JPS63119442A - Amine compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is formula II or formula III; ring A is benzene ring or cyclohexane ring; Y and Z are both H or together form -O-, -S-, -CH=CH-, -CH2CH2-, -CH2O-, etc.; R2 is H, lower alkyl or lower alkoxy; R3 is H, lower alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, saturated heterocyclic group, etc.; R4 is aryl, heteroaryl, etc.; R5 is H, halogen, OH, NO2, lower alkyl, carboxy, etc.; R6 is H, halogen, OH, NO2, lower alkyl, etc.; V is CO or sulfonyl; W is single bond, lower alkylene, etc.) and salts thereof. EXAMPLE:[4-(N-benzyl-N-cyclopropylamino)butylylamino]diphenylmethane. USE:A calcium antagonist. PREPARATION:A compound expressed by formula IV is reacted with a compound expressed by formula V in the presence of a base at 40-150 deg.C to provide a compound expressed by formula I.

Description

[Detailed Description of the Invention] Industrial Application Field The present invention is directed to a novel method that has a calcium antagonistic effect and the like.
This article relates to basic amine compounds and their salts.

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. Representative examples include prenylamine and verapamil.

Nifedipine and diltiazem compounds are known.

Purpose of the Invention The present invention provides a new type of calcium antagonist #X1 (
lj.

According to the present invention, the general formula (1) [wherein R1 means a group represented by, A ring means a benzene ring or a cyclohexane ring, and Y and Z both mean a hydrogen atom, or Y and 2
together, -o-, -8-.

R2 means a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R3 means a hydrogen atom, a lower alkoxy group or an alkyl group.

Alkenyl group, alkynyl group, cycloalkyl group, 1-
A cycloalkyl group having two substituents (the substituents are a halogen atom and a hydroxy group).

Lower alkyl L&, cycloalkyl group, lower alkoxy group, lower alkylthio group, acyloxy group, acylthio group, di-substituted amine group, acylamide 7 group, carboxy group,
lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, oxo group or acetalized or ketalized oxo group), saturated polycyclic group, having 1 to 2 substituents Saturated heterocyclic group (the substituent is a halogen atom, a hydroxyl group2, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an acyloxy group, an amino group,
lower alkylamino group, di-substituted amino group, anrulamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkylcarbamoyl group), aryl group, 1 to 4 substitutions Aryl 2 & (the substituent is a halogen group).

Hydroxy group, nitro group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group,
Amino group, lower alkylamino IX, disubstituted amino r&
, acylamino group, cyan group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkylcarbamoyl group, and when two substituents are adjacent, they together form an alkylene/dioxy group. (may be formed).

a cycloalkenyl group condensed with an aryl group (the aryl moiety and/or the cycloalkenyl moiety may be substituted), a heteroaryl group;

Heteroaryl group having 1 to 3 substituents (M substituents are halogen atom, hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, acyloxy group, ami7 group).

(lower alkyl 7 groups, di-substituted amino l&, acyl ami/ groups, cya/ groups, carboxy groups, lower alkoxycarbonyl groups, carbamoyl groups, lower alkyl carbamoyl groups or di-lower alkyl carbamoyl groups), lower alkyl groups having a substituent (The substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group.

Okyne group, acetalized or ketalized Okyne group, di-substituted ami7 group, acylamino group, acyloxy group, acylthio group, carboxy i, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, cycloalkyl group.

Cycloalkyl group bearing 1 to 2 substituents.

Saturated heterocyclic group, saturated polycyclic group having 1 to 2 substituents, aryl group, aryl group having 1 to 4 substituents,
a heteroaryl group or a heteroaryl group having 1 to 3 substituents).

An alkenyl group or an alkynyl group having a substituent (the substituent is a halogen atom or a hydroxy group).

lower alkoxy7 group, lower alkylthio group, acyloxy group or acylthio group), acyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkylcarbamoyl group, R4 is an aryl group, 1- An aryl group having four substituents (the substituents are a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkyl group, a dio group, an acyloxy group, an ami7 group, Lower alkylamino group, di-substituted amino group, acylamino LC, sia/group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkylcarbamoyl group, and when two substituents are adjacent may be taken together to form an alkyrefudioxy group), a heteroaryl group, or a heteroaryl group having 1 to 3 substituents (the substituents include a halogen atom, a hydroxy group, a nitro group, a lower Alkyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, di-substituted amine group, acylamino group, sia/group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkyl group carbamoyl group), and R5 is the same or different and is a hydrogen atom or a halogen/atom.

Hydroxy group, nitro group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group,
Acyloxy group, amide 7 group.

Lower alkylamino group, di-substituted amine 7 group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl! , means a low-m alkylcarbamoyl group or a di-lower alkylcarbamoyl group, and Re is the same or different and is a hydrogen atom or a halogen atom.

Hydroxy group, nitro group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group,
means an acyloxy group or a cyano group, (1) means a carbonyl group or a sulfonyl group, W means an alkyref group, and X means a single bond, a lower alkyref group, lower alkoxycarbonyl, carbamoyl, lower alkylcarbazoyl, di Lower alkylcarbamoyl means a syl group or an acyl group, where d is 1 or 2), or a lower alkyleph group substituted with -CO-<ketalized form).

-O-, -3-, -NRa - (in the formula, Ra means the same as lower alkyleph), -CH=
means a lower alkylene group interrupted by a group selected from Cll- and -CmiC- or bonded to R4 through these groups, a and b each mean an integer from 1 to 4, C is 0-2
means an integer of

However, when the A ring is a cyclohexane ring, Y and Z both mean a hydrogen atom, or Y and an atom mean an atom.

] An amine compound and its salts are provided.

Salts of the compound represented by formula (I) refer to salts of the compound in which an amino group or substituted amino group is present in formula (I). The salts are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and oxalate;
Compounds of formula (1) and their salts include organic acid salts such as maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, etc. They may exist in the form of hydrates or solvates, so
Hydrates and solvates of these are also included in the compounds of the present invention.

The compound of the formula (summer) may exist as stereoisomers because it may contain one or more asymmetric carbon atoms and, in some cases, one asymmetric sulfur atom. compounds, mixtures thereof and racemates are included in the compounds of the present invention.

Terms used in this specification will be explained below.

The lower alkyl group, lower alkyl moiety, alkyl group, alkyl moiety, lower alkyref group, or alkylene group may be linear or branched. "Lower alkyl group" means one having 1 to 6 carbon atoms, and "alkyl group" means one having 1 to 12 carbon atoms, such as methyl, ethyl,
Propyl, isopropyl, butyl, inbutyl, bethyl, impentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-ethylbutyl, heptyl.

Examples include octyl and decyl. "Lower alkoxy group" means a group having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, impropoxy, butoxy, t-butoxy, and the like.

"Alkenyl group" means an acyclic or cyclic group having 1 to 2 double bonds and 3 to 10 carbon atoms, such as allyl, 2-butenyl, 3-methyl-2-butenyl,
3- or 4-pentenyl.

2-. 3-. 4- or 5-hexenyl, cyclobe/
thenyl, cyclohexenyl, cyclopentenylmethyl,
Examples include cyclohexenylmedyl, 2,4-pe7tadienyl, and the like. "Alkynyl group" means 3 to 1 carbon atoms
Examples thereof include 2-propynyl, 3-butynyl, 5-hexynyl, and the like. "Cycloalkyl group" means a group having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododenyl, adama/thyl, norbornyl, decahydronaphthyl, etc. It will be done. "Halogen atom" means fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred. "Acyl group" means an aliphatic carboxylic acid residue or an aromatic carboxylic acid residue having 1 to 7 carbon atoms, such as formyl, acetyl, 2-methylacedel,
Propionyl, butyryl, imbutyryl, benzoyl.

Examples include naphthoyl. "Di-117-substituted ami7 group" means a di-lower alkylamino group or a cyclic amino group, and specific examples of the cyclic amino group include morpholino, 1-pyrrolidinyl, piperictu, 4-methyl-1-piperazinyl, etc. Can be mentioned. Examples of the "aryl group" include phenyl, naphthyl, and the like. "Heteroaryl group"
means a unilocular or bicyclic type containing a nitrogen atom or a sulfur atom, such as furyl, chenyl, imidazolyl, thiazolyl, oxasilyl, inoxasilyl, pyridyl, indolyl, The term "lower alkyl group having a substituent" means one having one or two of the above substituents at any position, but the substituent may be a halogen atom, a hydroxy group, Alkoxy group, lower alkylthio group, oxo group, acetalized or ketalized okyne group,
When it is an acyloxy group or an acylthio group, these substituents are bonded to a carbon atom other than the 1-position.

"Saturated heterocyclic group" means a group derived from a cyclic ether, cyclic thioether or cyclic amine containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms, such as tetrahydrofuryl, tetrahydrochenyl, tetrahydropyranyl. , ], 3- or 1,4-dioxacyclohexyl, 2- or 3-pyrrolidinyl, 2-. 3- or 4-piperidinyl, 2- or 3-morpholinyl,
2- or 3-piperazinyl, etc., but the nitrogen atom in the group derived from a cyclic amine may have a substituent such as a lower alkyl group, an aralkyl group, an acyl group, or a lower alkoxycarbonyl group. When is a saturated heterocycle containing an oxygen atom or a sulfur atom,
These l! R8 is bonded to a nitrogen atom at a position other than the Ir6 atom or the carbon atom adjacent to the sulfur atom. "Lower alkylev group" means one having 1 to 6 carbon atoms, and "alkylene group" means one having 1 to +2 carbon atoms, such as methylene/, ethylene, methylmethylene, trimethylene.

Examples include tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, and decamethylene.

Preferred among the compounds of the present invention are formula (I) in which Y and Z taken together are -S-, -CH=CH-.

R2 is a hydrogen atom, one of R11 and Re is a hydrogen atom, the other is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a lower alkylthio group, and ■ is a carbonyl group, W = (C
) h) Compounds and physiologically acceptable salts thereof, wherein n-, n is an integer of 1 to 5, a and b are each 1 or 2, and c is an integer of 0 to 2.

The compound of the present invention can be produced, for example, by the following method.

General formula (■) R+-N-V-W-T (■) (in the formula,
RI+ R*+ v and W mean the same as above, and T means a reactive ester residue of alcohol. ) and the compound represented by the general formula (Ill) (wherein R4 means the same as above, and X' is the above-mentioned X other than a single bond)
R3' means the same as R3 above, but includes an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an acyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group. group or di-lower alkylcarbamoyl group. ) By reacting with a compound represented by formula (1)
in which R3 is a group other than an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, acylva, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, or dilower furkylcarbamoyl group, and X is other than a single bond. A compound that is a group can be obtained.

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

A halogen atom such as iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, an arylsulfonyloxy group such as be/zenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy Can be mentioned.

The reaction between the compound of formula (II) and the compound of formula (Ill) is carried out without a solvent or in a suitable solvent, and specific examples of the solvent include aromatic carbonization compounds such as benzene, toluene, and xylene. hydrogens, ketones such as methyl ethyl ketone,
Ethers such as tetrahydrofuran and dioxane,
Examples include alcohols such as ethanol and isopropyl alcohol, acetonitrile, and dimethylformamide.

These solvents can be used alone or in combination! A mixture of i or more is used. This reaction is preferably carried out in the presence of a base, and specific examples of the base include alkali carbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate,
Examples include alkali carbonates such as potassium carbonate, or bases such as triethylamine and N-methylmorpholine, but an excess amount of the compound of formula (m) may also serve as the base.

Furthermore, when using a compound in which T is chlorine or bromine in formula (II), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. 0℃ to about 200℃,
Preferably the temperature is about 40°C to about 150°C. In addition, an amine 7 reactive with R3 or R4 of the compound of formula (Iff)
When groups are present, it is desirable to protect these groups according to conventional methods and to remove them after the reaction.

■ R+-NH(IV) (In the formula, R1 and R2 have the same meanings as above.)
A compound represented by the general formula (V) (hereinafter referred to as the blank) (in the formula, R3, Ra, W and X have the same meanings as above) or a reactive derivative thereof are reacted. By doing so, a compound in which V in formula (I) is a carbonyl group can be obtained.

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

24+ 5+ -)! J Rio phenyl ester, pentachlorophenyl ester, cyanomethyl ester.

Examples include N-hydroxysuccinimide ester and N-hydroxyphthalimide ester.

As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include ethyl chloroformate, inbutyl chloroformate, mixed acid anhydride with an alkyl lorformate, and chloroformate. Mixed acid anhydrides with lorformic acid aryl esters such as phenyl acids, mixed with alkanoic acids such as isovaleric acid, pivalic acid r! l
Examples include i-anhydrides and the like.

When using the compound of formula (V), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyldiimidazole, 1-ethoxyl-2-ethoxy-
The reaction can be carried out in the presence of a condensing agent such as 1,2-dihydroxy/phosphorus.

The reaction between the compound of formula (IV) 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 raw material compound, etc., and for example, be/then. Aromatic hydrocarbons such as toluene and quinoa, ethers such as diethyl ether and tetrahydrofuratodioxa, halogenated hydrocarbons such as ethyl chloride/l chloride, ethyl acetate, acetonitrile, dimethylformamide, Dimethyl sulfoxide, water, etc. are mentioned, and these eB soots are used alone or in a mixture of 2:1 or more.The reaction is carried out in the presence of a base if necessary, and specific examples of the base are , (a) The specific examples of the bases mentioned in the method section can be listed as they are. reaction m
The degree of the raw material compound used! It varies depending on the type, etc., but it is usually -20℃ to about ! 50°C, preferably about 0°C to about 80°C. In addition, a reactive amine 7 is present in R+ of the compound of formula (■) or R3 or R4 of the compound of formula (V).
When a group or a carboxy group is present, it is desirable to protect these groups according to a conventional method and remove them after the reaction.

When the product obtained by the production method (a> and (b) has a hydroxy group, an amino group, or a monosubstituted amine 7 group in its structure, it is converted into an acylmi-g form by acylation according to a conventional method. be able to.

The compound of formula (I) produced by each of the above production methods can be isolated by conventional methods such as chromatography, recrystallization, or reprecipitation.
Refined.

The compound in which an amino group or a substituted amino group is present in formula (I) can be obtained in the form of a free base or a salt depending on the selection 1 reaction and treatment conditions of the raw material compound.

Salts can be converted to the free base in conventional manner, eg, by treatment with a base such as an alkali carbonate. on the other hand,
Free bases can be converted into salts by treatment with various acids according to conventional methods.

The compound of formula (RI) and its physiologically acceptable salts have excellent calcium antagonistic effects, and therefore are effective against hypertension and/or
It is also useful for the prevention and treatment of ischemic cardiovascular disorders.

Below, the results of pharmacological tests on representative compounds of the present invention and diltiazem hydrochloride, a commercially available calcium antagonist, will be shown, and the pharmacological action of the compounds of the present invention will be explained.

Test Example Calcium antagonism This test was performed using the method of Godfralnd and Kaba [1
1r, J.

Pharmac, 30.549-500 (190
9)].

Male Wistar (1li) body weight 1250-300g
The isolated thoracic aorta of a star) rat was incised in a spiral fashion to prepare an artery section specimen with a width of 3 to 4 mm and a length of approximately 3 (++n).

Specimens were placed in a Magnus tank containing 101 Krebs bicarbonate solution kept at 37°C and a gas mixture of 95% 02 + 5% CO2 was aerated, and a tension of 1 g was applied. The contraction response of the specimen was recorded with an inkjet oscillograph via a tension-displacement transducer.

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 CaC1z was cumulatively added.
A dose-contraction curve due to Ca'' was determined. Next, a similar experiment was conducted in the presence of the test compound, a dose-contraction curve due to Ca'' was determined, and Van Rossum (7) method [^rc
h, +nt, Pharmacodyn, 143
．． pA2 of calcium antagonism was calculated according to 299-330 (1903>).
Dose - is the number defined as the antilogarithm of the mole of test compound 0 degrees required to translate the contractile flexure (in the absence of test compound) by a factor of 2 to the higher 15 degrees.

The results are shown in Table 1. The numerical values in Table 1 represent the average value and standard error for the three pieces 3 to 6e'.

Table 1 Calcium antagonistic effect 0 means the compound of Example 1 (the same applies hereinafter) 6 Table 1
(Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) As is clear from Table 1, most of the compounds of the present invention tested exhibited much stronger calcium antagonistic activity than diltiazem hydrochloride.

Test Example 2 For antihypertensive effect experiments on spontaneously developing hypertension (Rough) (SHR), 18-26 week old male SHR [Kaimoto-Aomoto line;
Jap, CIrcul, J., 27.282-2
93 (1983) was used. The average blood pressure of most animals was 150-170 m++l-1 g. Wee
ks and Jones' method [Proc.

SOC, EXP, old of, Med,, 104.64
A cannula (polyethylene tube, PE-50, manufactured by CIay Adams, USA) was implanted into the abdominal aorta of the rat according to the method described in [0-048 (1900)]. The other end of the cannula was exposed and fixed on the back of the neck. After 1 to 4 days, the cannula was transduced using a pressure transducer (Nihon Kohden,
MP-4Tu) and the awake blood pressure was measured by the direct method. On the day of the experiment, pre-administration blood pressure was measured for 1 hour and then 0.5% tragacanth aqueous solution was added! ! ! The cloudy test compound was orally administered (3, Oal Yagiri Heshi), and blood pressure was continuously measured for 5 hours thereafter. 2 to 5 animals were used per group.

Table 2 shows the maximum degree of hypotension in mean blood pressure of the test compounds. Most of the compounds of the present invention showed their maximum hypotensive effect 30 to 60 minutes after administration.

Table 2 Antihypertensive effect ”) means the compound of Example 4 (the same applies hereinafter).

Table 2 (Continued) As is clear from Table 2, all of the compounds of the present invention have I
Oral administration of 0 to 30 liters of water showed a clear hypotensive effect.

On the other hand, diltiazem hydrochloride did not show any noticeable hypotensive effect at 30 μg.

The compound of formula (I) and its physiologically acceptable salts may be administered via oral, parenteral or rectal administration, but oral administration is preferred. The dosage varies depending on the type of compound, administration method, patient's symptoms, age, etc., but is usually 0.001 to 20 g/day. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As pharmaceutical carriers, substances that are commonly used in the pharmaceutical field and do not react with the compound of formula (I) or its salts are used, specifically, for example, lactose, glucose, mannitol, dextrin/l cyclodextrin, etc. , starch, white sugar.

Magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose.

Ion exchange tree 1111t, methyl cellulose, gelatin.

Gum arabic, pullulan, hydroxypropylce, lk
lj-su, low substituted e-hydroxypropyl cellulose,
Human axypyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc.

Tragacanth, bentonite, vegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester,
Sodium lauryl sulfate, cocoa butter.

Glycerin, fatty acid glycerin ester, purified phosphorus/phosphorus, glycerogelatin, porin rubate, macrogol,
Examples include vegetable oil, wax, propylene glycol, water, and the like. Dosage forms include tablets, capsules, granules, fine granules, powders, and syrups.

Examples include suspensions, injections, and small portions. These formulations are prepared according to conventional methods. In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use. Also tablets and granules.

Granules may be coated by known methods.

These preparations can contain the compound of formula (I) or a physiologically acceptable salt thereof in a proportion of 0.5% or more, preferably 1 to 70%. These formulations may also contain other ingredients of therapeutic value.

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. , IR spectrum, NMR spectrum, etc.

Further, in the following reference examples and examples, the following abbreviations may be used to simplify the notation α.

Mc: Methyl group Et: Ethyl group Ph: Phenyl group 〇 Niacetyl group e-Cml-12m=tortoise 2m-membered ring cycloalkyl A
: Ethanol AE : Ethyl acetate CH : Chloroform E Nidiethyl Nitilt ■ : Hexane T : Tol/ Reference Example 1 +1-(5-chlorovalerylamino)-8,I+-dihydrodibenzo[b,elProduction of chepin= 11-Ami/
-6.11-Dihydrodihenzo[b,elchepin8.
8g, 5-chlorovaleric acid chloride e. A mixture of 7100 ml of dioxa and 7100 ml of dioxa is heated under reflux for 15 hours with stirring. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 12.5 g of the desired product.

Melting point: 155 to +5 [i° C. Reference Examples 2 to 27 Using the corresponding raw material compounds, the compounds shown in Tables 3 to 5 are obtained by reacting and treating in the same manner as in Reference Example 1.

(Margins below) Table 3 ') m/z (M") (Same below) (Margins below) Table 4 ") m/z (M") (Same below) (Margins below) Table 5 Reference example 28 11-( 4-chlorobutyrylamino)-6,11-dihydrodibenzo[b,el Chepia-5,5-dioxide production: !+-(4-chlorobutyrylamino)-6,11-dihydrodibenzo[b,e 75.0 g of Kochepi was dissolved in 1001 chloroform, and 12 g of m-chloroperbenzoic acid was added thereto while cooling with water, followed by stirring at 0° C. for 1 hour.

The reaction solution was washed with 10% hydroxide), water, and saturated saline in this order, and then dried over magnesium sulfate.

The solvent was distilled off, and the residue was recrystallized from methanol to obtain 5.1 g of the desired product. Melting point 215-227°C Reference Example 29 Production of 11-(4-di1jbutyrylamino)-6,11-dihydrodibenzo[:b,e]chepin-5-oxide: +1-(4-chlorobutyrylamino)- all-dihydrodibenzo[b, ell Chepi 10 to methylene chloride 5
00ml of m-chloroperbenzoic acid under water cooling. After adding Og, stir at room temperature for 30 minutes.

The reaction solution was washed with 10% magnesium hydroxide, water, and saturated saline, and then dried over magnesium oxide.

Methylene chloride was distilled off, and the residue was dissolved in chloroform-hexane 7
860 g of the target product was obtained by recrystallization from the following.

Melting point 210-212°C Reference example 30 trans-11-(4-chlorobutyrylamino)-G,
Ga,? , 8, 9, 10. Production of IQa, 11-octahydrodibenzo[b, el chepin: (1) trans-〇+61+7+8+9+ 10. l
oa, It-octahydro-11-oxodibenzo[
b, e] After melting and stirring a mixture of 6 g of Chepia and 40 g of ammonium formate at 220°C for 2 hours, 1 H of 40 g of ammonium formate was added, and the mixture was further stirred at 220°C for 2 hours. After cooling, add water to the reaction mixture and extract the precipitated oil with toluene. After washing the extract with water, it was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography and eluted with chloroform to obtain trans-11-formylamino-〇, Oa, 7,8,9.10. loa, I+-octahydrodibenzo[b,e]chepin5g8nlI
Obtained as a solid product.

(2) A mixture of the above 11-formylamino compound 5ff, ethanol 401 and salt production ff120m+ is heated under reflux at 100°C for 30 minutes. The reaction solution was concentrated under reduced pressure, 10% potassium carbonate was added to the residue, and the precipitated oil was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain trans-11-amino-G.
, Oa, 7, 8, 9.10. 74 g of IOa, ++-octahydrodibenzo[b,e cochepi are obtained as an oil.

(3) A mixture of 2.513 g of the above 11-ami7 body, 501 toluene, and 1.9 g of 4-chlorobutyric acid chloride is heated under reflux at 130° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 3.0 g of the desired product as an oil wipe. Mass spectrum m/z: 337 (M
”) Example 1 [Production of 4-(N-benzyl-N-cyclopropylamino)butyrylaminocodiphenylmethane: (4-riaa
Butyrylamine/) diphenylmethane 2.0g, N-benzyl-N-cyclopropylamine:/4. A mixture of Og and xylene 501 was heated under reflux for 6 hours with stirring. Toluene 100 x 1 was added to the reaction mixture, and 10% potassium carbonate,
After sequentially washing with water and saturated saline, drying with magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with aaa form to obtain 1.5 g of the desired product. Melting point 107-109°C (recrystallized from diethyl ether) Example 2 Production of [4-(N-benzyl-N-cyclopropylamino)butyrylaminococyclohexylphenylmethane: (4-chlorobutyrylamino)cyclohexyl A mixture of 1.5 g of phenylmeth/2.0 g of N-benzene-N-cyclopropylamine, 5 g of sodium iodide, and 151 g of dimethylformamide is stirred at 60° C. for 10 hours. After cooling, add 10% potassium carbonate to the reaction solution and extract with chloroform. Drain the t111 fluid into water.

After sequentially washing with saturated saline, drying with magnesium sulfate. Distill the chloroform away! i! The supernatant was subjected to silica gel column chromatography and eluted with chloroform to obtain 1.2 g of the desired product.

Melting point 85-87°C (recrystallized from diethyl ether-hexane) Example 3 Preparation of 5-[5-(N-benzyl-N-butylamino)valerylaminoco-5H-dibenzo[a,d]cycloheptene: 5-(5 -chlorovalerylamino)-5H-dibenzo[
a, d] cyclohepte 71.5 g, N~benzyl-N-
Butylamine 1.5g, sodium iodide 2.0g
and dimethylformamide (50 ml) at 100°C.
The reaction solution stirred for 1.5 hours was treated in the same manner as in Example 2 to obtain 1.1 g of the desired product as an oil.

1.0 g of the above free base and Shu! Dissolve 0.4 g of II in 51 ml of ethanol. This m solution of ethanol was added dropwise to diethyl ether 2001 with stirring, and the precipitate was collected by filtration to obtain 1.0 g of the target oxalate 3/4 hydrate. Melting point 98-101°C Example 4 +1- [4-[N-bearzyl-N-(2-hydroxy-2-methylpropyl)amino]butyrylamino]-2
-Methyl-11-dihydrodibenzo[:b,elChepin production: +1-(4-chlorobutyrylamino)-2-methyl-+
3. I+-dihydrodibenzo[b, el chepin 1.
0g.

1.0 g of N-be/gi-N-(2-hydroxy-2-methylpropyl)amine, 3.0 g of sodium iodide
and 20 ml of dimethylformamide is stirred at 60° C. for 18 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 0.7 g of the desired product as an oil.

The above free base was treated in the same manner as in Example 3 to obtain the desired oxalate salt.! Obtain hydrate. Melting point 87-90°C (reprecipitation from ethanol-diethyl ether) Example 5 11 [4-CN-benzyl-N-(2-hydroxybutyl)aminocobutyrylamino]-(3,+1-dihydrodibenzo[b,e ] Chapin's!!!ifl:1l-
(4-Chlorobutyrylamino)-all-dihydrodibenzo[b,e]Chepia 2. Og, N-benzyl-N-
(2-hydroxybutyl)amine 2.0 g.

Sodium iodide 4.0g and dimethylformamide 3
The mixture of 01 was stirred at 60°C for 10 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 1.3 g of the desired product as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the desired product, oxalate 3/4 hydrate.

Melting point 90-92°C (reprecipitation from ethanol-diethyl ether) Example 6 +1-[4-(N-benzyl-N-butylamino)butyrylamino]-all-dihydrodibenzo[b,e]
Preparation of chepin-5-dioxide: -(4-chlorobutyrylamino)-8,11-dihydrodibenzo[b,
e] Chepine-5,5-dioxide 2.0g, N-bebutyl-N-butyl 7mi72. Og.

3.0 g of sodium iodide and 1 part of dimethylpolamide
The mixture of No. 51 is stirred at 00° C. for 20 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 0.35 g of the target product as an oil. Mass spectrum m/z: 490 (M”
) Example 7 trans-11-[4-(N-benzyl-N-cyclopropylamino)butyrylamine/ ]-G, Gλ, 7.
8,9゜10, IOa, II-octahydrodibenzo [
b, e] Production of chepin Nidoran-71-(4-chlorobutyrylamino)-0,
6a, 7, 8, 9, 10. IOa, 11-octahydrodibenzo[b,e]chepine 1.0 g, N-benzyl-
N-cyclopropylamide/1.0g and Xylef 50m
The mixture of 1 was heated under reflux at 150° C. for 10 hours. , the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (+00:3
) to obtain 0.6 g of the target product as an oil.

Mass spectrum m/z: 448 (M") The above free base is treated in the same manner as in Example 3 to obtain the target product, oxalate 5/4 hydrate. Melting point: 88-90°C (ex/-
Example 8 +1-[4-[N-benzyl-N-(2-tetrahydropyranylmethyl)aminogobutyrylamino]-〇,I
Production of I-dihydrodibenzo[b,elchepi/-4-
[N-Be/Gi-N-(2-tetrahydropyranylmethyl)amino]butyric #2. Og, 1-ethyl-3-(3-dimethylami/propyl)carbodiimide hydrochloride 2.2g
and dimethylformamide 20-1 to ■-ami/-11-dihydrodibenzo[b,e]chepin 1,
Add 8 g and stir at room temperature for 3 hours. The reaction solution is poured into water and extracted with toluene, and the extract is washed with water and then dried over magnesium sulfate. Distill toluene! ilt! I was subjected to silica gel column chromatography and eluted with chloroform to obtain 2.2 g of the desired product as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the desired product, oxalate trihydrate. Melting point 90-93°C (reprecipitation from ethanol-diethyl ether) Example 9 +1-[4-(N-benzyl-N-cyclopropylamino)butyrylamino]-N-methyl-6,11-dihydrodibenzo[b,el Production of Chepi/: 4-(N-benzyl-N-cyclopropylamino)acetic acid 1.5 g, 1
A mixture of 1.5 g of -ethyl-3-(3-dimethylamino/propyl)carbodiimide hydrochloride and 30-1 of chloroform is stirred at 0°C for 1 hour. 11 to this
-methylamino-8,1-mono-dihydrodibenzo[b,e
Add 1.5 g of Chepia and stir at room temperature for 3 hours. The reaction solution was washed with water and then dried with magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 2.0 g of the desired product as an oil. Mass spectrum m/z: 450
(M”) Example 10 Preparation of 5-[4-(N,N-dibenzylami/)butyrylamino]-5H-dipenzo[a,dl cycloheptene: 4-(N,N-dibenzylami/)butyric acid 1.1°1 - A mixture of 1 g of ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 201 chloroform was heated at 0°C.
Stir for 1 hour. To this was added 1.0 g of 5-ami7-5H-dibenzo[a, dl cycloheptene, and 2
Stir for an hour. The reaction solution was washed with water and then dried with magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 1.2 g of the desired product. Melting point: 138-140°C (recrystallized from chloroform-hexane) Example 11 11-[4-[N-benzyl-N-(2-acetoxybutyl)ami/butyrylamide/]-6. Ii Dihydrodibenzo[b,e Preparation of cochevine: 11-[4-[
N-benzyl-N-(2-hydroxybutyl)amino]
butyrylamino]-a11 dihydrodibenzo[b,el
Add 0 acetic anhydride to a solution of 1.0 g of Chepin in 101 pyridine.
．． Add 5g and leave at room temperature overnight. The reaction solution was poured into water and extracted with toluene. After washing the extract with water, it is dried over magnesium sulfate, and the solvent is distilled off to obtain 0.9 g of the desired product as an oily substance.

The above free base is treated in the same manner as in Example 3 to obtain the target product, oxalate monohydrate. Melting point 81-84℃ (ethanol
(Reprecipitation from roof ethyl ether) Examples 12 to 380 Using the corresponding raw material compounds, reactions and treatments were carried out in the same manner as in Examples 1 to 11 to obtain the compounds shown in Tables 6 to 15.

(Left below) Table 6 “) m/z in mass spectrum (M”) (
Same hereafter) ") Decomposition table 7 ") m/z in mass spectrum (M") (
Table 7 (continued) Table 7 (continued) Table 7 (continued) Table 7 (41!) Table 8 ”) m/z (M”) (same below) ’) Recrystallization or reprecipitation solvent (same below) Same) Table 8 (G
! Table 8 (continued) Table 8 (continued) Table 8 (continued) Table 9 ″) m/z in mass spectrum (M”) (same hereinafter) Table 9 (continued) Table 9 (continued) Table 9 (continued) ) Table 9 (Continued) Table 9 (Continued) Table 9 (I2) (Left below) Table 10') Recrystallization or reprecipitation solvent (same below) m/
z (M”) (same hereafter) Table 10 (continued) Table 11 ”) m/z (M”) (
(same below) Table 11 (continued) Table 11 (continued) Table 12 ”) m/z (M”) (same below) ”) Recrystallization or reprecipitation solution #x (same below) Table 12
(Continued) Table 13 ") Recrystallization or reprecipitation solvent (same below)") m/
z(M”) Table 14 ゝ) Recrystallization or reprecipitation stage r11 medium (same below)”)
m/z (M"> (same below) (margins below) Table 15 ') m/z (M") (same below) ') Recrystallization or recrystallization precipitation solvent (same below) Table 1
5 (continued)

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 mean a hydrogen atom, or Y and Z
together, -O-, -S-, -CH=CH-, -
CH_2CH_2-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH_2O- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R_2 means a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R_3 is Hydrogen atom, lower alkoxy group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, 1-2
A cycloalkyl group having 1 substituent (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkylthio group, an acyloxy group, an acylthio group, a di-substituted amino group, an acylamino group, Carboxy group, lower alkoxycarbonyl group,
carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, oxo group or acetalized or ketalized oxo group), saturated heterocyclic group, saturated heterocyclic group having 1 to 2 substituents ( Substituents include halogen atom, hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, di-substituted amino group, acylamino group, cyano group, carboxy group, lower an alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, or a di-lower alkylcarbamoyl group), an aryl group, an aryl group having 1 to 4 substituents (the substituents include a halogen atom, a hydroxy group, a nitro group, a lower Alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group. Carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, and when two substituents are adjacent, they may form an alkylenedioxy group together), a cycloalkenyl group condensed with an aryl group (the aryl moiety and/or or the cycloalkenyl moiety may be substituted), a heteroaryl group, a heteroaryl group having 1 to 3 substituents (the substituents are a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a lower alkoxy group) , lower alkylthio group, acyloxy group,
amino group, lower alkylamino group, di-substituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or di-lower alkylcarbamoyl group),
A lower alkyl group having a substituent (the substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group, an oxo group, an acetalized or ketalized oxo group, a disubstituted amino group, an acylamino group, an acyloxy group, Acylthio group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, cycloalkyl group, cycloalkyl group having 1 to 2 substituents,
Saturated heterocyclic group, saturated heterocyclic group having 1 to 2 substituents, aryl group, aryl group having 1 to 4 substituents,
a heteroaryl group or a heteroaryl group having 1 to 3 substituents), an alkenyl group or an alkynyl group having a substituent (the substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group, an acyloxy group) or an acylthio group), an acyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, or a di-lower alkylcarbamoyl group; Substituents include halogen atom, hydroxy group, nitro group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group , a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, and when two substituents are adjacent, they may be taken together to form an alkylenedioxy group. ), heteroaryl group or 1
A heteroaryl group having ~3 substituents (the substituents are a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a lower alkylamino group, a di-substituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, or di-lower alkylcarbamoyl group), and R_5 is the same or different and represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group group, lower alkylcarbamoyl group, or di-lower alkylcarbamoyl group, and R_6 is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group, a lower alkyl group, or a lower alkylthio group. , means an acyloxy group or a cyano group, V means a carbonyl group or a sulfonyl group, W means an alkylene group, X means a single bond, lower alkylene group, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower a lower alkylene group substituted with alkylcarbamoyl or ▲a mathematical formula, chemical formula, table, etc.▼ (in the formula, R_7 means a hydrogen atom, a lower alkyl group, or an acyl group, and d means 1 or 2), or -CO- (may be in ketalized form), -O-, -S-, -NR
_8- (In the formula, R_8 means a lower alkyl group or acyl group), ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_7 means the same as above), -CH=CH
- and -C≡C-,
or a lower alkylene group bonded to R_4 through these groups, a and b each mean an integer of 1 to 4, and c is 0 to 2.
means an integer of However, when the A ring is a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together form ▲Numerical formula, chemical formula, table, etc.▼, and R_6 represents a hydrogen atom. means. ] An amine compound and its salts represented by these.