JPS62153280A - 1,4-diazacycloalkane derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R1 is group shown by formu la II or formula III (A ring is benzene ring or cyclohexane ring; Y and Z are both H or bonded to form single bond, O, S, CH=CH, CH2-CH2, etc.,; R4 and R5 are H, halogen, alkyl, etc.,); R2 is H, alkyl or alkoxy; R3 is phenylalkyl wherein alkyl part is substituted with OH, diphenylmethyl, naphthyl, aromatic heterocyclic, etc.,; W is carbonyl or sulfonyl; X is alkylene; a is 2 or 3] or its salt. EXAMPLE:11-[4-(4-Cinnamyl-1-piperazinyl)butyrylamino]-6,11-dihydrobenz o[b,e] thiepin. USE:Having improved calcium antagonism, useful for preventing and remedying ischemic diseases of circulatory organs and hypertension, having an antiallergic action. PREPARATION:For example, a compound shown by formula IV (V is alcohol reactive residue) is reacted with a compound shown by formula V preferably in the presence of a base to give a compound shown by formula I.

Description

[Detailed Description of the Invention] Industrial Application Field The present invention is directed to a novel and industrial field of application that has calcium antagonistic effects and the like.
This invention relates to JTI 1,4-diazacycloalka/derivatives and salts thereof.

BACKGROUND OF THE INVENTION In recent years, as the physiology of calcium in living bodies has been elucidated, calcium antagonists having various chemical structures have been commercially available or studied. Typical examples include Brenylamino and Verapamil.

Nifedipine and diltiazem compounds are known.

Aspects of the Invention The present invention provides a new type of carnow antagonist, which does not belong to any family of carnow antagonists since 7f. stomach'
The purpose is to provide a new compound that has one purpose.

Formation and Effect of Invention (1) According to the present invention, general formula (1) [wherein 1 s 1 means a group represented by
means a hydrogen atom ring, and Y and Z both represent a hydrogen atom, or Y and Z together form a single bond, -
0-, -3-, -CII=CII-.

1 and 2 mean a hydrogen atom, a lower alkyl group, or a lower alkoxyl, and R3 is a phenyl (lower) alkyl group in which the alkyl moiety is substituted with human
llt class) alkenyl group, diphenylmethyl Jλ, naphthyl group, aromatic polycyclic group optionally substituted with lower alk, tolu or lower alkoxycarbonyl, benzoyl(lower)al, torno^, 70yl group, phenyloxy means a phenyloxysulfonyl group or a phenylsulfonyl group, and R4 and R5 are the same -
or differently, a hydrogen atom, a halogen atom, a lower alkyl atom, a trifluoro-methyl group, a lower alkyl group,
means a lower alkylthio group or a cyano group, W means a carbonyl group or a sulfonyl group, X means an alkylev group, a means 2 or 3, b means an integer from θ to 2 .

However, 1°11 "phenyl moiety in the above definition"
Phthylnoλ may be halogen IQ, human II
↑~n group, 2) may be substituted with r+ group, lower alkyl group, trifluoroI+methyl), r, or lower alkoxy group, and when A ring is a cyclohexane ring, Y
and 2 both mean hydrogen 15; 1 child, and R4 hydrogen II; Ru.

As salts of the compound represented by formula (1), physiologically
Preference is given to salts that can be tolerated, such as the hydrochloride salt.

Inorganic acid salts such as hydrobromide, hydroiodide, sulfate, phosphate, and oxa IcJ, maleino acid salts.

Fumarate, lactate, malate, citrate.

Alcoholic acid, benzoate, methane sulfonate, etc. 4
One example is an acid salt. Since the compound of formula (1) and its salt may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

The compound of formula (I) exists as stereoisomers because it contains two asymmetric carbon atoms on one side and, in some cases, one sulfur atom. obtain. These 1r solo forms, mixtures and racemates thereof are included in the compounds of the present invention.

Terms used in this specification will be explained below.

The lower alkyl group, lower alkoxy group, lower alkylthio group, or alkylev group may be linear or branched, but linear ones are preferable. Halogen I! ``Chi'' means fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, and particularly preferably 7 chlorine. Lower alkyl-containing (toke, carbon p, ', i means those containing 1 to 6 atoms, such as methyl.

Examples include ethyl, propyl, isopropyl, butyl, and methyl is preferred. The term "lower alkoxy group" means a group having carbon h7+ and 1 to 6 molecules, and examples thereof include methoxy, ethoxy, propoxy, impropoxy, ton, etc., with methoxy being preferred. The term "lower γ-alkylthio group" refers to a group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, etc., with methylthio being preferred. Alkylev group means one having 1 to 10 carbon atoms, such as methylene.

Examples include ethylene, trimedylene, tetramethylene, benkumethylene, hexamethylene, heptamethylene, and the like. Examples of unsubstituted or substituted phenyl (lower) alkyl λ in which the alkyl moiety is substituted with hydro or ton include 2-human 1x-2-phenylethyl, 2-human 1
xy-3-phenylpropyl, 2-human11. ton-2
-(4-fluoro'I phenyl)ethyl and the like.

An unsubstituted or -substituted phenyl (lower) alkenyl group means one in which the alkenyl moiety has 3 to 5 carbon atoms,
Examples include cinnamyl, o-, m- or p-fluorocinnamyl, o-, m- or p-chloro[J cinnamyl, o-, m- or p-methylcinnamyl and the like. Examples of aromatic polycyclic groups optionally substituted with iX by lower alkyl or lower alkoxycarbonyl include 2-thiazolyl, 2- or 4-pyridyl, 3-
Methyl-2-pyridyl, 3-ethoxycarbonyl-2-
Pyridyl, 2-pyrimidinyl, 6-methyl-4-pyrimidinyl.

Examples include 2-quinolyl. As 70 Ile J&,
For example, benzoyl, 2-riftyl, 2-70yl,
Examples include 2-thenoyl.

The compound of formula (1) and its physiologically acceptable salts are:
Compounds in which R3 is a 2-pyridyl group in formula (1) are also useful for the prevention and treatment of ischemic cardiovascular disorders and/or hypertension because they have excellent calcium antagonistic effects. Since it exhibits excellent antiallergic effects, it is useful for the prevention and treatment of allergic diseases such as bronchial asthma, allergic inflammation, i) measles, and atopic dermatitis.

Among the compounds of the present invention, those suitable as calcium antagonists have formula (1) in which ring A is benzene/ring, Y and Z together are -3-, -C11=C11-.

and R,ll is a cinnamyl group, 2-pyridyl group, 2
-pyrimidinyl group or 2-quinolyl group, one of Ra and R5 is a hydrogen atom, the other is a hydrogen atom or methyl J, U, W is a carbonyl group, and X is -(
C1h) n-, n is an integer from 1 to 5, a is 2,
Compounds and physiologically acceptable salts thereof, in which R is an integer of 0 to 2.

Particularly suitable compounds include, for example, the following compounds and their physiologically acceptable salts.

11-Cd-(4-y/Nami-1-piperazinyl)butyrylaminoco0,11-dihydrodibenzo[b
, el Chepin.

11-[-(4-di/reimi-1-piperazinyl)butyrylaminoco-2-methyl-6,11-dihyde-enriched dibe7zo[b, cldiepi/, and 5-[4-(4-cin-mil- 1-piperazinyl)butyryl aminoco-5
-dibenzo[a,dl cycloheptene Among the compounds of the present invention, those suitable as antiallergic agents include, for example, the following compounds and their physiologically acceptable salts.

11-[/I-[4-(2-pyridyl)-1-piperazinylcobutyrylamino]-0,11-dihydro 11-dibenzo[b,cl oxepin, and 5-[4-[4-(2- pyridyl)-1-piperazinylcobutyrylamino]-511-dibenzo[a,d]cyclohepte/ The compound of the present invention can be produced, for example, by the following method.

Method (a) General formula (■) R+-N-W-X-V (II)
(In the formula, R+, R2, W and Medium, R3
and a have the same meanings as above. By reacting with a compound represented by the following formula, a compound represented by the general formula (ri) can be obtained.

Examples of the reactive ester residue of alcohol represented by V in formula (II) include chlorine and bromine.

Halogens such as iodine, methanesulfonyloxy, etha/sulfur21. lower alkylsulfonyloxy groups such as niroquine;
-) Ruensl: 1. Arylsulfonyloxy JI1. can be mentioned.

The reaction between the compound of formula (II'I) and the compound of formula (In') is carried out in the absence of a solvent or in a suitable medium; specific examples of the solvent include benzene, toluene, xylene, etc. Aromatic hydrocarbons such as methylene chloride/, halogenated hydrocarbons such as chloroform, keto/classes such as methyl ethyl keto/, tetrahydrofuran/, ethers such as dioxane, ethanol, isopropyl alcohol, etc. alcohols, acetonitrile, dimethylformamide, etc. These solvents can be used alone or in a mixture of two or more. This reaction is preferably carried out in the presence of a salt bath, and the base Specific examples include: ■ Alkali bicarbonates such as sodium carbonate and potassium carbonate, alkali carbonates such as sodium carbonate and potassium carbonate, or organic bases such as triethylamine, trilobylamine, diisopropylethylamine, and N-methylmorpholine. Formula (III
) can also serve as an excess amount of the compound. Also, the expression (
When using a compound in which V is chlorine or bromine in II), the reaction proceeds internally when an alkali gold I+1 iodide such as 9'thorium iodide or potassium iodide is added.

The reaction temperature is usually about θ°C to about 200°C, preferably about 40°C to about 160°C.

A compound represented by the general formula (V) (in the formula, R3, X and 1 are the same as listed in 11if. ) or a reactive derivative thereof, a compound in which W is a carbonyl group in formula (1) can be obtained.

As reactive derivatives of the compound of formula (V), mention may be made, for example, of active esters, acid anhydrides, acid halides (especially acid halides). A specific example of an active ester is p
-Two phenyl esters.

2.4,5. -Triku'jro phenyl ester, Pe/Taku IJ l'l phenyl ester, nanomethyl ester.

N-hydroxysuccinimide ester, N-human (l
Examples include xyphthalimidonisal and the like.

As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include monoalkalic carbonates such as L-methyl carbonate and isobutyl carbonate, mixed acid anhydrides with toluester, and carbonic acid. ), mixed acid anhydrides with carbonic acid monoaryl esters such as nil, isokichi f, r fi ,
Examples include mixed acid anhydrides with alkali/acids such as pivalic acid.

When using a compound of formula (V), zinc II hexylcarbodiimide, 1-ethyl-5-(3-dimethylaminoprobyl)carbodiimide hydrochloride, luponyldiimidazole, 1-ethoxycarbodiimide, The reaction can be carried out in the presence of a condensing agent such as nyl-2-ethoxy-1,2-dihydroquinol.

The reaction between the compound of formula (TV) and the compound of formula (V) or a reactive derivative thereof is usually carried out in a solvent.

The solvent to be used should be appropriately selected according to the type of paint compound, etc., and examples include aromatic hydrocarbons such as penze, toluene, and xylene, needles such as diethyl ether, and tetrahydro-dioxa. , methylene chloride, halogenated hydrocarbons such as chloroform 11, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, water, etc., and these solvents may be used alone or in combination of two or more. This reaction is carried out in the presence of a base, if necessary, and as specific examples of the base, the specific examples of salt bars mentioned in the method (a) can be cited as they are. reaction/! I use the degree! :iF) (It varies depending on the type of compound, etc., but is generally about 0°C to about 150°C.

The compound of formula (1) produced by each production method is
1. By the method of madography, recrystallization or reprecipitation! 1111i, purified.

The compound of the formula (i) can be obtained in the form of a free base or salt, or a hydrate or solvate depending on the reaction and treatment conditions etc. It can be converted to the free base by treatment with a base such as alkali carbonate. On the other hand, a free salt can be converted into a salt by treatment with various acids according to conventional methods.

Below, a representative compound of the present invention, diltiase hydrochloride, a commercially available calcium antagonist!・Shows the results of pharmacological tests on tranilast, a commercially available anti-allergy drug,
The pharmacological action of the compounds of the present invention will be explained.

Test Example 1 Calcium t+'i anti-effect This test was carried out using the method of Godfraind et al. [rlr, J
, r'harmac,.

36, 549-5 GO (1909)].

Male rice skoo (Wist) with a body length of 250-300 g.
ar) Cut the isolated thoracic aorta of the rat into a spiral shape.
Arterial section specimens with a width of 3 to 411 m and a length of approximately 3011 m were prepared.

Aerated with a mixed gas of 95%02+5%CO2 and heated to 37°C.
I kept it warm! The specimen was placed in Krebs bicarbonate solution of 0.01 p% and a tension of 1 g was applied. The contraction response of the specimen was recorded three times with ink via a tension-displacement transducer and an oscillograph.

First, the solution in the Magnus bath in which the specimen was suspended was exchanged with a Ca''-free solution of Krebs bicarbonate to induce depolarization, and then CaCl was cumulatively added.
The Q-contraction curve due to Ca'' was determined.Next, a similar experiment was conducted in the presence of the test compound, and the contraction I curve due to C^'' was determined.
[^rch, int, I'harmac
odyn,, 1441. 299~ :l:1
O(14](F)] was used to calculate PA2 of Karun-ul* tt'j reaction. Note that r'At is Ca″
According to 1. )-yield curve (in the absence of test compound)
It is a numerical value defined as the antilogarithm of the molar concentration of the test compound required to shift the test compound twice in parallel to the higher concentration side.

The results are shown in Table 1. Values in the table do not represent the average (i±standard: 1E; C: for 3-G samples.

Table 1 Calcium antagonism 0 Combine the compound of Example 2 (the same applies below).

Test Example 2 Passive cutaneous anaphylaxis (1'CA) inhibition 11 This test was conducted using the method of Parper et al.
c'o1. EXP.

Thcr,,,Su13(2), 594~(i02(1)
975>].

The method of Lcvine et al. [1 nt, ^rc
h.

^Ilcrgy Appl', lsmunol,,
39.1513-I (i8 (+970))].
48 hours later, ovalbumin 2n
0.5 LA Eva/Sprue solution 1-1 containing 0.5 LA Eva/Sprue solution 1-1 was injected into the tail vein. Pigment note! After 11,430 minutes, the rats were killed by buffeting, and the shoulder skin of the nape was separated, and the area and color tone of the dye BF were measured. The average value of the measured values of the pigment spots at two locations was taken as the reaction value for each rat. Test compound is dissolved in 0.5% tragacanth aqueous solution or! The mixture was made cloudy and administered orally 1 hour before dye injection.

The inhibition rate was determined by comparing the response value of the test compound administration group with that of the 0.5% tragacanth aqueous a (vehicle) administration group.

Examples 4, 8, 9. Compounds II, +4 and 15 are all 80. / showed a suppression rate of over 50% in Nininokawa tit. On the other hand, tranilast showed an inhibition rate of 29.5% at a dose of 320 μ/bg.

The compound of formula (1) and its physiologically acceptable salts may be administered by oral administration, parenteral administration, single administration or D'f intestinal administration, but oral administration is preferred. The administration IA depends on the type of compound, the method of administration, i! !
It varies depending on the person's symptoms, age, etc., but usually 0.05 to 30
■1kt per day. The compound of formula (1) or its salt is i
It is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. Specific examples of formulations include tablets, capsules, granules, fine granules, powders, syrups, suspensions, IL injections, inhalants, patches, and small portions.

In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc. In addition, the following abbreviations are used to abbreviate the notation α in the following reference examples and examples. Sometimes.

MC: Methyl group EL: Ethyl group Ph: Phenyl group A: Ethanol ACN7T AE: Ethyl acetate C ■: Chloroform I]: Diethyl ether ■ 20-Hexane M: Methanol T: Toluene Reference Example 1 11-( Preparation of ■-amino-G, 11-dihyde "1 dibenzo[b, cl chepin 8.8H, 5-ri rJ O A mixture of 0 g of valeric acid and dioxane 1001 was heated under reflux for 15 hours with stirring. The solvent was distilled off under reduced pressure, and the residue M was recrystallized from ethanol to obtain 12.5 JT of the product 1). hru.

Melting point: 155-1513'C Reference Examples 2-8 Using the corresponding raw material compounds, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 1.

・II-(3-chlorobu[J pionylami/)-G, 1
1-dihydrodibenzo (b, clchepi/・1/
51; to11 melting point 177-177.5°C (ex/-
tlT viscous product)・11-(/I-chlorobutyrylamino)-G,II-dihyde[Idibenzo[b,cl
Chepia melting point 189-190℃ (recrystallized from ethanol) e■-
(4-chlorobutyrylamino)-2-methyl-6,11
-dihydrodibenzo[b, cl Chapin melting point 1118
~190°C (recrystallized from ethyl acetate) 5-(5-chlorovalerylamino)-511-dibenzo[a, dl cyclorJ Heptene Melting point 221~222°C (recrystallized from ethyl acetate)
;l; recrystallized from toluene) @5-(4-chlorobutyrylamino)-511-dibenzo[a, dl cyclorj heptene melting point 220-223°C (recrystallized from toluene) ・5-(3-di10 Propionylamino)-511-dibenzo[a,d]cycloheptene Melting point 220-223
°C (recrystallized from ethanol-n-hexane)・5-(
4-Chlo-11-butyrylamino)-511-10゜If-
dihydrodibenzo [a, dl cyclohebde/a point 22
0 to 222°C (recrystallized from toluene/toluene) Reference Example 9 +1-(4-chlorobutyrylamino)-2-methyl-0
, II-dihydro "Fujibenozo [b, alchepi/-5,
Preparation of 5-dioxide: +1-(/I-rjr+pudilylamino)-2-methyl-G,I! -dihydrodibenzo[b, cl chepin 5
．． 0 g was dissolved in 100 ml of τJroform, 12 g of m-chloroperbenzoic acid was added thereto under water cooling, and the mixture was stirred at 0° C. for 101 hours. The reaction solution was sequentially washed with 10% sodium hydroxide, old solution, water, and saturated saline, and then dissolved in magnesilla sulfate. , dry. The solvent was distilled off, and the residue was recrystallized from methanol to obtain 5.1 g of the desired product.

71 points 203-204°C Reference example 10 +1-(4-1111butyrylamino) -0,II
-Preparation of dihydrodibenzo[b,cl chepin-5,5-dioxide.

Corresponding 1! ;Using the compound, react and treat in the same manner as in Reference Example () to obtain the desired product. 1) Melting point 215-22
7°C (recrystallized from methanol) Reference Example 11 trans-1l-(4-ri[]butyrylamino)-G
, Oa, 7, 8, 9. IQ, lOa, II-Octahytone [I dibenzo[b, c Preparation of cochepine: (I) trans-[i, Oa, ? , 8, 9, 10. IO
a, ll-Oktahi Fu -11-# -+-7shi/
After melting and stirring a mixture of <7zo[b, cl chepin[71r and 40 g of ammonium formate] at 220°C for 2 hours, ammonium formate 1, 405' was added, and an additional 20I! Stir for a while. After 6 hours, water is added to the reaction mixture, and the precipitated 711i-like substance is extracted with toluene. After washing the extract with water, IQ condensation was carried out under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 10 form to obtain trans-11-formamide-〇, Ga, 7,8,
9.10. IOa, 11-octahydrodibenzo[
b. 5 g of cl chepin are obtained as an oil.

(2) A mixture of 5 g of 11-formamide, 401 parts of ethanol, and 20 parts of concentrated hydrochloric acid was heated at 100° C. for 30 minutes. The reaction solution was condensed under reduced pressure, and the residue contained 10%
Aqueous hrium carbonate solution I+1 is added, and the precipitated oil is extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then condensed under reduced pressure to trans-II-amino-G, Oa, ? , 8, 9, 10. IOa, II-octahyto'1 dibenzo[b, cll Chepi 4 is obtained as an oil.

(3) I-11-ami7 body 2.5 (ig, )
Luene 501 and 4-rill II butyric acid chloride 1.
The mixture of 91r was heated to 130°C for 2 hours. The solvent was distilled off under reduced pressure, and the residue 11r was subjected to silica gel column chromatography to obtain chloro! , to obtain 3.0 g of the desired product as an oil. mass spectrum m
/z: 331 (M+) Example 1 Production of [4-[:4-(2-pyridyl)-1-piverazinylcobutyrylamino]tsuk[+hexylphenylmethane: (4-lyl- + [l-butyrylamino)cyclohexylphenylmethane 1.5 ff, 1-(2-pyridyl)piperazine 2.3 g, sodium iodide 3γ3
A mixture of g and dimethylformamide 30-1 was heated at 60°C.
Stir for 15 hours. After 6, add 10% potassium carbonate aqueous solution and add chlorine 1;1. Extract with rum. The extract is washed with water, then with saturated saline, and then dried over magnesium sulfate. The solvent was distilled off, and the remaining trt was subjected to silica gel column 11 chromatography and eluted with methanol (too: 2) to obtain the desired product 1. :1
Get one gun.

Melting point 110-+32°C (recrystallized from ethyl acetate-diethyl knee pool) Example 2 +1 [/I-(4-sinli-mil-1-piperazinyl)butyrylamino]-6. II-dihydro l'l dibe/
zo[b, cl Chepia ummarei/acid salt 3/4 hydrate 'tA crystal: +1- (4-ri'10 butyrylamine/)-6, If-
Zohid 11 dibenzo [b, c] Chebini/1. Q Ir
, l −'/7namylpiperazine 1. An iQ compound of Og, 3.0 g of sodium iodide and 201 dimethyl, 1-lumamides is stirred at 100°C for 1 hour. After 6, the reaction solution was treated in the same manner as in Example 1, the residue was subjected to silica gel column chromatography, the part eluted with chloroform methanol (+00:3) was collected, and the solvent was distilled off. The remaining 1lIffi was converted into a maleate salt according to the +i° method and recrystallized from ethanol.
Obtain 8g.

Melting point 183-184°C Example 3 5-[4-[4-(2-pyrimidinyl)-1-piperazinylcobutyrylamino]-511-dibenzo[a, d
] Preparation of cycloheptene: 5-(4-di110butyrylamino)-511-dibenzo[a,d]cycloheptene2. Off! -(2=pyrimidinyl)piperazi72. Off, a mixture of 4.8 g of thorium iodide and 201 g of dimethylformamide was heated at 60°C for 16
Stir for 1111 minutes. After cooling, the reaction solution was treated in the same manner as in Example 1, and the residue r+'f was subjected to silica gel column 1 magnetography and diluted with chloroform-methanol (100:3).
Then, 11th time is obtained and 1.4 g of the target product is obtained. Melting point 19
9-2 old"C (recrystallized from ethyl phosphoric acid) Example 4 11-[/l-[4-(2-pyridyl)-1-pipecidinyl]butyrylamino]-0,11- Dihydrodibenzo [b, cll osevin quarter hydrate preparation ゛1
l-(4-di'10-butyrylamino)-0,II-dihydrodibenzo[b, cl oxepin 2.0 g,
2.81 units of 1-(2-pyridyl)piperazine, 4.8 g of sodium trichloride, and 301 units of dimethylformamide
The mixture is stirred at 60° C. for 16 hours. After 6, the reaction solution was treated in the same manner as in Example 1, and the remaining rri was subjected to silica gel column chromatography, the portion eluted with ethyl acetate was collected, and the solvent was distilled off. Recrystallization from [1.3 g] was obtained. Melting point +41-143°C Example 5 11-[4-(4-cy/namyl-1-piperazinyl)butyrylami7]-2-methyl-6,11-dihydrodibenzo[b,c]chepia-5,5-dioxyto. IfI: 1l-(4-
Chlorobutyrylamine/)-2-methyl-6,II-dihydrodibenzo[b,cl 2.5 g of chepin-5,5-dioxide, 1.5 g of 1-nnnamylpiperazine, 1.0 g of sodium iodide and dimethyl, 1. Stir the mixture of Lumamide 201 at 100°C for 1 hour. After 6, 1
Add 0% aqueous potassium carbonate solution and extract with II+I;l;rum. The extract is washed with water, then with saturated saline, and then dried over magnesium sulfate. 1δW was distilled off, the remaining tN was subjected to silica gel column chromatography, and the IB portion was collected using 10 form-methanol (+00:5). After the solvent was distilled off, the residue was purified using a conventional method. It was converted into a maleate salt according to
] Target 2.0 +r (1). Melting point 174-17
6°C Example [l +1- [4-(4-cinnamyl-1-piperazinyl)
Production of dibenzo[b,a]diepin-5,5-dio,tondo simalate hemihydrate: Using the corresponding +(1 compound) The desired product is obtained by reacting and treating in the same manner as in Example 5. Melting point: 175-176°C (recrystallized from ethanol) Example 7 trans-1k [4-[4-(2-pyridyl)-1-
Piperazinylbutyrylamino]-G, Oa, 7゜8
．． 9,10. IOa, 11-octahyto 11 dibenzo[
b, Al Chepin's "JJ-made Nidorans-1l-(4-chlorobutyrylamino)-(i
,Ga,? , 8, 9, 10. IOa, II-Occuhide [1 dibenzo[b, cl chepin 3.0 g, 1-
(2-pyridyl)piperazine 3.2g and xylene 5
01 mixture on an oil bath at 160°C! Heat for 6 hours. After washing with 10% potassium carbonate solution and then with water, the solvent was distilled off, and the residue was subjected to silica gel column column 1. (1:1) to obtain 1.8 g of the target product as an oil.

Mass spectrum m/z: 4 (i4 (M+)) Example 8 Preparation of 5-[4-[4-(2-pyridyl)-1-piperazinylcobutyrylaminoco-511-dibenzo[a, dl] cloheptene : 5-amino-5II-dibenzo[a, dl cyclohezotene 2.4 ff+ 4-[4-(2-pyridyl)-1
-Piperazinyl] A mixture of 2.9 g of acetic acid, 2.3 g of synchlohexylcarbodiimide and 50-1 methylene chloride is heated in #2 at room temperature for 15 hours. The precipitate was removed by filtration, the a4 liquid was concentrated under reduced pressure, and the residue was recrystallized from 10 formhedethyl ether to obtain 2.0 g of the desired product.

Melting point! 71-173°C Examples 9-52 Using the corresponding raw material compounds, reactions and treatments were carried out in the same manner as in Examples 1-8 to obtain the compounds shown in Tables 2-5.

(Margin below) Table 2 Table 3 Table 3 (continued) (Margin below) Table 4 1 Disassembly Table 5 Patent applicant: Dai [Ippon Seibin Co., Ltd. A small island - continuation of Brothers 1 page [Stock] Int, C1, 4 identification symbol Internal office reference number BM 337:00)

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a group represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A ring means a benzene ring or a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together represent a single bond, -O-,
-S-, -CH=CH-, -CH_2CH_2-, -CH_2O
− or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R
_2 means a hydrogen atom, lower alkyl group or lower alkoxy group, R_3 is a phenyl (lower) alkyl group, phenyl (lower) alkenyl group, diphenylmethyl group, naphthyl group, where the alkyl moiety is substituted with hydroxy, optionally means an aromatic heterocyclic group, benzoyl (lower) alkyl group, aroyl group, phenyloxycarbonyl group, phenyloxysulfonyl group, or phenylsulfonyl group substituted with lower alkyl or lower alkoxycarbonyl, and R_4 and R_5 are the same or Differently means a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group or a cyano group, W means a carbonyl group or a sulfonyl group, X means an alkylene group, a means 2 or 3, and b means an integer from 0 to 2. However, the phenyl moiety and naphthyl group in the above definition may be optionally substituted with a halogen atom, hydroxy group, nitro group, lower alkyl group, trifluoromethyl group, or lower alkoxy group, and if ring A is In the case of a cyclohexane ring, Y and Z both mean a hydrogen atom, or Y and Z together form ▲Numerical formula, chemical formula, table, etc.▼, and R_4 means a hydrogen atom. ] A 1,4-diazacycloalkane derivative and its salts.