these compounds.
Another aspect of the present invention is to provide analgesics which contain 1, 1-dialkyl-l,2,3,4- tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts therof, as the active ingredient.
Further aspect of the present invention is to provide drugs with the above-mentioned pharmacological effects, i.e., drugs which comprise 1, 1-dialkyl-l,2, 3,4- tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts thereof and, more specifically, drugs for treating schizophrenia which comprise 1, 1-dialkyl-l,2,3,4- tetrahydrσisoquinolines of formula (I) or pharmaceutically acceptable salts thereof.
BRIEF DESCRIPTION OF DRAWING
Figure 1 shows the changes in body weight of individual mice used in Pharmacological Test 3.
BEST MODE FOR CARRYING OUT THE INVENTION
The term "drug(s)" referred to in the present specification and claims means drug(s) and quasi-drug(s) as defined in the Pharmaceutical Affairs Law which are intended for use in the treatment of diseases in humans.
The term "lower" means that the number of the carbon atom in a group or a compound to which this term is attached ranges from 1 to 7, preferably from 1 to 4. Therefore, the term "lower alkyl", which is the definition of the R1 or R2 in formula (I) stands for a straight- chained or branched-chain alkyl group having 1 to 7 carbon atoms and may include, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n- hexyl, isohexyl, n-heptyl, isoheptyl and the like. Among them, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl are especial- ly preferable.
Typical examples of 1, 1-dialkyl-l, 2, 3, 4-tetra- hydroisoquinolines of formula (I) are the following: 1, 1-Dimethyl-l, 2,3, 4-tetrahydroisoquinoline; 1, 1-Diethyl-1,2,3, 4-tetrahydroisoquinoline; 1, 1-Dipropyl-l, 2,3, 4-tetrahydroisoquinoline;
1, 1-Diisopropyl-1, 2,3, 4-tetrahydroisoquinoline; 1, 1-Dibutyl-l, 2,3, 4-tetrahydroisoquinoline; 1, 1-Di-tert-butyl-1, 2,3, 4-tetrahydroisoquinoline; 1-Methyl-l-ethyl-l ,2,3, 4-tetrahydroisoquinoline; 1-Methyl-1-propyl-l,2,3,4- etrahydroisoquinoline; 1-Methy1-1-isopropyl-1,2,3,4-tetrahydroisoquinoline; l-Methyl-l-butyl-1,2, 3,4-tetrahydroisoquinoline; 1-Methyl-1-sec-butyl-1,2,3,4-tetrahydroisoquinoline; 1-Methyl-l-tert-butyl-l,2,3,4-tetrahydroisoquinoline; 1-Ethyl-l-proρyl-l,2,3,4-tetrahydroisoquinoline; 1-Ethyl-l-isoρropyl-l,2,3,4-tetrahydroisoquinoline; 1-Ethyl-1-butyl-1,2,3,4-tetrahydroisoquinoline; 1-Ethyl-l-sec-butyl-l,2,3,4-tetrahydroisoquinoline; 1-Ethyl-l-tert-butyl-l,2,3,4-tetrahydroisoquinoline; 1-Butyl-l-proρyl-l,2,3,4-tetrahydroisoquinoline; 1-Butyl-1-isopropyl-1,2,3,4-tetrahydroisoquinoline.
Some of the 1, 1-dialkyl-l,2, 3,4-tetrahydroiso- quinolines of formula (I) listed above are known compounds and may be produced in high yield according to the proce¬ dure described by H. E. Lape et al. in J. Med. Chem., 16(2), 151-156 (1973) (See Examples mentioned later).
The final product obtained according to the pro- cedure may contain an asymmetric carbon atom at the 1- position. Therefore, 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.
1, 1-Dialkyl-l,2,3,4-tetrahydroisoquinolines of formula (I) and pharmaceutically acceptable salts thereof, hereinafter also referred to as "active compounds (I)", exert an antipsychotic effect, more specifically, an antischizophrenic effect, through their antidopaminergic effect (more particularly, their dopamine D2 receptor- blocking effect).
Antipsychotics are generally thought to act pri¬ marily through blocking dopamine receptors present in the frontal lobe, mesolimbic system, corpus striaum, and hypo- thalamus. Since schizophrenic patients show a remarkable increase of cerebral dopamine D2 receptors and enhanced cerebral dopamine turnover, excessive dopaminergic activity has been implicated in the development of some symptoms of this psychosis. Based on these findings, many dopamine D2 receptor-blocking agents have been assessed for their therapeutic potential. Among them, butyrophenone derivatives such as haloperidol, benzamide derivatives such as sulpride, dibenzoxazepine derivatives such as clozapine, and other agents have now become available clinically.
The active compounds (I) exert a dopamine D2 re¬ ceptor-blocking effect without causing any of the side effects (e.g., catalepsy) produced by haloperidol and sulpiride, and show much less toxicity. Among the active compounds (I), 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquinoline hydrochloride is as effective as haloperidol, the most effective antipsychotic currently available, while it has no such side effects as the induction of catalepsy. Thus, this compound has been found to have a very wide safety margin.
Therefore, in a preferred embodiment the present invention provides antipsychotics containing as the active ingredient 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquinolines or pharmaceutically acceptable salts thereof, which act through the dopamine D2 receptor-blocking activity of these compounds, as well as drugs especially for treating schizophrenia which act through said activity.
The active compounds (I) have also been found to have a potent analgesic effect in addition to dopamine D2 receptor-blocking activity. When tested using Haffner's method, the active compounds (I) exhibited an analgesic effect more potent than that of aminopyrine and about three times less potent than that of morphine, the most potent analgesic. On the other hand, the compounds caused no addiction such as caused by morphine, i.e., there was no morphine-like dependence potential. Furthermore, the compounds had no adverse gastrointestinal effects such as an ulcerogenic effect. Because of its potent analgesic effect, morphine is used for the relief of severe cancer pain, but its clinical use is more or less limited by its addictive potential. In this respect, the active com¬ pounds (I) may be used as morphine substitutes for achieving analgesia. Among them, 1, 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride exhibited the most potent analgesic effect.
Therefore, in another preferred embodiment the present invention provides analgesics which contain as the active ingredient 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquino- lines of formula (I) or pharmaceutically acceptable salts thereof.
These compounds exhibit very low toxicity. For example, 1, 1-dimethyl-l,2, 3, 4-tetrahydroisoquinoline hy- drochloride caused no deaths in mice during the 3 days following a single subcutaneous dose of 100 mg/kg.
1, 1-Dialkyl-l, 2,3, 4-tetrahydroisoquinolines of formula (I) may be used in the form of free base or in the form of pharmaceutically acceptable salts thereof for the purposes of the present invention. The compounds of formula (I) may be converted to such salts with organic or inorganic acids. Suitable organic acids may include, for example, aliphatic acid such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, trichloroacetic acid and the like; organic acid 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)alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid and the like; substituted or unsubstituted arylsulfonic acid such as benzenesulfonic acid, p-nitrobenzensulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2, 4, 6-triisopropylbenzene- sulfonic acid and the like; and organic phosphinic acid such as diphenylphosphinic acid. Suitable inorganic acids may include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodinic acid, hydroborofluo- ric acid, perchloric acid, nitric acid and the like.
Among the salts thus produced, most desirable 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.
1, 1-Dialkyl-l, 2,3, 4-tetrahydroisoquinolines of formula (I) or pharmaceutically acceptable salts thereof may be administered orally or parenterally to human being in the form of a pharmaceutically acceptable composition containing an effective amount thereof. The dose to be administered may vary in a wide range according to the age, weight and condition of patients, physicians' diag¬ noses and so on; however, 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 dose for parenteral route is within the range of 0.0005 - 100 mg/kg, preferably 0.002 - 50 mg/kg and more preferably 0.005 - 30 mg/kg. These compounds may be prepared as various oral formulations, including tablets, capsules, powders, troches, and liquid preparations. These formulations may be formed by procedures known per se to those skilled in the art in the field of pharmaceutical formulations. 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 compounds may also be administered in the form of injectable formulations for parenteral route. Such formulations may include, for example, injectable solutions 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, they 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, and any other necessary inactive substances. The injectable formula- tions may be administered intravenously, intra-arterially, subcutaneously, intraperitoneally, or via other appro¬ priate route depending on the patient's pathophysiological state. Each dose may be administered as a bolus injection or by infusion over an appropriate time period. 1, 1-Dialkyl-l, 2, 3, 4-tetrahydroisoquinolines of formula (I) and pharmaceutically accetable salts thereof have potent dopamine D2 receptor-blocking activity and are effective as antipsychotics, especially for the treat¬ ment of schizophrenia. These compounds also exert a potent analgesic effect without causing morphine-like addiction such as dependence or any other side effects, including an ulcero- genic effect. In this respect, these compounds may have a unique mechanism of action. Therefore, the present invention provides excellent antipsychotics and analgesics and is of a high therapeutic benefit.
The following Examples and Pharmacological Tests are given for the purpose of illustrating this invention in more detail.
Example 1; Production of 1, 1-Dimethyl-l, 2, 3, 4-tetrahydro- isoquinoline
9.6 g (66.2 mmol) of l-methyl-3, 4-dihydroiso- quinoline produced according to the procedure described in J. Med. Chem., 16(2), 151-156 was dissolved in 40 ml of acetonitrile, then 12.4 g (72.6 mmol) of benzylbromide was added, and the reaction mixture was refluxed for 3 hours. When the reaction was over, ethyl ether was added and the resulting precipitate was collected to give 19.1 g (91%) of l-methγl-2-benzyl-3,4-dihydroisoquinolinium bromide.
Then, to a mixture solution of 17 g (53.8 mmol) of the compound obtained above in 100 ml of dry tetrahydro- furan, 71.7 ml of methylmagnesium bromide solution (3M solution) was added dropwise. The reaction mixture was refluxed for 3 hours. After the reaction, the mixture was added to IM ammonium chloride solution and the solvent was removed under reduced pressure. The resulting residue was extracted with ether and dried over magnesium sulfate. The solvent waε removed to give 13 g of 1, l-dimethyl-2- benzyl-1, 2, 3, 4-tetrahydroisoquinoline in oil form.
To a mixture solution of 3.6 g of the 1,1-di- methyl-2-benzyl-l, 2,3, 4-tetrahydroisoquinoline obtained above in 60 ml of acetic acid, 10% palladium-carbon (3.6 g) was added and catalytic hydrogenation was carried out at a room temperature under 1.0 atmosphere. After the theoretical amount of hydrogen gas was absorbed, the catalyst was removed and a 10% sodium hydroxide aqueous solution was added to the filtrate in order to change the pH to basic side. Then, the solution was extracted with ethyl acetate and the organic layer was re-extracted with a 10% hydrogen chloride aqueous solution. The aqueous solution was removed under reduced pressure and the re¬ sulting residue was treated with ether to give 4.0 g of 1 , 1-dimethy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride in the form of colorless crystals.
1 H-NMR (CD3OD)δ : 1.74 (6H, s), 3.14 (2H, t, J=6.4Hz), 3.53 (2H, t, J=6.4Hz), 7.1-7.5 (4H, m) .
Example 2 : Production of 1-Methyl-l-ethyl-l, 2, 3, 4-tetra- hydroisoquinoline
1-Methyl-l-ethyl-l, 2,3, 4-tetrahydroisoquinoline hydrochloride in colorless crystals was obtained according to the process of Example 1 by using the above-obtained 1- methyl-2-benzyl-3,4-dihydroisoquinolinium bromide, and ethylmagnesium bromide instead of methylmagnesium bromide.
'H-NMR (CD3OD)δ : 1.00 (3H, t, J=7.6Hz), 1.74 (3H, s), 2.11 (2H, q, J=7.6Hz), 3.0-3.3 (2H, ) , 3.3-3.7 (2H, m) ,
7.1-7.4 (4H, m).
Other 1, 1-dialkyl-l,2,3, -tetrahydroisoquinolines of formula (I) listed before were also obtained according to the procedures of Examples 1 and 2.
Pharmacological Test 1: Antipsychotic effect
1, 1-Dimethyl-l, 2, 3, 4-tetrahydroisoquinoline hydro¬ chloride was used as the test compound. The antipsychotic effect was assessed by comparison with haloperidol and sulpiride.
1) Antagonism of apomorphine (estimation of the minimum effective antipsychotic dose) Methods: Each mouse was placed in a test cage at 20 minutes after a single subcutaneous dose of apomorphine (3 mg/kg). The climbing behavior was observed for 3 minutes to deter¬ mine the cumulative duration of this behavior. The test and control compounds were administered by subcutaneous injection 30 minutes prior to administra¬ tion of apomorphine. For each compound, the dose which reduced the climbing duration by 50% relative to that in mice treated with apomorphine alone was taken as the minimum effective dose. Groups of 3 mice were used in this experiment.
2) Induction of catalepsy (estimation of the minimum dose inducing catalepsy)
Methods: Following a single subcutaneous dose of each com¬ pound, the individual mice were allowed to hang from a horizontal wire by their forelimbs and were observed for catalepsy (defined as immobility for at least 30 seconds) for up to 5 hours. For each compound, the minimum dose which induced catalepsy was determined. Groups of 3 mice were used in this experiment.
3) Lethality (estimation of the minimal lethal dose) Methods:
Following a single subcutaneous dose of each compound, the individual mice were observed for death for 3 consecutive days. For each compound, the minimum lethal dose was estimated. Groups of 3 mice were used in this experiment. Results: The results of the above three pharmacological tests are summarized in Table 1-1).
Table 1-2) shows the following safety parameters calculated for each compound:
A: Minimum dose inducing catalepsy / Minimum dose antagonizing apomorphine (minimum effective anti¬ psychotic dose) B: Minimum lethal dose / Minimum effective antipsy¬ chotic dose
Table 1-1)
Efficacy Side effect Toxicity Compound MED(mg/kg, sc) MCD(mg/kg, sc) MLD(mg/kg, sc)
Test compound 0 .1 >100 >100
Haloperidol 0 .1 0.03 60
Sulpiride 30 30 290
MED: Minimum Effective Dose
MCD: Minimum Cataleptogenic Dose
MLD: Minimum Lethal Dose
Table 1-2)
Safety margin
Compound A=MCD/MED B=MLD/MED
Test compound >1000 >1000
Haloperidol 0.3 600
Sulpiride 1 9.7
As shown in Table 1-1), the minimum effective (antipsychotic) dose of the test compound was lower than that of sulpiride and comparable to that of haloperidol, which has the most potent dopamine D2 receptor-blocking activity among the antipsychotics currently available.
On the other hand, the test compound did not induce catalepsy, a typical undesirable side effect of antipsychotics, even at doses as high as 100 mg/kg and its minimum lethal dose was also above 100 mg/kg. These values were much higher than the corresponding values for haloperidol and sulpiride. Thus, as shown in Table 1-2), the test compound was found to have a very wide safety margin (as indicated by ratio A: minimum cataleptogenic dose relative to minimum effective dose and ratio B: minimum lethal dose relative to minimum effective dose) . These results indicate that 1, 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride has a potent dopamine D2 receptor-blocking activity and an excellent safety profile.
Pharmacological Test 2: Analgesic effect and ulcerogenic potential Methods:
1, 1-dimethyl-l, 2,3, 4-tetrahydroisoqinoline hydro¬ chloride was used as the test compound. It was tested at doses of 30 and 100 mg/kg. For positive controls, morphine hydrochloride (30 mg/kg), indomethacin (100 mg/ kg), and aminopyrine (100 mg/kg) were used.
Mice which appeared to have a normal pain sensa¬ tion were treated with a subcutaneous dose of the test compound or the control compounds. The animals were tested at various time intervals for 5 hours after administration to assess the degree of analgesia using the Haffner's method (tail pinching). Mice receiving the vehicle alone served as negative controls. After completion of the experiment, the mice were sacrificed. Their stomachs were removed and observed for ulcers under a stereomicroscope.
Groups of 3 mice were used to assess the test compound, morphine hydrochloride and indomethacin, while 2 mice were given aminopyrine. Results:
The results are shown in Table 2
Table 2
Dose No.of Analgesic Ulcerogenic (mg/kg, sc) Animals Effect Effect
Negative control 0/3 0/3
Test com¬ 30 3 0/3 0/3 pound 100 3 2/3 0/3
Morphine- HCl 30 3 3/3 0/3
Indomethacin 100 3 0/3 2/3
Aminopyrine 100 2 0/2 2/2
The analgesic effect of 1 , 1-dimethyl-l, 2, 3, 4- tetrahydroisoquinoline hydrochloride was less potent than that of morphine, but more potent than that of indomethacin or aminopyrine. In addition, the test com¬ pound showed no ulcerogenic potential, while gastric ulcers were detected in mice treated with indomethacin or aminopyrine and mild gastric mucosal bleeding was also noted in both of the 2 mice given aminopyrine.
Pharmacological Test 3: Addictive potential Methods:
1 , 1-Dime hyl-1,2,3, 4-tetrahydroisoquinoline hydro- chloride was used as the test compound and morphine hydro¬ chloride was used as the positive control.
Mice were subcutaneously given the test compound or morphine hydrochloride at escalating daily doses of 10, 20, 40, 60, 80, and 100 mg/kg (b.i.d.) for the first 6 days followed by a maintenance dose of 100 mg/kg for an additional 3 days. On each of these 9 treatment days, the doses were given at 9:00 and 18:00. Then, an additional dose of 100 mg/kg was administered subcutaneously at 9:00 on day 10. At 2 hours after the last dose, each mouse was given a subcutaneous dose of 3 mg/kg of naloxone and then observed for 60 minutes for the naloxone-induced with¬ drawal signs. Each mouse was also weighed serially after administration of naloxone and changes in body weight were calculated.
Untreated mice served as negative controls.
Groups of 9 mice were used for the two active treatments and the negative control group consisted of 20 mice. Results:
The results are shown in Table 3.
Table 3
Withdrawal Negative Test signs control compound Morphine- HCl
Diarrhea 0/20 0/9 9/9
Ptosis 1/20 0/9 5/9
Jumping 0/20 0/9 2/9
Body shaking 0/20 0/9 1/9
Writhing 0/20 0/9 1/9
more than 2 signs or severe diarrhea 0/20 0/9 9/9
As shown in the table, the morphine-treated mice showed various signs of withdrawal, including diarrhea, ptosis, jumping, body shaking, and writhing behaviors. No such signs were induced by naloxone in the mice previously given increasing doses of 1, 1-dimethyl-l,2,3,4-tetrahydro- isoquinoline hydrochloride.
The mice treated with morphine also showed significant weight loss, while the mice treated with the test compound had a body weight similar to that of the negative control mice (Fig. 1).
These results suggest that 1, 1-dimethyl-l,2,3, 4- tetrahydroisoquinoline hydrochloride has no morphine-like dependence potential.
The results of these pharmacological studies indicate that the compounds of formula (I) or pharmaceu¬ tically acceptable salts thereof have dopamine D2 receptor blocking activity and a therapeutic potential as antipsy¬ chotics. They also have a potent analgesic effect without causing morphine-like dependence or gastrointestinal damage.
The following are typical and non-limiting for- mulation examples which can be used for the purposes of the present invention.
Formulation Example 1 (Tablet):
1, 1-Dimethyl-l, 2,3, 4-tetrahydro- isoquinoline hydrochloride 30 g
Lactose 105 g
Microcrystalline cellulose 20 g
Corn starch 20 g
5% aqueous solution of hydroxypropylcellulose 100 ml
Magnesium stearate 2 g
The above components (other than magnesium stearate) were mixed, sieved and granulated using a stan¬ dard 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 punched into tablets each weighing 150 mg.
Formulation Example 2 (Capsule): 1, 1-Dimethyl-l, 2, 3,4-tetrahydro- isoquinoline hydrochloride 30 g
Lactose 105 g
Corn starch 48 g
Magnesium stearate 2 g All the above components were pulverized and mixed well to make a homogenous mixture, and filled in conven¬ tional hard gelatin capsules. Each capsule was filled with 0.15 g of the mixture.

Claims

1. An antipsychotic containing as the active ingredient a 1, 1-dialkyl-l, 2, 3, 4-tetrahydroisoquinoline represented by the following formula (I):
Figure imgf000021_0001
wherein R1 and R2 are, independently each other, lower alkyl groups, or pharmaceutically acceptable salt thereof.
2. An antipsychotic containing as the active ingre¬ dient the 1, 1-dialkyl-l, 2, 3,4-tetrahydroisoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof, which acts through the anti- dopaminergic activity of the compound.
3. An analgesic containing as the active ingredient the 1, 1-dialkyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof.
4. A drug comprising the 1, 1-dialkyl-l, 2, 3, 4-tetra- hydroisoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof.
5. A drug for treating schizophrenia comprising the 1, 1-dialkyl-l, 2, 3, 4-tetrahydroisoquinoline of formula (I) set forth in Claim 1 or pharmaceutically acceptable salt thereof.
6. A drug comprising 1, 1-dimethyl-l, 2, 3, 4-tetrahydro- isoquinoline or pharmaceutically acceptable salt thereof.
7. An antipsychotic containing as the active ingre- dient 1, 1-dimethyl-l, 2,3,4-tetrahydroisoquinoline or pharmaceutically acceptable salt thereof.
8. An antipsychotic containing as the active ingre¬ dient 1, 1-dimethyl-l, 2, 3, 4-tetrahydroisoquinoline or pharmaceutically acceptable salt thereof, which acts through the antidopaminergic activity of the compound.
9. An analgesic containing as the active ingredient 1 , 1-dimethyl-l , 2, 3, 4-tetrahydroisoquinoline or pharmaceu- tically acceptable salt thereof.
PCT/JP1997/001062 1996-03-29 1997-03-28 Use of 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines for the manufacture of a medicament for the treatment of psychosis and pain WO1997036588A2 (en)

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JP9535125A JP2000507569A (en) 1996-03-29 1997-03-28 Use of 1,1-dialkyl-1,2,3,4-tetrahydroisoquinoline for producing antipsychotics and analgesics

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