WO1986000017A1

WO1986000017A1 - Psychotropic drugs and method for treating psychosis

Info

Publication number: WO1986000017A1
Application number: PCT/JP1985/000325
Authority: WO
Inventors: Kazutoshi Horikomi; Masanori Fujita; Akira Awaya; Takuo Nakano; Yoshiaki Furuya; Hiroyasu Ohno; Keiichi Yokoyama
Original assignee: Mitsui Petrochemical Industries, Ltd.; Mitsui Pharmaceuticals, Inc.
Priority date: 1984-06-08
Filing date: 1985-06-08
Publication date: 1986-01-03
Also published as: JPS60260516A; JPH0542409B2

Abstract

Use of compounds represented by general formula (I), wherein R1 representes hydrogen, formyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, or pharmacologically acceptable salts thereof as psychotropic drugs. They show excellent effects as, for example, anti-depressives with less side effects and low toxicity.

Description

Specification

Psychotropic drugs and psychosis treatment methods

Technical field

The present invention relates to a new medicinal use of a 2- (1-piperazinyl) -cycloheptomidazole derivative known as an antihypertensive agent, and particularly useful for the treatment of mental illness in mammals including humans and a psychotropic drug. About the method. Background art

2- (1-H.perazinyl) -cycloimidazole derivatives, for example of the general formula N N -R

[Wherein, is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, phenyl (lower) alkyl, hydroxy (lower) alkyl, lower alkoxycarbol, honoleminore, 2-furanylcarpo'nole, 1-oquin (fi Alkoxy ^ / (lower) alkyl, aminoiminomethyl, hydridinothioxomethyl or sodium dithiothioxomethyl) or a pharmacologically acceptable salt thereof is disclosed in -Patent Publication No. 1,2,5,3,4 • 4 (corresponding to U.S. Patent No. 4,258,188) discloses its production method and usefulness as a therapeutic agent for hypertension, especially as an antihypertensive agent It has been done. In addition, Japanese Patent Publication No. 57-500561 discloses that a compound of the type (2) is used as a hypotensive agent. None of the above prior arts mentions any psychotropic drug use of the above compound or any finding that could suggest the use.

Conventionally, various compounds are known to have a psychotropic effect, but it is also completely unknown that the compounds of the above general formula include compounds capable of exhibiting such effects.

The present inventors have studied various compounds which exhibit psychotropic effects, particularly antidepressant activity, have low toxicity, and can be used in combination with other psychotropic drugs. -(1-H. Perazinyl)-Detected that certain compounds contained in cycloheptimidazole derivatives have psychotropic effects, and cultivated the use of the known compounds as new therapeutic agents. Things.

Disclosure of the invention

The present invention provides the following formula (I)

N, N-R _l (0

(In the formula,? I represents hydrogen, honolemyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, or isopropyloxycarbonyl.) A compound represented by _. Or a pharmacologically acceptable salt thereof as an active ingredient Related to psychotropic drugs.

The 2- (1-'d.perazinyl) -cycloheptoimidazole derivative described in the above-mentioned JP-A-56-125584 is extremely dependent on the type of the substituent R. In a wide variety! According to the studies by the present inventors, Ri in the formula (I) of the present invention corresponding to the substituent R represents a hydrogen atom, formyl, methoxycanoleboninole, ethoxycanolebonyl, propoxy. When the compound is a canoleboninole or an impoxycarbonyl group, the compound or a pharmacologically acceptable salt thereof has been found to have a psychotropic effect.

Some of the compounds in which is a hydrogen atom or a substituent are those disclosed in the above publication; and the physical properties thereof are as follows.

R! = 5 "Compound willow hydrochloride (): mp 280 ° C (decomposition) (methanol) R _{ = -COOCH ₃ compound kiss (B): p 1 ό 9-17-1 C. Getyl ether)

? i = -C r 0 ₅ compound 'Chinese (C): mp 144-14.5 ^u C (ethyl acetate

_{NMR (CDC 1 3) 5 1.3} (5ヽt

3.6 8 (4 m), 4.0 4 {H, κη) 4.2 (211,, and

7.9 (5 m)

Ri =-CEO CD): mp 170-173. C (Ethyl acetate-hexane mixed solvent)

COO iso-B ^ (E): p130 ~ 153 ° C (Ethyl acetate, fractionated by silica gel column chromatography using mixed solvent of methanol) R _l =-CE ₃ (F): mp 9 ό to ta 7. C (same as (^)) R, = -COH (G): j? 17ό-178 ° C (ethyl acetate) In the above-exemplified compounds, the compounds of M)-( ) Is a compound included in! ) And compounds (E) to (G) are specific compounds not included in the formula (I).

The melting point (p) is based on the MP-85 trace melting point analyzer manufactured by Yanagi Head Office. Physical properties other than those described above are substantially the same as those described in Japanese Patent Publication No. 56-125384. Examples of pharmacologically acceptable salts of the compound of the formula (I) include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, acid phosphate, and acetic acid. Salt, benzoate, maleate, fumarate, succinate, tartrate, lactate, citrate, dalconate, malate, saccharate, methanesulfonate, V-toluenesulfone Organic acid salts such as acid salts can be exemplified.

The compound represented by formula (I), which is an active ingredient of the psychotropic drug of the present invention, has a psychotropic effect, that is, an antipsychotic effect, particularly an antidepressant activity, and further has an anorectic activity in mammals including humans. And at least part of this activity is Norr ェ dani. It may result from the ability to enhance activity at either or both synapses of nephrin and / or serotonin.

The pharmacological effect of each compound of the present invention was measured in mice as shown in the following experimental examples. And tested antagonistically against apomorphine, reserpine, and tetrapenazine. In addition, the presence or absence of central anticholinergic effect, which is a major undesirable side effect of antidepressants, was examined using the drug's effect on tremor-induced tremor as an index. On the other hand, almost all of the compounds of the present invention have been found to have no effect, and are considered to be useful drugs for central nervous system in this regard.

Hereinafter, the pharmacological effect of the compound of the present invention as a psychotropic drug will be described in comparison with the comparative compounds (1) to (2) having similar chemical structures. In each experimental example, the term “drug” indicates a drug obtained by dissolving each compound of the present invention or the specific example in physiological saline or 0.5% carboxine methylcellulose saline (hereinafter abbreviated as CM), and is referred to as a solvent. In this case, it means physiological saline or CMC used as a control. In Experiment 2 and below, the operation was the same as in Experiment 1 unless otherwise specified.

Experimental Example 1 Antagonism of high-dose avomorphin-induced hypothermia

The hypothermia induced by high doses of morphine is specifically antagonized by a number of antidepressants. J. Peuch et al.-

(See Psycho-Pharmacolgy. 75, 84-91 ヽ 981). Five-week-old ddF male mice were used in groups of 5 or 10 mice. 30 minutes after intraperitoneal administration of the drug or solvent or 0 minutes after administration of the drug. Morphine 1 皮下 / was subcutaneously administered. 3 Q minutes after administration of amorphin, thermistor j. (Rectal temperature) was measured, and the inhibition rates,, and were calculated as compared with those of the control group, and the results were used as the efficacy. The results are shown in Table 1.

Table 1 High-dose avomorphin suppression of induced hypothermia

(Aho morphine 1 1 ^ ό «subcutaneous administration)

Dosage Intraperitoneal administration of drug

Drug

Suppression rate ED _zo {H

1 9 (1 0)

3 2 5 (1 0)

A 1 Θ 6 4 (1 0) 6.6

1 7

3 Q

B 1 0 4 3 (1 0)

1

5 ό (5)

C 1 0 5 5 (5) 1 0.0

1 7 5 8 (5)

5 0 1 0 0 (5)

D 1 0 2 0 (1 0) E 1 0-3 (1 0)

(Comparison) F 0 4 (1 0)

(Comparison)

G 1 0 1 (1 0)

(Comparison)

0.1 5 (1 0)

ミ Mipla 0.3 1 ό (1 Q)

Min 1 3 5 (1 0) 1.2 4

(Control) 5 6 9 (1 0)

1 Q 1 0 0 (1 0)

1 7 1 Continuing dose Oral administration of drug Suppression rate

o

1 7 (1 0)

δ 2 6 (1 0);

A 1 0 4 9 (1 0) i ό. Q

1 7 9 ό (1 0);

5 0 1 0 0 (1 0);

B 1 0

1 2 (1 0) 3 1 0 (1 0) c 1 0 4 8 (9) 1 2.7

1 7 5 5 (1 0) 3 0 7 0 (1 0)

D 1 0

E I 1 0

(Comparison)

F 1 0

(Comparison)

0.1

0.5 1 (1 0) mmipra 1 2 0 (1 0)

Min 3 2 6 (1 0) 3.8 (Control) 0 ό ό (1 0)

7 0 0 (1 0) Number of mice used Experimental Example 2 Low usage amount. Resistance to morphine-induced hypothermia According to the method of Experimental Example 1, The dose of morphine is 1 /

After 15 minutes, the body temperature of the drug administration group was measured, and the inhibition rate was calculated as compared with that of the control group. The results are shown in Table 2. Table 2 Antagonism of low-dose avomorphin-induced hypothermia

(Avomorphin 1 ZK subcutaneous administration, drug

Intraperitoneal administration)

G (comparison) 10-26 (5) Imibram (control) 10: 56 (5)

As shown in Table 1 and Table 2, the compounds according to the present invention, B, C, and は inhibit the amorphin-induced hypothermia in a dose-dependent manner as in the control imipramine. However, the compounds of Comparative Examples, ^ and G, did not suppress the decrease in body temperature. The high dose in Table 1 shows antidepressant activity and the low dose in Table 2 In some cases, it shows antimitotic activity and is active in both oral and parenteral administration.

Experimental Example 3 Reserch. Cultivation of the induction-induced decrease in body temperature

Most antidepressants are reserch.する], a force that antagonizes induced hypothermia ^ :, n 2 t, etc. (Ar zne im tte IF orsc hun g ^ 28 (Π), H ft 1 0, 1 87 4 to 1 87 The experiment was carried out according to 9, 1978). 0 minutes after oral administration of the drug or solvent to 1α mice of each mouse, reserpine 10 ^ / ι¾ was intraperitoneally administered. Thermistor;), Mouse body temperature was measured before drug administration, immediately before reserpine administration, and 1, 2, 3, 4, 5, and 5 hours later, and the effect of drug on mouse normal body temperature and drug reserpine-induced The effects on body temperature in mice were investigated. The results are shown in Table 3.

Table 5 Inhibition of reserpine-induced hypothermia

* Inhibition rate against average body temperature of physiological saline group 4 hours after reserpine administration As shown in Table 3, the compound of the present invention, C, had no significant effect on normal body temperature, but exhibited the same effect on reserpine-induced decrease in body temperature as the control imipramine. .

Experimental Example 4 Antagonism of tetrabenazine-induced eye drop

Most antidepressants are known to counteract tetrapenazine-induced eye drop. The experiment was performed according to the method of wflf e Z ac (see Afe cL Chem. E. 52-33-32, 1968). Tetrabenazine 32 was intraperitoneally administered to 10 mice orally, 10 minutes after oral administration of the drug or solvent. 50 minutes and 0 minutes after tetrapenazine administration, according to the following score: 1) Degree of eye drop (0: fully open, 1: + closed eyes, 2: + closed eyes, 3: + closed eyes, 4: closed eyes) The measured values were compared with those of the test drug-untreated group, and the inhibition rates,, and were calculated as the drug efficacy. The results are shown in Table 4.

Table 4 Inhibition of eye-induced ptosis induced by tetrabenazine j

Extractant suppression rate * ED _{5 Q}

(Oral) {%) (oral)

3 2 1

1 0 2 4

5 0 6 5 1 7.5

5 5 7 4

1 0 0 8 4

3 1 3

1 0 2 4 c 3 0 3 3 4 0.4

!

5 5 5 5

1 0 Q 7 4

0.5 | 5

1; 2 1 mipramine 3 ■ 5 3 3.5

! (Control)

1 0 7 1

1 7 8 2.

* Inhibition rate against the average score in the saline group. 9 mice and 1 Q mice were used for each dose. As shown in Table 4, the compound of the present invention and C exhibited the same action as imi-pramine.

Experimental example 5

In order to investigate the presence or absence of central anticholinergic action, which is an undesirable major side effect of antidepressants, the method of F. Lenschner et al. (Arzne imi t-te IF or schung 28 (Π), He According to ft10 &, 1883-1895, 19778), the effect of the drug was studied using tremorin as an index. After 10 minutes from the oral administration of the drug or solvent to 10 mice, Tremolin 20 was intraperitoneally administered and the presence or absence of tremor was examined. The efficacy was calculated by dividing the number of mice in which tremor appeared by the total number of mice and calculating the inhibition rate ().

5 Tremolin suppresses induced tremor

Drug amount Induction example Experimental example Inhibition rate ED ₅₀ k?

P) Saline 10

1 0 1 0 0 0

A 3 0 1 0 0 0 N.E. 1 0 0 1 0 0 0

B 1 0 0 0 N.E.

1 0 1 0 0 0

C 3 0 1 0 0 0 N.E. 1 0 0 1 0 0 0 N.E.

D 0 0 0/1 0 0 N.E.

1 0 9 1 0 1 0 1 7 9 1 0 1 0 Imipramine 3 0 4 1 0 5 6 2 8.7 (control)

5 5 1 0 9 0 0 0 0 0

NE: Function As shown in Table 5, the control imipramine suppressed tremor in a dose-dependent manner, whereas the compounds of the present invention, B and C

In terms of amount, tremor was also suppressed.

Experimental Example 6 Acute toxicity

Five weeks old dd Y male mice were used in each group. The drug was used in the form of a water-soluble drug suspended in physiological saline, and the others were suspended in 0.5 CC / physiological saline solution. The dose of drug was 0.1 for mice.

Drugs were administered orally by gavage using an oral probe. Then, the progress of the mouse 24 hours after the drug administration was observed. Table 6 shows the results.

Table 6 Acute toxicity

* Suspended in saline

** 0.5% carboxymethyl cell orally suspended in saline Z As shown in Table 6, the compounds according to the present invention, B, C and! ) Is acceptable to the extent of acute toxicity as well as imipramine.

Taken together from the above experimental results, the compounds of the present invention, other structures similar 2 - (1 - arsenate ⁰ Perajiniru) - specific in their psychotropic effects in comparison with consequent opening hept I Mi Dazo Ichiru derivatives (See Tables 1 and 2). It differs from imipramine, the main antidepressant, in part of its action (see Table 5), and is effective as a psychotropic drug. These compounds can be used not only alone, but also in combination with imipramine in a time-shifted manner, or in combination with imipramine in a timely manner.] It can also be used in combination with other antidepressants, such as danpramine and amide. Triptylin, nortriptyline, amoxahi. Doksehi. Can also be used in combination with arginine, macrotilin, mianserin, fleafensin, pyroxazine, L-5-oxa and the like.

The compounds of the present invention are used as psychotropic drugs in the form of various pharmaceutical compositions. Examples include tablets, granules, powders, capsules, syrups, Injection, suppository and the like can be mentioned. These preparations may be used as pharmaceutically acceptable diluents or carriers such as ordinary additives such as binders, excipients, disintegrants, lubricants, flavoring agents, preservatives, stabilizers and the like. Can be formulated by a conventional method. At this time, the content of the compound of the formula (I) or a pharmaceutically acceptable salt thereof may be, for example, about 0.2 to about 50% by weight based on the weight of the composition.

The dosage of the psychotropic drug of the present invention varies depending on the age, health condition, weight, nature and degree of symptoms, presence / absence and type of other drugs for co-treatment, and the like. 1 to: Administered orally or intramuscularly, intravenously or subcutaneously by dividing it into 1 to 4 times a day within the range of I000 days, preferably 10 to 500 days. It may also be useful to administer the drug in a sustained release form. 0.5 W, 1,5,10,20,20 -W ^ 2 5 5 0 1 0 0 ^ Examples of each dose are the powers that can be mentioned, but not limited to .

Thus, according to the present invention, a psychotropic drug effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a psychotropic drug comprising a pharmaceutically acceptable diluent or carrier. A composition can be provided.

Furthermore, according to the present invention, a psychiatric patient, particularly a manic-depressive patient, is administered with a psychotropically effective amount of the compound of the above formula (I) or a pharmacologically acceptable salt thereof. _(The present invention also provides a method for treating the compound of the formula (I) or a pharmaceutically acceptable salt thereof. Provides the use of salt as a psychotropic drug. BEST MODE FOR CARRYING OUT THE INVENTION

Gang

Next, specific examples of the psychotropic drug preparation of the present invention are shown. Since the compounds which are the active ingredients of the present invention are equivalent in terms of formulation technology, in each of the examples, each compound is simply shown as an active ingredient instead of showing each compound. Example 1 Capsule (hard) A capsule was prepared by filling a hard gelatin capsule with the following mixture using an ordinary capsule manufacturing apparatus.

5 τπ% / cuff. Senoré 10 kappa cuff. Senole Active ingredient 1 0

2 0 0 9 5 Corn starch 1 0 0 0 0

Magnesium stearate 5

3 1 0 ^ 3 1 0

2 5 ¾ cuffs. Senor 5 0 τ¾ / cuff. 1 10 Omg Power ° ° -ί レレ Active ingredient 2 5 5 0 1 0 0 Lactose 1 8 0 6 5 1 4 0 Maize starch 1 0 0 9 0 8 2 Magnesium stearate 5 5 8

3 1 0 ^ 3 1 0 ffl? 3 3 0 ^ Example 2 Capsenole preparation (soft)

Nfu Tozerachi Narun force effective in the large set oil to prepare a mixture of components, containing the active ingredient ^{2 5:.} 7. A cell was manufactured. _C to give the product The capsules were dried after washing with petroleum ether

Example 3 Tablet

0 L 5 0 Z tablets

Effective minute 1 0 5 0

Corn starch 5 0 5 0

1 0 8 0 3

Phosphoric acid dicanolesum 5 0 4 5

Calcium stearate 2

2 2 0 ^ 2 5 0

Use the usual method so that the above composition is contained in one tablet! _C ) Example 4 in which a tablet was manufactured

Composition Ampoule Active Ingredient 1 Sodium Canoleboxy Methynoresenorelose 0.76 Weight

Resolvate 8 0 0. 0 5 weight Henzinolen 0 0.8 5 weight Sodium chloride 0.8 5 fold i¾ Water for injection 1 ampule 1 Injection ampoule was prepared by a conventional method so that the above composition was contained.

Example 5 Oral suspension

Active ingredient 2 5

Methyl cell π-space 5 weight

Canoleboxy Methynoresenorelose 5 weight

Shiguchi. 2 5 weight? S

^ Lithonolate 80.0 0.3 weight ° h Saccharina sodium 3 η

Sodium benzoate 6

Water

In an amount of 5 ml per vial, an oral preparation was prepared by a conventional method so that the above composition was contained.

Industrial applicability

As is apparent from the above description, the 2- (1-hi.perazyl) -cycloheptymidazole derivative of the present invention is imif. Like Lamin, it can be effectively used as a psychotropic drug.

Claims

The scope of the claims

The following formula (I

However, in the formula, R! Is hydrogen, formyl, methoxycarbonyldiethoxycarbonyl, or f. Represents roboxycarbonyl or isopropoxycarbonyl;

A psychotropic composition comprising a psychotropically effective amount of a compound represented by the formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

2. The composition according to claim 1, wherein the content of the compound of the formula (I) or a pharmaceutically acceptable salt thereof is about 0.2 to about 50% by weight based on the weight of the composition. object

3. The following formula (I

However, in the formula, R i represents hydrogen, formyl, methoxycarbonyl, ethoxycarbonyl-propoxycarbonyl or isopropoxycarbonyl.

Use of the compound represented by or a pharmacologically acceptable salt thereof as a psychotropic drug.

4. The following formula (I

However, in the formula, R i is hydrogen, formyl, methoxycarbonyl, ethoxycanolebonyl, or f. Mouth-boxy ruboninole or isov. Mouth ^ Kisika no repo '

A method for treating a psychiatric patient, comprising administering to the psychiatric patient a psychotropically effective amount of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof.

5- The treatment method according to claim 4, wherein the administration is oral administration.

6. The treatment method according to claim 4, wherein the administration is injection administration.

7. The treatment method _{c according} to claim 4, wherein the dose is 0.000 ^ / day for an adult.