JPS58109482A - Anti-anxiety - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides generalized anxiety disorder symptoms.
aAnxiety disorder S71S71n
ptO) ;J) or other anxiety disorders, such as fear (ptO);
for use in human medicine in the treatment of anxiety and especially general anxiety disorder in patients previously identified as having or having ho'bia) and other symptoms associated with panic disorder. The present invention relates to compounds and, in particular, to medical institutions containing them.

Australian Patent No. 201.630 and French ifF No. 1.1.67.510 disclose the following patents: R1 represents a hydrogen atom, a lower alkyl group, an aryl group, or an araliphatic group, and Y and Yl each represent hydrogen or a halog''/atom, or lower alkyl, alkoxy, aryl or An aryloxy group containing Y or Yl may have a substituent in addition to Y and Yl,
And is one or more of the carbon atoms of the piperazine ring a substituent in the form of a methyl group? σ) It is stated that carbazoles have antiepileptic properties.

South African Patent No. 76/7352 discloses the compound disclosed herein for use in the treatment of aggression and psychosis. A compound of the formula (A1 1 , shown herein as 1carbazole 1, 9-(3-(3,5-iodimethylbiverazono)globil)-carbazole (sometimes 9-(
5-(6,5-zomethylbiperazinyl)-propyl]-
9-[6-(2-6,5-dimethyl-1-piperazinyl)-zolovir]-rbazole), its pharmaceutically acceptable 4 and its pharmaceutically acceptable medicaments. The electrically conductive material that can be accepted is
First.

(Unexpected CI) In particular, they are associated with aggression and treetops in humans! It has also been found that useful in the treatment of leopards, V) exhibits valuable counterattacks, J6 and antipsychotic rotation. Unexpectedly, this drug has a toxic effect, such as LJ Lug U Machine Temple, antipsychotic 2 N punishment, and convulsions, such as 4 external tract dysfunction or sedative effect 2 Not shown. These compounds have now unexpectedly also been found to be useful in the treatment of individuals suffering from anxiety, which is associated with certain types of schizophrenics. The compound vD of the present invention can also be used to treat general anxiety, phobia disorder (fear'Pfl+neurosis), panic disorder, and obsessive-compulsive disorder (Ob8θ5aive”Oompulsiv).
e aiorder ) and postexternal stress disorder (
Po5t-Trauraatic 5tress d
isorder) is used in the treatment of patients who have or are confirmed to have had f.

The word ``heavy speed'' used here used to refer to the anxiety level τ.
The prophylactic administration of 0 carbazole to a patient (person) who has previously been determined to have symptoms of anxiety;
1 mBl re-administration of ``carbacinone'' to humans).

Clinical methods used to assess anxiolytic effects,
[Report by Peychol, Re.
p,) IQ.

799-812 (1962)) Brief, Psychiatric, Rating Scale (Br1ef i
'5ychiatric Rating 1llcal
e), and one relative [Consulting,
Psychologists, Press (Consulting i'
aycho 0g1st day Press) Hello, Aldo (
Pa1o Alto), California (1963)
) in-page end, multi-dimensional,
Psychiatric, scale
Jultidim6n810nal Payahiat
It is based on rice cale).

“Carbazole 1 is of particular value because its anxiolytic effects are largely free from undesirable side effects such as rigidity, catallegia and extrapyramidal dysfunction.” The relationship is necessitated by the inability to antagonize the stereotypic behavior of abomorphs in rats [Anchef (N, Iiii, An
Illien), 9 Yana E 4j, -4 Ryo 1 Za-7) Link, L Ko to Yuyo Otsu ('XPay
cniat, supra), 97.1974. It also has anticholinergic and antihistamine properties associated with a significantly lower potency compared to phenotheazines.

1 Although the useful biological properties of carbazole 1 lie in the basic moiety, it can form acid addition salts,
And all such salts α) are included within the scope of the present invention V). Pharmaceutically unacceptable salts may be used as intermediates for conversion to the corresponding pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are halides, especially 7- and di-salts, sulfates, and anions of organic acids such as tosylate, meta/sulfonate, tartrate and maleate. In addition, 'carbazole 10
The 1M radical moiety can form well-defined solvates of salts, such as hydrates, but also alcohols such as ethanol, methanol Q), and these solvates are also included within the scope of the invention. be done.

``Carbazole 1 can be synthesized by any method known in the art (by synthesis of compounds with similar structures).

1) A preferred synthesis involves linking an alkylene chain with either or both of carbazole and viverazo/yellow. This is the formula (Ill, (IIA) or (
IIB) z -(cH2)3-z (■B) [
In each formula, 2 is the atom or group to be removed]. This is optionally carried out by reacting with carbazole, 6,5-dimethylpiperazine or both carbazole and 6,5-dimethylpiperazine, respectively. For the optional 9 substituted 2 occurring on the appropriate amine group, any atom or group such as halo (preferably 1, -1), arylsulfonyloxy (preferably p-toluenesulfonyloxy) , meta or alkylsulfonyloxy (preferably meta/sulfonyloxy) can be used.

Although the compounds of formulas (II) and (IIB) can react directly with carbazole, it is advantageous to use carbazole derivatives; sometimes suitable t+fii conductors are alkali or alkaline earth metals, especially lithium, sodium,
Carbazole magnesium halides such as those with potassium, zinc, cadmium and calcium or iodite can also be used.

Alkali gold-canonbazole & carbazole, conveniently prepared by reaction with a suitable alkali metal hydride or amide in an inert, preferably polar, agetic bath medium such as adult ammonia, dimethylformamide or dumenal sulfoxide; Other carriers include hydrocarbons such as alka/alkanes, Schiff-alkanes and aromatics. The same reaction medium can then be used to carry out the note-substitution, which is preferably carried out by heating.

Note - 16' It is appropriate to create an inert atmosphere during the 14 rinsing process, such as in a room.

Q: Separately, the compound of formula (1) may be prepared in the presence of an alkali hydroxide or an alkali all-alkoxide in an alkanol of dimethylformamide, dimethylacetamide, water or optionally 11, with a polar carrier and λ. Potassium t, er, t- in tert-butanol
In the presence of butoxide, it reacts with carbazole.

6. When 5-dimethylpiperazine is reacted with a compound of formula (IIA), it is a polar aprotic medium such as dimethylpolamide, dimethyl sulfoxide or acetonitrile, or a zolotic medium such as water or an aliphatic alcohol. It can be done inside.

Intermediates of formula (II) are readily obtained from the corresponding alcohols by conventional techniques. For example, alcohol can be converted to chloride by reaction with thionyl chloride. Alcohol is a formula that has the same meaning as -1 in formula (11) "lyc"
cHz) 3-OH substituted alcohol and 6,5-dimethylpiperazi/.

The synthesis of the σ intermediate of formula (IIA) can be carried out by a 1-1 conversion similar to the reaction of compound CIIB) with carbazole to produce the compound of formula (1).

A variation of 1 and above described is that instead of using the removed Z, V between the terminal and the second carbon atom is
Neutral positive j of formula (IN) or (nA) with C double bond
Thus, an addition reaction rather than a substitution takes place; the reaction takes place at high temperature and pressure in the presence of an alkali, for example in an autoclave, such as sodium hydroxide. It can be carried out in an alkali metal hydroxide solution at a temperature of about 115°C. Preferably, equimolar amounts of alkali are used.

Similarly, the intermediates of formulas (11) and (IIA) may themselves contain piperazine or carbazole and acrylic dehydrogenation or its v5 conductor, such as an acid halide,
Ester, amide TFC. Miebael-type condenser with nitrile
tion). A single generated compound can be reduced to the corresponding alcohol.

0 2) "Carbazole" also represents formula (III) [wherein, Y
l and Y' together form oxo, thioxo or 6imino, or Yl is hydroxy7 and Y'
is hydrogen, and the groups Y3 and Y4 are defined in the same way as Yl and Y', except that Yl and Y'' cannot both be hydroxy, except when from Yl to Y' they do not contain a nitrogen atom.] The reduction takes place in the presence of ammonia or an ammonium salt such as ammonium chloride.

A number of reducing agents are suitable for this purpose, depending on the particular case involved. An example is (Raney) hydrogen in the presence of nickel or palladium, or zinc in the presence of an acid. Alternatively, after initial closure of the compound of formula (m), lithium aluminum hydride, vitrido, dibora/, which is known to reduce amides,
And other aluminum and boron hydrides can be used.

In formula (■1), one for Yl and Y, and Y
When one of 3 and ¥4 is hydroxy, the compound is reduced in the presence of ammonia without the aid of a reducing agent υ
The reaction conditions may be selected from those known in the art as suitable for ammonia decomposition, for example under pressure in the presence of a catalyst such as copper chromite or alumina. ,
Heat to 710°C, optionally in the presence of an inert bath medium.

Intermediates of formula (Ill) are compounds of formula (V) and formula (IV
) of 3-(9-carbazolyl)propylamine 2 (in the formula, Z, Yl and Y2 are as defined above in the formula) and (m), respectively]
: It can be produced by the reaction described in 1. The reaction may conveniently be carried out in an inert polar solvent at ambient temperature and in the presence of an acid acceptor such as triethylamine to scavenge the hydrogen ions liberated during the reaction.

Intermediates of formula (11) suitable for conversion to compounds of formula (1) by ammonialysis are themselves amino/(IV)
can be prepared by reacting with 1,2-epoxypropane of formula (Vl).

The reaction may proceed if the reactants are simply heated to about 100°C, but optionally the lower alkanol is added to the solvent and 100°C.
For example, when used at a temperature of 45° to 60°C. Lower alkali means hexanol.

Compounds of formula (IV) can be prepared by ammonialysis of the halide or by corresponding alcohol lysis using a large excess of ammonia, preferably under pressure, using a catalyst and λ in the presence of copper chromite or alumina; It can be obtained by reduction of a suitable nitrile or amide. The desired alcohol, halide, nitrile or amide may be prepared by the methods described above for the preparation of compounds of formula (nA).

6) ``Multiple syntheses of carbazolpa can be synthesized using the formula (■) [(
a) In the formula, two hydrogens on one or more carbons from 1 to 4 are di-substituted by oxo (many reducing agents capable of reducing the amide carbonyl group can be used for 1). Can be done;
Examples include water accumulation using nickel, platinum, palladium or copper chromite as a catalyst at elevated temperatures and pressures; diluted hydroiodic acid with red phosphorus; and particularly suitable are lithium aluminum hydride or zipora/. Alternatively, in formula (1), the two hydrogens on the fifth carbon are replaced by oxo groups (many reagents capable of reducing ketone groups can be used); hydrogenation using, for example, nickel, platinum, palladium or copper chromite as catalysts at specified temperatures and pressures; zinc and hydrochloric acid (Clemense); ) reduction of a similar carbonyl compound of l),
Included as the final pillar.

Formulas in which the oxo group is on either the 6th or 4th carbon (
(ii) Compounds (e) of 1) may be prepared by analogous reactions as described above involving compounds of formula (IIA) or using substituted piperazids of formula (via) H3.Convenience of (vi) A typical preparation involves the preparation of a compound of formula (IX) in which W is the group to be removed, for example halo, such as chloro or zolo, or alkylthio, and a large excess of 1,2- of formula (X). reaction with diaminopropane.Although reaction ii can be carried out by simply heating the reactant, it is preferable to use an inert bath medium such as ace)nitrile or thioxane, and the lower alkanols It is particularly advantageous to use ethanol as bath medium.

Alternatively, compounds of formula (■) can be prepared by reacting piperazine or carbazole, or their reactive conductors, such as those described above, with an acrylyl halide, such as an acrylyl chloride or an alkyl acrylate of the formula %. A compound of the formula C/Fl is 3,5-dimethylpiperazinyl or carbazolyl, respectively, may be prepared by subsequent reaction with carbazole or 6,5-dimethylbiperazine, as appropriate.

A compound of formula (■) in which the oxo group is on carbon number 5 can be used, for example, in the reaction of α', α'-dichloroacetone and 2,5-dimethylbibecidi/14-(3-
10 rho 2-oxinprovir) = 2,5-dimethylbibe2dine, which can then be prepared by reacting with carbazole in dimethylformamide in the presence of a strong base such as sodium hydride.

4) "Carbazole" can also be prepared as a final pillar by forming a carbazole core from the corresponding phenothiazine analogue, for example by heating with copper. sell.

Separately, diphenylamine/of formula (XI) can be prepared by adding palladium(II) to
) Can be ring-closed by a reaction with the earth. Preferred palladium (1
1) Salts are acetate and chloride; 4. is commonly used in diphenylamine and chemical compounds. Preferred solvents are acetic acid, acetonyl, sulfolane, and especially trifluoroacetic acid, and reaction i is advantageously carried out in elevated freshness up to the reflux temperature of the reaction medium. The reaction is conveniently carried out in the presence of a catalytic amount of a strong acid or boron trifluoride.

Further syntheses of °゛carbazoles include the corresponding 1゜2,3
．． This is due to the oxidation of 4-tetrahydro derivatives (or homologous off-8tahydro compounds). Any conventional dehydrogenating agent may be used, provided it does not oxidize any of the elements in the remainder of the molecule;
Catalytically over chromium oxide, alumina, quinones such as tetrachloroquinone, or hot platinum or palladium.

The synthesis of the intermediate phenothiazines, diphenylamines, and tetrahydrocarbazoles can be carried out by current-carrying techniques well known in the art.

5) Substituted piperazine/Maki completion can also be used to synthesize °°carbazole'°.

Compounds of formula (xn) are those of formula (Xlml) [wherein can react with certain compounds. The reaction is &
! 1. This can be done by heating in a common medium, such as acetone, or a lower alkanol having 1 to 6 carbon atoms, such as ethanol or getanol.

``Carbazole'', its place of medical acceptance ■) [America/Psychiatric, Assoc.
erican Psychiatric Aasoci
ation) Published by WashiytoyDC (1980)]
1: It is useful for the treatment of anxiety disorders in people who have been diagnosed as suffering from anxiety disorders according to the criteria shown in 1. The candy ``Anxiety'' used here is situational disorder or vessel 1.
°Apprehension arising from disability
, fatigue or agitation.

°'Carbazole'° Compounds, their pharmaceutically acceptable salts and their pharmaceutically acceptable electrolytes NIIJ
Anxiety disorders such as those mentioned above, namely general anxiety disorder, panic disorder, obsessive-compulsive control disorder, fear disorder and post-traumatic stress disorder, are treated for the body of a mammal with NKg per day of 9.0% per day. It is preferably administered orally to a mammal, such as a human, at a dose of 25 g+1/ to 15111/(1 g as base), and most preferably ri
1 to 10 y/Ky, and this dose is preferably administered orally to treat those disorders. °'Carbazole'' compounds, pharmaceutically acceptable salts and molvates thereof are preferably used at the above doses for those conditions.
It is administered 1 to 4 times a day. For intramuscular injection, the dose is generally one-half the oral dose. The analogy is about anxiety.
A reasonable use l' is, for example, from 0.25 mushroom y/Ky to 1 151 Sf/h, and most preferably 1. It may be within the range from 0 to 10+y/Kr. Conveniently, 10 to 600 to 600 each of carbazole, a pharmaceutical salt thereof, or a solvate thereof, conveniently 2
It is administered as one or more tablets containing 5 + y or 50 tablets once or more times a day, and can be administered 4 times a day to treat general anxiety disorder, panic disorder, fear-mongering, etc. , Obsessive Compulsive Disorder and Traumatic Stress Disorder 3 Generally, in the treatment of the above-mentioned disorders, carbazole and its salts and medulants may be administered for a period of one week to one month.

For use in medicine, it can be administered as a 1-carbazole drug concentrate.The carrier, of course, is compatible with the other ingredients of the composition and is meant to be non-harmful to recipients of the composition. The carrier may be a solid or a liquid, or a mixture of solid and liquid materials, and is preferably combined with carbazole or a salt thereof to form a unit dosage composition, e.g. Formulated as tablets, capsules or cachets for oral administration, or suppositories for enteral administration.Other pharmaceutically active substances may also be present in the compositions of the invention, and the compositions For example, tablets may be formulated by any of the well-known techniques of pharmacy, consisting essentially of mixing of 300 mg, granule, etc.
ing ), stirring, punching, milling
), tampling, compression or molding.

Unit dose compositions for enteral or parenteral administration conveniently contain from 5 my to 75 my of a pharmaceutically acceptable salt or solvate thereof, calculated as the base.

For oral administration, finely divided powders or granules of the compound may contain diluents and dispersants and surfactants and may be taken up in draft form in water or syrup; capsules or wafers in the dry state. or when a suspending agent may also be included, an aqueous or non-aqueous agent; preferably a suspending agent; Alternatively, flavoring agents, preservatives, suspending agents, thickening agents and emulsifying agents may also be present in suspensions in water or oil or water/oil emulsions. The granules or tablets can be coated with λ, and the tablets can be marked anywhere.

For non-phasic administration (by intramuscular, intravenous, intraperitoneal or subcutaneous injection), "carbazole", preferably as a medically acceptable salt or hydrate, is an antioxidant,
Buffers, emollients and compounds in unit or multi-dose containers in aqueous or non-rinsing injection baths which may contain solutes to make them isotonic with blood; or suspending agents and thickeners. When the agent can be included, it can be present in an aqueous or non-aqueous suspension;
teml) OraneOu8) Injection baths and suspensions may be prepared from sterile powders, granules or tablets which may contain all N diluents, dispersing agents, surfactants, binders and lubricants9. It will be understood that what we claim in accordance with the present invention includes primarily, but not exclusively, any novel features described herein, such as: Dew.

For example, the above type of treatment f! l: Treatment and prevention methods for mammals (e.g. humans) suffering from anxiety include administering to said mammal "carbazole" or a medically acceptable salt thereof as limited above or #! * :lII
It consists of administering a non-toxic and effective anti-anxiety drug.

For example, the diagnosis of each anxiety disorder, such as general anxiety disorder, is diagnostic and statistical.
Natural of Ment, al l1lnes
s (DSM-111), pages 225-269 negative, (A
mericanPsychla tr I CA, 5S
OC1a tl, on publication).

In the group of disorders treated here, the primary disorders such as anxiety, panic disorder, and general anxiety disorder, or in panic disorder, the act of confronting the object or situation of fear; 1. Resisting compulsion or compulsion in Obsessive-Compulsive Disorder 5. Anxiety is experienced when an individual attempts to conquer the symptoms, such as in resisting compulsion or compulsion in Obsessive-Compulsive Disorder. The diagnosis of anxiety disorder is anxiety, schizophrenia, affective disorder (Affect I).
isorder), or organ mental book (Orp:
anj c: Ivlental I) 1 order
), it cannot be caused by other disorders such as

The following ten examples are presented by way of illustration of the invention; they are not to be considered as a limitation of the invention.

In these examples, unless otherwise specified, all excursions are in degrees Celsius, and vacuum distillations are carried out over a steam bath, about 2
A pressure of 0 Dragon Hg was used.

Production of 6-cis-dimethelbiverazine (114.2 g, 1
．． 0 mol), 6-chloroprono-7nol (94.5μ,
1.0 mol), sodium carbonate (105 g) and ethylene glycol monomenal ether (400, d).
! The mixture was stirred on stream F for 4 hours. The reaction mixture was treated with flies, and the mochi medium was stripped off from the P solution by vacuum distillation. 1 ml of the product was immersed in ethanol (500'Tni).
), and the bath solution was saturated with dry hydrogen chloride. The white precipitate was collected, dried in nitrogen, and used as a hydrochloride in the next step without further preparation.
Melting point 240-241°.

Naonyl chloride (300I!11) is 6-(5゜5
--7 fudimethylpiperazino)propanol di-smoked salt (2CJ Og) was added slowly. The reaction mixture was refluxed for 1 hour at -40°C, and then the thionyl chloride was removed using a prefecture steamer. Generated 1MI l'a
', rtn several times with pen bottle and then several times with needle, r & 1 point 291-292°.

Trade, 70 g of 57% distillate in mineral oil and dimethylform.
DMFi' (150 mg) of sodium hydroxide (DMI) (1,6 mo/l/) cvyQ-like product was added to DMFi' (150 mg)
of bath salt (83,!M, 0.5 mol) was added. When hydrogen is no longer generated, DMF (200rn
62(6,5-cis-dimethylpiperazino) in l)
Probyl chloride di 1t''#1n (161 &, 0.5
The slurry of mol) is slowly ejected into the mixture VC.
I was eaten by a horsefly. The reaction mixture 41 was mixed with deq7d yarn (de
As the slurry was added, some foaming occurred, and the speed of the cutting edge (a) was adjusted to minimize this. Let's taste it, ll4m
did.

The reaction mixture was heated (90° to 120') for 16 to 18 hours, cooled, and the Pj/i4L and common solvent were stripped off by vacuum distillation.

1N hydrochloric acid 2 for viscous cruelty! , cooled and washed with ether (500v). Ether j-, which may contain unreacted carbazole, was removed. water-based
was treated with activated carbon and passed through Celite (Goen trademark). The p solution was made basic to AlkaOld (trademark) paper using sodium hydroxide and then extracted four times with ether. Both the ether layer and the aqueous layer became wrinkled at the end of the extraction. 9-[6-(6,5''dimethylpiperazino)propyl] was obtained by drying the ether layer with anhydrous magnesium sulfate or molecular sieves and passing dry hydrogen chloride through a liquid solution.
The carbazole hydrochloride was precipitated. The precipitate was collected and recrystallized from ethyl vinegar or an ethanol/ether mixture to 9-(3-(3,5-dimethylpiperazino)propylcoupleurbazole dihydrochloride hemihydrate (50,! i/), melting point 288-29
0"C0 Example 2 The compound of Example 1 was administered to male mice to confirm pregnancy 1" and LD50, which was found to be as follows.

Oral Shimiuchi 977 ttv/nifl 31~/leg example
6 9-(3-(3,5-cis-dimethylpiperazino)-f
Lovir]-carbazole dihydrochloride hemihydre) (15
0 g), absolute ethanol containing about 5 timethanol (
68On11), water (27!M) and 1ON sodium hydroxide C76ml) were combined and heated to obtain a bath liquid. Slowly add water (500 yd) to the hot liquid,
It was then slowly cooled to a very warm temperature. Add the mixture to 0
The mixture was cooled to 50°C for 1 hour and then filtered. The product was washed thoroughly with water, drained and dried, and poured into a 9-(1-(3,5-stopper)
-dimenarubiperazino)propylcoupleurvazole (1
10 g, theoretically 92 g) was obtained, melting point 107-109.
°.

Elemental analysis value: C21H3o (42N30o, calculated value as 5: C7B, 46 H8° 47 N13.07
Measured value: C78,43H8,46N13.05 Example 4 9-[3-(3,5-gauge methylpiperazino) of Example 1
Propyl terkarul dihydrochloride hemihydrate (
5 g) was dissolved in water (250rnt) and the solution was neutralized to pH 7 with 5N sodium hydroxide. The formed precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 9-[:3-(3°5-7x-dimethylpiperazino)7″lopyl]-carba- Rumonohydrochloride (3°7g), the m point 309-611° (decomposition) was excellent, and it was determined by the following elemental analysis' directly performed near c tree analysis 411: C21H2BN3C1 as d
10 41 shift 2 C70,47N7.89N
11.74 Cf9.91 example foot value; C70,53
N7.93 N1j, 69 (49,83 cases 5 9-[3-(3,5-e4-dimethylpiperazino)propylcoucarbazole (10 g) from Example 4 was dissolved in warm setone (71 me). .Maleic acid (3,7,!i
') was added slowly and precipitate formation occurred.

The resulting slurry was stirred for 10 minutes while heating to reflux.

It was then cooled to room temperature and filtered. The collected precipitate was washed with acetone and then recrystallized from water to give 9-
(3-(3,5-dimethylpiperazino)70lopyl]-
Carba 1 unit - lumaleate (10,5&), melting point 162
~166° (decomposition) was obtained, which had the following elemental analysis values: Calculated as C25H31N304: C68,63N7.14 N9.60 4 phosphorus i = 1 direct: C6B, 91 N7. 25
N9.74 6 9-[ro-(3,5-cis-dimethylpiperazino)propylcucarbazole (10,!9) of Example 4 was heated to 5D3
A (ethanol containing about 5% methanol, 50 g) was poured, and succinic acid (5.8 g) was slowly added. The mixture was stirred and heated to reflux for 10 minutes, then cooled to 5°. The product was collected by strain and 5D3A
/water (9515v/v) to give 9-(
3-(3,5-?-dimethylpiperazino)propyl]
- Carbazole 3/4 succinate (10,1), melting point 175.5-176.5° (chemistry confirmed by nmr) was obtained, which had the following elemental analysis value 'C24 'Hs'1.5N30s total j4
-1st shift: C70,30H7,74N 10.24 cases Foot value: C70,21N7.71 N10.206 Example 7 9-(3
-(3,5-cis-dimethylpiperazino)propylcoupleurbazole (10 g) was added to il'F-acid (2,0++
f ) was lowered. The mixture was stirred and cooled to 2°. The product was collected by filtration and diluted with cyclohexane (6
5nrt) and dried under reduced pressure.
．． -9-[3-(3,5-dimethyl-1-piperazinyl)7°0 pill]-carba 1 unit-lua supratate 1/4 hydrate) (10,4,9), melting point 144-146° was obtained. and it has the following elemental analysis value fc: Elemental analysis value: C25H31,5NyaO2,25 as l1 Paralysis 1 direct: C71,56H8,22N10.8
8 Measurement 1st shift: C71,57H8,08N10.84U8 4 L) Sol 1 acid salt monoheat cis-9-(
5-(3.5-dimethyl-1-piperazinyl)70rovir]-carbasol (10.!T')K, water (5
A bath solution of 3.05.!i' in #+7 was slowly added while stirring, and a precipitate immediately formed. The slurry was stirred at reflux for 10 minutes and then cooled to 20°.

The product was collected by filtration and acetone (20d)
I washed it with It was resuspended with water (70 m), filtered, washed with acetone (40 m) and dried in vacuo to produce 72-9-(3-(3.5-dimethyl-1-piperazinyl). Propylcoupleurbazocarbate monohydrate (12.91), melting point 246-246° (decomposed)
was obtained, which had the following elemental analysis value: Elemental analysis value: Calculated as C21H31N3058 1 shift: C57
．． 46 N7.14 N9.60 Measured value: C5
．． 7.75. N7.10 N9.47 Ri09 According to the method of U6, 9-(3-(3,5-cis-dimethylpiperazino)propyl]carba-door, 11!
Reaction with equimolar filters of the appropriate acid gave the following salts.

9-C6-<5.5-? dimethylpiperazino)propyl J-ruvadel fumarate, so[5-(5,5
-cis-dimethylpiperazino)propyl]-carbazole citrate, 9-(5-(3,5-zx-dimethylpiperazino)propyl coulhater L maleate,
9-(3-(3,5-dimethylpiperazino)propyl)-carba-ol L-tartrate, 9-C5
-(3,5-zx-dimethylpiperazino)propyl]-
Rubazole methanesulfonate.

PHARMACEUTICAL FORMULATIONS In the following examples of pharmaceutical formulations according to the invention, unless otherwise indicated, the term active ingredient shall be used to refer to μ[1]-carbazonyl or its pharmaceutically acceptable derivatives. Shows the salt solvent content. The minerals described are suitable as bases; if salts are used, they must of course be enriched with 11C as appropriate.

Example 10 Preparation oily component (compound of Example 5) 60.0
Lactose 125.0 Cornstarch 50.0 Polyvinylpyrrolidone 6.0 Stearic acid 1.0 Magnesium stearate 1.0 Example 11 Capsule ingredients Amount per tablet (II#g) Active ingredient (Compound of Example 6>
60.0 Lactose 174.0 Cornstarch 174.0
Stearic acid 2.0 Example 12 Ampoule 8 Ingredients Filter ingredient per ampoule (as diurate of compound f6) 60.01
1 Da water for injection (appropriate amount) 1. 〇-Example 16 Suppository oily component (compound of Example 1) 60.01!
Theoproma oil (cocoa butter) suitable amount, 2.
0g agent remaining material 4 people from Kōgai

Claims (1)

[Scope of Claims] (1) A method for treating general anxiety disorder in a person confirmed to exhibit symptoms of general anxiety disorder,
-(5-(6,5-suzometelpiperazono)propylcouple) Rubazole, its pharmaceutically acceptable composition, or its pharmaceutically acceptable hemorrhoids A method comprising administering an effective, non-toxic, anti-competitive anti-anxiety treatment dose of 1 dose. (2) i, calculated as the base, from 0.25 to 15 + 1 evening/Kj 9 dishes.Claims: (3) The method of claim 2, wherein (3) the range is from 1 to 101 m/Ky, calculated as the base. (4) The method of claim 1 or 2, wherein the carbazole, compound or solvent is administered in a pharmaceutically acceptable carrier. (5) In the treatment of panic disorder in people who have been confirmed to have 9-[5-
(6,5-22-zometerbiperazino)norovir]-rubazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable electrosolvate of a pharmaceutically acceptable salt thereof. A method comprising administering an effective non-toxic antidepressant disorder treatment. (6) The method according to claim 5, wherein the violet is calculated as a base and has a skin weight of 25 to 15 to 15. (The method according to claim 6, wherein the force is 1 to 1 o/kg body weight, calculated as t or base.) 1 in a capable carrier,
Claim 5 or 6F(1) Method. (9) J9-(3-(6,5-2)-zomethylbiveracino)bouvir]-carbazole, its medical 9 !It consists of administering a non-toxic anti-fear 11#L harm cure, which is a medicinally acceptable electrolyte, or its medically acceptable □salt σ] Method. tII Children calculate 0.25 to 15 with base 1.
Claim vA No. 9, which is up to #Ifi+/yellow weight
term σ) method. (The method according to paragraph 1U, wherein the amount of the carbazole, salt or solvate is less than 10 m9/kg body weight, calculated as 10 m9/kg body mass). 11. The method of claim 9 or claim 10, wherein the method is administered in: U■ Fear #L Harm or agoraphobia, the method of claim @9 or 10. (141) In the treatment of post-vaginal stress disorder in a person confirmed to have symptoms of traumatic sickle stress disorder, the person is given ]-carbazole, sulfur) a medically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof; σ) an effective anti-A/positive stress disorder agent; A method consisting of administering filtration. (151: Assuming that jt is the base, calculate from 6.25 to i
15. The method of claim 14, wherein the weight is up to 5 my/kg. (16) Assuming that it is a base, the calculation is 1 or 61011
Claim 15, which is up to 9 body weight in 1fi'/
Section method. a7)' The method of claim 14 or 15, wherein the carbazole, salt or electrolyte is administered in a pharmaceutically acceptable carrier. (+81) In the treatment of obsessive-compulsive disorder in a person confirmed to exhibit symptoms of obsessive-compulsive disorder,
(5-<3, b-l-cymenalbiperazino)-p-U-carbazole, SoQ) a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof. A method comprising administering an effective non-toxic anticompulsive solvate capable of responding to compulsive disorders. ([9) Calculated as a base, 0.25 to 15
19. The method of claim 18, wherein the percentage is up to 1.5 kg/kg body weight. (20) From 1 to 10+w/calculated as electric base
20. The method of claim 19, wherein up to kg. Claim 1, wherein the carbazole, salt or solvate is administered in a pharmaceutically acceptable carrier.
The method of either Section 8 or Section 19. v'lJ In a treatment for anxiety that can be treated in a person who has been confirmed to exhibit symptoms of anxiety, the person is given 9-
C5-<5.5-2-zomethylpipe2zono)glovir]
- a pharmaceutically acceptable solvent for Rubazole, a pharmaceutically acceptable substance thereof, or a pharmaceutically acceptable substance thereof;
A method consisting of administering an effective non-toxic anxiolytic treatment Wkw in the proboscis. (2 cloudy person calculates it as a base from 0.25 to 15 ~ /
23. The method of claim 22, wherein the weight is up to 1. ψno If the bar is calculated as a base, it might be 1[]r+vlK
27. The method of claim 26, wherein the method is up to y body constitution. 19. The method of claim g 22 or claim 26, wherein said carbazole, salt or solvate is administered in a pharmaceutically acceptable carrier. (The method of claim 22, wherein the carbazole or its salt is administered as part of a tablet or capsule. t7!7) 9-(5(6*) for use in the treatment of anxiety in humans. 5-9 X-zometel biverazino)
Noropyrucourvazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof. (To) 9-(6-15,5
-2-dimethylpiperazino)flovir] - Rubazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof. 129) yl-[,3-(5,5-dimethylpiperazino)propylcucarbazole, its pharmaceutically acceptable drug, or its pharmaceutically acceptable drug as an effective drug for the treatment of anxiety in humans. Pharmaceutically acceptable electrolyte salts. - 9-(3-(5,5-
y; 611 5-(6-(3゜5-zomethyl vipera 7
/)7'''1. A pharmaceutical composition for use in the treatment of anxiety in humans, which is included with the book. Norovir] - Rubazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, together with an acceptable carrier therefor. A medical composition for use in humans with a condition selected from general anxiety disorder, panic disorder, phobia disorder, post-traumatic stress disorder and obsessive-compulsive disorder. 9-(5-(1,5-□-dimethylpiperazonone, Ibiru)-rubazole, its pharmaceutically acceptable form, or its medically acceptable form, as an effective drug) Q) A pharmaceutical composition comprising a medically acceptable agent together with an acceptable carrier. ■ General anxiety disorder, panic disorder, phobia disorder, traumatic stress disorder. 9-(3-(5,
5-Zomethylpiperazono)pyl]-lupazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof. Pharmaceutical compositions including together with an acceptable carrier. (to) 9-1-(5,5-Z-zometerubipe2dino)-flovir]-carbazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; Agents effective in the treatment of anxiety in humans, including solvates capable of responding to (to) 3-('3-(,5,5-21zomethylpiperazino)zologyl)-carbazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A drug effective for the treatment in humans of a condition selected from general anxiety disorder, panic disorder, phobia disorder, Sototsusa stress disorder and obsessive-compulsive disorder, comprising a medically acceptable solvate of Uru salt. (b) A drug according to any of claims 65 and 66 in unit dosage form. (2) A drug according to any of claims 65 to 57JJij in a form suitable for oral administration. - a medicament according to claim 6 in a form VC suitable for internal administration;
Drugs according to any of paragraphs 5 to 67. (iv) A drug according to any of claims 65 to 67 in a form suitable for parenteral administration. 1iI A medicament according to claim 67 in the form of an orally ingestible tablet. A medicament according to claim 67 in the form of a capsule. θ1 9-(:3-(6,5-dimethylbiperazono)lupir)-rubazole, 70) Pharmaceutically acceptable tomb, or pharmaceutically acceptable salt thereof V) Medical The drug product according to claim 67 in the form of an orally ingestible tablet containing from 10 to 300 ffl& (calculated as base) of a solvate compatible with 3,5-Ekomi-dimeter piperazono)
propyl] - Rubazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof. or a medicament according to claim 67, suitable for parenteral administration. a pharmaceutically acceptable salt of @tyr 9-C3-(5,5->x-zometerbiperazono)propyl]-rubazole, or a pharmaceutically acceptable salt of a pharmaceutically acceptable salt Claims 65 to 4 featuring solvates
Drugs that comply with any of items up to Section 4. Song 9-(6-(5,5-beg Δ-zomethylbiperazono)
A medicament according to any of claims 65 to 44, characterized in that it is flovir]-rubazole dihydrochloride or a pharmaceutically acceptable solvate thereof. Claims 35 to 4 as set forth above with particular reference to Examples 10 to 16.
Drugs that comply with any of items up to Section 6.