KR880000043B1 - Process for preparing n-aryl-piperazinalkane amides - Google Patents

Abstract

N-Aryl-piperazinealkaneamides (I) were prepd. by the reaction of (II) and (III) in the presence of basic(where X is hydroxy C1-4 alkyl, C1-4 alkyloxy, C1-4 alkyloxy carbonyl or aminocarbonyl; m is 1 or 2; R2is H or C1-4 alkyl; R3, R4 and R5 are H, hydroxy, C1-4 alkyl, C1-4 alkyloxy, trifluoromethyl or amino; Alk is C1-6 alkanediyl; Q is dihalophenylmethyl, phenyl or phenylmethyl; W is halo). (I) increase the oxygen tension (pO2) of coronary sinus venous blood on oral or i.v. admin.

Description

Preparation of Aryl-Pyrazine Alkanamides

-아릴-피페라진알칸아미드의 제조방법에 관한 것이다. 탄소원자, 저급알킬옥시카르보닐 라디칼이나 또는 히드록시메탈라디칼중의 하나와 결합된 피페라진 유도체에 관해서는 1962년 발행의 Helv. Chim. Acta 제45권, 제2383 내지 2402면에 기재되어 있다. 이 피페라진 유도체들은 구충약, 항히스타민약 그리고 정신안정제로서 유용한 것으로 인식되어 있다. 피페라진 탄소원자의 하나에서 메틸 라디칼로 임의로 치환시킨

-아릴-4-(4,4-디아릴부틸)-1-피레라진알칸아미드류는 미국특허 제3267104호에 기재되어 있다. 이 피페라진알칸아미드는 관상혈관 이완약, 국소마취약, 중추신경계통 자극제 및 항카트라지이닌제로서 유익한 것이라고 인식되어 있다.The present invention is novel

It relates to a process for preparing -aryl-piperazinealkanamide. For piperazine derivatives bound to one of carbon atoms, lower alkyloxycarbonyl radicals or hydroxymetal radicals, see Helv. Chim. Act 45, pp. 2383-2402. These piperazine derivatives are recognized as useful as antiparasitic, antihistamine and psychostable agents. Optionally substituted with a methyl radical at one of the piperazine carbon atoms

-Aryl-4- (4,4-diarylbutyl) -1-pyrazinealkanamides are described in US Pat. No. 3267104. It is recognized that this piperazine alkanamide is beneficial as a coronary relaxant, a local anesthetic, a central nervous system stimulant and an anticatrazinin.

-아릴-피레라진아세트아미드는 C.A.90, 168547에서 진통약제제의 유용한 중간체로 기술되어 있다.Optionally substituted piperazine moieties with methyl or phenyl radicals

-Aryl-pyrrazineacetamide is described in CA90, 168547 as a useful intermediate of analgesic agents.

The compounds of the present invention differ from the aforementioned prior art compounds in the properties of substituents on pyreazine residues and the pharmacological properties of these compounds.

The present invention relates to novel piperazine fluids represented by the following general formula (I), their stereochemical isomers and pharmaceutically acceptable acid addition salts.

R ¹ in formula (I) is a member selected from the group consisting of hydrogen, lower alkyl; X is hydroxy lower alkyl, lower alkyloxy lower alkyl, aminocarbonyl, mono- and di (lower alkyl) aminocarbonyl, carboxyl, lower alkyl oxy carbonyl, (aminocarbonyl) lower alkyl, [mono-and Di (lower alkyl) aminocarbonyl] -lower alkyl, carboxy lower alkyl, (lower alkyloxycarbonyl) lower alkyl and (hydroxy lower alkyl) aminocarbonyl; m is an integer of 1 or 2, R ² is a member selected from the group consisting of hydrogen and lower alkyl, R ³ , R ⁴ and R ⁵ are each hydrogen, hydroxy, lower alkyl, lower alkyloxy, halo, tri Consisting of fluoromethyl, lower alkylcarbonyl, aminocarbonyl, lower alkyloxycarbonyl, cyano, amino, mono- and di (lower alkyl) amino, (lower alkylcarbonyl) amino and (aminocarbonyl) amino Selected from the group, wherein R ³ and or R ⁴ may also be nitro; And R is a member selected from the group consisting of radicals having the general formula (a) and the following general formula (b),

-벤즈아미다졸-1-일, 할로겐원자로 임의 치환된 10

-페노티아진-10-일카르보닐, 1,2,3,6-테트라히드로-1,3-디메틸-2,6-디옥소-7

-푸린-7-일, 1-아릴-1,3-디히드로이소벤조푸란-1-일 및 2,2-디아릴-1,3-디옥솔란-4-일로 구성되는 군으로부터 선택되는 일원이며, 또 여기서 아릴은 페닐, 치환페닐, 나프탈텐일, 티에닐 및 피리디닐로 구성된 군으로부터 선택되는 일원인데 전술한 치환 페닐은 1 내지 2의 치환기를 가지며, 각 치환기는 각각 할로 및 (할로-치환페닐)카르보닐로 구성된 군으로부터 선택된다.Wherein Ar ¹ and Ar ² are each aryl radacal, and Alk is an alkanediyl radacal or lower alkenediyl radical, wherein the lower alkanediyl radicals described above are optionally substituted with hydroxy or lower alkyl radicals, and Q Is aryl, aryloxy, diarylmethoxy, 2,2-diarylethenyl, diarylmethylcarbonyl, arylcarbonyl, mono- and diarylaminocarbonyl, methyl residues optionally cyano-, aminocarbonyl- , Diarylmethyl substituted with mono- or di lower alkylaminocarbonyl- or lower alkyloxycarbonyl radical, the amino moiety optionally being aryl, arylcarbonyl-, lower alkylcarbonyl-, arylsulfonyl- or lower alkylsulfur Arylamino substituted with phenyl radicals, 2,3-dihydro-2-oxo-1 optionally substituted with halogen at the 5- or 6-position

-Benzimidazol-1-yl, optionally substituted with halogen atoms

-Phenothiazine-10-ylcarbonyl, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7

Is a member selected from the group consisting of -furin-7-yl, 1-aryl-1,3-dihydroisobenzofuran-1-yl and 2,2-diaryl-1,3-dioxolan-4-yl And wherein aryl is a member selected from the group consisting of phenyl, substituted phenyl, naphthaltenyl, thienyl and pyridinyl, wherein the aforementioned substituted phenyl has 1 to 2 substituents, each substituent being halo and (halo-substituted, respectively) Phenyl) carbonyl.

In the foregoing definitions, the halogen term is a generic name for fluoro, chloro, bromo and iodine; The term "lower alkyl" is meant to include straight and branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms of, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl, etc. ; "Lower alkyldiyl" as used in the definition of Alk consists of straight and branched alkanediyl chains having 1 to 6 carbon atoms; The "lower alkenediyl" used in the definition of Alk also consists of straight and branched alkenediyl chains having 2 to 6 carbon atoms.

Suitable compounds of the present invention are compounds wherein R is a radical of formula (b) wherein Q is diarylmethyl and Alk is a 1,3-propanediyl radical. Particularly suitable compounds of the invention are those in which R is Q is diarylmethyl, Alk is 1,3, -propanediyl, X is aminocarbonyl m is 1, and both R ¹ and R ² are hydrogen ( compounds that are radicals of b).

-(2,6-디클로로페닐)-1-피페라진아세트아미드, 이의 입체화학적 이성질체 및 약제학적 허용 산부가염으로 구성된 군으로부터 선택된다. 상기 일반식(I)의 화합물은 일반적으로 다음 일반식(IV)의 피페라진을 다음 일반식(V)의 시약과

-알킬화반응시켜서 제조될 수 있다.The most suitable compounds of the present invention are 3- (amino carbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-

-(2,6-dichlorophenyl) -1-piperazinacetamide, its stereochemical isomers and pharmaceutically acceptable acid addition salts. The compound of general formula (I) generally comprises piperazine of the following general formula (IV) with a reagent of the following general formula (V)

It can be prepared by alkylation reaction.

-알킬화 반응은 일반적으로 예컨대 메탄올, 에탄올, 프로판올, 부탄올 및 기타 알칸올류 등의 저급알칸올 ; 벤젠, 메틸벤젠, 디메틸벤젠 등속의 방향족 탄화수소 ; 1,4-디옥산, 1,1'-옥시비스프로판 등속의 에테르 ; 4-메틸-2-펜탄온등의 케톤 ;

,

-디메틸포름아미드 ; 니트로벤젠 ; 및 기타 또는 이같은 용매들의 혼합물들과 같은 적합한 반응비활성 용매에서 이루어진다.In the above scheme, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and X are as defined above and W is for example halogen or methylsulfonyloxy, chloro, bromo and iodine isotropic, Reaction leaving group, such as a sulfonyloxy group of the 4-methylphenylsulfonyl oxy constant velocity is shown. Of the general formulas (IV) and (V)

-Alkylation reactions generally include lower alkanols such as methanol, ethanol, propanol, butanol and other alkanols; Aromatic hydrocarbons such as benzene, methylbenzene and dimethylbenzene; Ethers of 1,4-dioxane and 1,1'-oxybispropane constant velocity; Ketones such as 4-methyl-2-pentanone;

,

-Dimethylformamide; Nitrobenzene; And suitable or inert solvents such as other or mixtures of such solvents.

,

-디에틸에탄아민등의 아민과 피리딘 및 그 유사체와 같은 적합한 염기의 존재는 반응과 정중에 유리되는 산을 취득하는데 유리하다.Alkali or alkaline earth metals such as potassium carbonate, sodium bicarbonate, carbonate or bicarbonate,

,

The presence of amines such as diethylethaneamine and suitable bases such as pyridine and analogs thereof is advantageous for obtaining an acid which is liberated during the reaction.

If W is not an iodide radical, the presence of a small amount of alkali or alkaline earth metal such as sodium iodide or potassium iodide may also act as a reaction promoter. The slightly elevated temperature is suitable for promoting the reaction rate, and preferably the reaction proceeds at the reflux temperature of the reaction mixture. According to the property of X, the compound of general formula (I) can be mutually converted by the following known functional group conversion method. A functional group conversion example is shown in Table 1 with the following radicals denoted by D.

-알킬화 방법에 따라 적당한 할로겐화 저급알킬과 교반시키고 또 필요한 경우에는 가열함으로써 아미노카르보닐 기능은 모노-또는 디-(저급알킬)아미노카르보닐 기능으로 전환시키고 또 저급알킬아미노카르보닐 기능은 디(저급알킬)아미노카르보닐 기능으로 전환시킬수도 있다.The carboxylic acid function may be converted to the ester function or the amide function according to known methods of stirring the starting carboxylic acid with a suitable alcohol or a suitable amine, respectively, or heating if necessary. The carboxylic acid function may also be converted to the ester function by reacting the starting carboxylic acid with a suitable halogenated alkyl, for example in the presence of a base of sodium methoxide isotropic. The ester function and the amide function may be converted to the carboxylic acid function by stirring the starting amide or the ester in an acidic or alkaline aqueous medium or, if necessary, heating. The ester function may convert the starting ester in the presence of a suitable amine in a suitable reaction inert solvent and, if necessary, to the amide function under heating. The starting amino carbonyl compound and the lower alkylamino carbonyl compound are known, respectively.

The aminocarbonyl function is converted to mono- or di- (lower alkyl) aminocarbonyl function and the lower alkylaminocarbonyl function is di (lower) by stirring with an appropriate halogenated lower alkyl and heating if necessary according to the alkylation method. Alkyl) aminocarbonyl function.

The carboxylic acid function and the ester function can be converted to the alcohol function according to known reduction methods such as using metal hydride, diborane and the like. The alcohol function can be converted to the carboxylic acid function according to known alcohol carboxylic acid oxidation methods such as using potassium permanganate, chromium trioxide, silver oxide and the like. The alcohol function can be converted to the ether function according to a known method such as reacting a suitable alkyl halide with a starting alcohol in the presence of a suitable base of the same rate of sodium hydride in a suitable reaction inert solvent.

The ether function can be converted to the alcohol function according to known ether decomposition methods such as reacting the starting ether with a strong Lewis acid of boron trifluoride constant velocity. In addition, depending on the properties of R, R ¹ , R ² and R ³ , the compounds of the general formula (I) can be converted to each other by a known functional group conversion method. For example, compounds of general formula (I) in which at least one of R ³ and R ⁴ contain nitro radicals correspond according to known nitro-amine reduction methods such as catalytic reduction in the presence of suitable catalysts such as platinum on charcoal and analogs thereof. Can be converted to an amine fluid.

The compounds of the general formula (I) include, for example, inorganic acids such as halogen acid, sulfuric acid, nitric acid, phosphoric acid and the like, such as hydrochloric acid and bromic acid; Or for example vinegar acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanediolic acid, butanediolic acid, (Z) -2-butenediolic acid, (E) -2- Butenediol acid, 2-hydroxybutanediol acid, 2,3-dihydroxybutanediol acid, 2-hydroxy-1,2,3, -propane-tricarboxylic acid, benzoic acid, 3-phenyl-2-propenic acid, α Suitable organic acids such as hydroxybenzene acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methyl-benzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like Treatment with acid can convert the therapeutically active non-toxic acid addition salts. On the contrary, the salt form can be converted to the free base form by treating with alkali.

It is evident from the general formula (I) that the compound of the invention has at least one asymmetric carbon atom in its structure, ie having piperazine carbon atoms with X radicals. Chiral centers can be represented by R- and S-arrays, which are R.S.Cahn. C. Ingold and V. Prelog in Angew. Chem. Int. Ed. Conforms to the rules set forth in Engl., 5, 385, 511. In conclusion, the compound of general formula (I) is present in two different colon forms, for example, this colon mixture is converted to acid addition salt type with optically active acid, and this diastereomeric salt is separated and subjected to alkali treatment by screen crystallization method. Can be separated from each other by isolating pure colon.

If R ¹ is not hydrogen and has one or more additional chiral centers with the radicals R and C _m H _2m , each of them can be represented by the R- and S-configurations and The compounds of I) have different diastereomeric forms that can be separated from each other by physical separation methods such as screening crystallization and chromatographic separation methods such as countercurrent chromatography, column chromatography, and similar techniques.

When R ¹ is not hydrogen, the substituents X and R ¹ may be attached to the piperazine ring in a cis- or trans-relationship with respect to each other, and the compound of general formula (I) may be respectively "cis", "trans""Is displayed. Compounds of formula (I) wherein R is a radical (b) in which Alk is lower alkenediyl may be characterized by the symbols "E" and "Z" and the aforementioned E- and Z-symbols are published in 1970, J. Org. Chem., Vol. 35, pp. 2849 to 2868. Pure stereochemically isomeric forms can be derived from the corresponding pure stereochemically isomeric forms of suitable starting materials, provided that the reaction proceeds stereospecific or highly stereoselective. For most compounds and starting materials, stereochemical arrangements can be determined experimentally. In such a case, the first isolated stereochemical isomer is named "A" and the second is named "B" without further explanation on the actual stereochemical arrangement.

Stereochemically isomeric forms of the compounds of formula (I) are believed to naturally fall within the scope of the present invention. The functional group conversion reaction described in Table 1 can also be performed for all intermediates having radicals X in their structure. When administered orally or intravenously to vertebrates, the compounds of formula (I), their pharmaceutically acceptable acid addition salts and their stereochemically isoforms increase the oxygen partial pressure (PO ₂ ) of coronary venous blood. Increase of the PO ₂ is evidenced by the experimental data obtained in The Journal of Pharmacology and Experimental Therapeutics, 152, (2), 265-274 (1966) in which coronary sinus of anesthetized interposed PO ₂ test.

Coronary artery sinus in anesthetized dog

The cardiac catheter was placed in the coronary sinus of the anesthetized dog. And the Gleichmann-Lubbers variation Cloud arc electrode contained the oxygen partial pressure (mmHg of PO ₂₎ of the venous coronary blood was measured in the blood stream keubet used were translated into correction scale (Scale) of the measurement value PO ₂ spot galvanometer. Aorta, blood pressure, respiratory rate and electrocardiogram were recorded throughout the experiment. The experimental animals performed natural breathing. A steady state was obtained after a 30 minute adjustment period.

At this point a dose of active compound was administered by slow intravenous infusion. Intravenous doses of other compounds were continued at each time point when a new steady state of at least 10 minutes was ended.

Table 1 shows the lowest effective intravenous dose (mg / kg body weight) in which PO ₂ in the coronary artery was increased by 100% compared to the control (column 1) and the duration (column 2) due to the lowest effective dose described above. Display. The data shown in Tables 1 and 2 describe the present invention but do not limit the scope thereof.

[Table 1]

[Table 2]

Intravenous or oral administration of a compound of formula (I), its pharmaceutically acceptable acid addition salts, and stereochemically isoforms, also showed protection against localized phenotypes of complete normal body temperature of one heart. This test, which demonstrates this protection, is based on the Royal Society of Medicine Imternational Congress and Symposium Series No. 29, P. 89-95 (1980), "Myocardial Protection and Exercise Tolerance: the Role of Lidoflazine, a New Anti-anginal Agent.

Protection against myocardial localized anemia of normal body temperature in dogs.

Experiments were tested with anesthetized growth dogs weighing 9 kg to 15 kg. Systemic blood pressure was measured through the left femoral artery using a JF Millar tip manometer.

The Swann-Ganz heat lime catheter was inserted through the right thigh vein into the pulmonary artery, and the cardiac output by heat lime and central nervous pressure were measured through the proximal cavity.

It was intubated in another thigh vein to facilitate saline injection at room temperature. It was intubated in the right thigh artery and connected to the artery line of the cardiopulmonary bypass.

The heart was exposed to the right chest incision and walked in the gastric cradle. The right gastric cavity was intubated for venous line connection of cardiac lung. Left ventricular pressure was measured after insertion of a JF Millar tip manometer through the pulmonary vein. Two occluded roller pumps, bubble oxygenators and heat exchangers were used for cardiopulmonary bypass. The cardiopulmonary system was filled with 200 ml of fresh, anticoagulant blood obtained from the donor. Blood samples were sequentially taken during the experiment to monitor PO ₂ · PCO ₂ and PH. The left ventricle made an outlet to the proximal tubing at the start of coronary bypass over focal anemia and subsequent 30 min reperfusion period.

Experimental Design :

A) Intravenous administration

About 25 minutes after intravenous administration of the active compound, the animals were clamped ascending aorta for 60 minutes for total cardiopulmonary bypass at 37 ° C. At the beginning of complete ischemia, an active amount of compound was added to the total blood content.

During the whole period of complete ischemia, myocardial temperature was maintained at 37 ° C. The coronary artery was reperfused for 30 minutes while the heart was empty and stationary.

Ten minutes after reperfusion, the heart was defibrillated.

At the end of the reperfusion period the system was weaned from cardiopulmonary bypass and the function mediation was recorded until the end of the experiment. Column 1 of Table 3 shows the minimum intravenous dose (mg / kg body weight) in which the dog will resume its normal function after 60 minutes of complete ischemia. However, column 2 shows the total compound amount added to the total blood content.

B) oral administration

The experimental method was the same as described for intravenous administration except that the active compound was not orally administered, nor was it added to the total blood content. Column 3 of Table 3 shows the minimum effective oral dose of the compound in which the heart regains its normal function after 60 minutes of complete ischemia. The data shown in Table 3 is intended to illustrate the invention, but not to limit the scope thereof.

[Table 3]

In view of their pharmacological action, the compounds of general formula (I) partially or completely improve the perfusion of the muscle tissues of the heart and also cause planting myocardial injury caused by some short-term occurrence of focal anemia, oxygen deficiency or hypoxia. In view of the above, the compound of the present invention can be used for the treatment or prevention of patients suffering from angina pectoris and pre or post myocardial infarction by intravenous or oral administration thereof.

The compounds of the present invention can be formulated in a variety of pharmaceutical forms depending on the purpose of administration. In order to prepare a pharmaceutical composition of the present invention, an effective amount of a specific compound in the form of a base or an acid addition salt is mixed with a drug-acceptable carrier which may have a wide variety of forms depending on the dosage form required for administration.

This pharmaceutical composition is preferably a single dosage form suitable for oral, rectal or parenteral injection. For example, in the preparation of oral dosage forms, for the preparation of oral solutions such as suspensions, syrups, extracts and solutions, conventional pharmaceutical media such as water, glycols, oils, alcohols, etc. may be used or powders, pills, capsules and For tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like may be used. For ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are often used. In the case of parenteral compositions, the carrier may typically contain other ingredients, such as, for example, to enhance solubility, but most of the sterilizing water is constituent.

Injectables can be prepared, for example, in which the carrier consists of a saline solution, a flucose solution or a mixture of saline and glucose solution.

Injectable suspensions can also be prepared using suitable liquid carriers, suspending agents and the like.

The acid addition salts of (I) are much more suitable for the preparation of aqueous solutions due to the increased solubility in the corresponding base form.

It is particularly advantageous to prepare the aforementioned pharmaceutical compositions in the form of a dosing unit for ease of administration and uniformity of dosage. The grant unit form used in the specification and claims herein is a physically divided unit suitable as unit dosage, each unit of which is pre-calculated to express the required therapeutic effect in combination with the required carrier. Contains the active ingredient. Examples of such dosage unit forms include tablets (including slotted or coated tablets), capsules, pills, packaged powders, oblides, injectable solutions or suspensions, tea spoons, tablespoons, etc. have.

The following formulations exemplify typical pharmaceutical compositions in dosage unit form for systemic administration to patients associated with the present invention.

Oral Drops:

-(2,6-디클로로페닐)-1-피페라진아세트아미드를 함유한 10l의 경구점적용액을 제공한다.The following formulation is an active ingredient, 5 mg of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-per ml

10 l oral drop solution containing-(2,6-dichlorophenyl) -1-piperazineacetamide is provided.

A.I. … … 50 g methyl-4hydroxybenzoic acid. … 18g

2-hydroxypropanoic acid... … 2.5 ml propyl 4-hydroxybenzoic acid. … 2 g

Pyrogen-yuris qs s ad 10l

Methyl and propyl 4-hydroxybenzoic acid were dissolved in about 5 l of boiling pyrogen-free water. After cooling to about 50 ° C., 2-hydroxypropanoic acid was added with stirring followed by A.I. The solution was cooled to room temperature and supplemented with pyrogen-free water addition.

This solution was sterilized by filtration (U.S.P. XVII p. 811) and placed in a sterile container.

Injection solution:

The above-mentioned oral drop solution may be used as an injection solution.

capsule :

-(2,6-디클로로폐닐)-1-피페타진-아세트아미드를 함유하게 다음의 조성물로 조제하였다.10,000 hard gelatin capsules, each capsule containing 20 mg of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorotonnyl) butyl]-as an active ingredient (AI)

The following composition was prepared containing-(2,6-dichlorophenyl) -1-pipetazine-acetamide.

A.I. … … 200 g

Lactose… … 1000g talc… … 300 g

Starch… … 300 g calcium stearate. … 10 g

A homogeneous mixture of active and supplemental ingredients was prepared and placed in a two-part hard gelatine capsule.

refine :

-(2,6-디클로로페닐)-1-피폐라진아세트아미드를 함유하게 다음의 조성물로 조제하였다.Each of the 5000 compressed tablets contains 25 mg of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-as an active ingredient (AI).

The following composition was prepared containing-(2,6-dichlorophenyl) -1-piperazineacetamide.

A.I. … … 125g dibasic calcium phosphate … 650 g

Starch… … 150 g calcium stearate … 35 g

The fine powder components were mixed well and granulated with 10% starch to dry the fine particles and compressed to tablets.

Oral suspension:

-(2,6-디클로로페닐)-1-피폐라진 아세트아미드를 함유한 5l의 경구현탁액을 제조한다.15 mg of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-as an active ingredient per tea spoon (5 ml)

Prepare 5 l oral suspension containing-(2,6-dichlorophenyl) -1-piperazine acetamide.

A.I. … … 15.0 g propylene glycol. … 52.0 g

Per party… … 300.0g FD & C Yellow # 5. … 0.1g

Dioctylsulfosuccinate sodium… … 0.5 g Sodium Cyclamate ... … 5.0 g

Bentonite… … 22.5 g soluble saccharin. … 5.0 g

Methylparaben… … 7.5g orange flavor … 7.5g

Propylparaben… … 1.5 g filtered purified water q · s · ad. … 5l

Antifoam A.F. … 0.15 g

Parabens were dissolved in propylene glycol and the solution was added to a solution in which sodium cyclate, soluble saccharin and soluble sucrose were dissolved in 1/2 purified water. The bentonite was suspended in hot water (about 85 ° C.), stirred for 60 minutes, and an igntonite solution was added to the solution described above. Sulfosuccinate was dissolved in some water and suspended A.I. with this solution. Bubble A.F. The emulsion was added diluted to a lotion concentration with a minimum amount of water and mixed well. This A.I.suspension was added to the mixture described above and mixed well. Subsequently, FD & C yellow # 5 dissolved in a small amount of water was added, orange seasoning was added, and the remaining amount of filtered water was added.

The whole solution thus prepared was subjected to a homogeneous mixture. This mixture was passed through a colloid mill and placed in a suitable container. In view of the drug activity of the target compound, an effective amount of the compound of general formula (I), its acceptable acid addition salt, or its stereochemically isomeric form is mixed with the drug carrier to provide systemic administration, thereby improving blood perfusion of the muscle tissue of the heart. It has also been found that it can provide a way to protect the heart from myocardial injuries caused by some occurrences of ischemia, oxygen deficiency and hypoxia.

The following examples are intended to illustrate the invention, but not to limit the scope thereof.

Unless otherwise stated, all parts of these embodiments are based on weight.

end. Intermediate formulation

Example 1

-(2,6-디클로로페닐)-1-피페라진아세트아미드, 45부의 벤젠과 20부의 메탄올 혼합물을 상온에서 3시간 교반하고 다시 환류로 30분간 교반하였다. 반응혼합물을 냉각하고 용리액으로 트리클로로메탄과 혼합물(90 : 10용량으로)을 사용하여 실리카겔 칼람 크로마토그라피 방식으로 정제하였다.2.5 parts [(2-naphthalenyloxy) methyl] oxirane, 3.31 parts 3- (aminocarbonyl)-

A mixture of-(2,6-dichlorophenyl) -1-piperazineacetamide, 45 parts of benzene and 20 parts of methanol was stirred at room temperature for 3 hours and then stirred at reflux for 30 minutes. The reaction mixture was cooled and purified by silica gel column chromatography using trichloromethane as a eluent (90:10 volume).

Purified fractions were recovered and the eluent was evaporated.

-(2,6-디클로로페닐)-4-[2-히드록시-3-(2-나프탈렌욱시)프로필]-1-피페라진아세트아미드 디히드로클로라이드 모노히드레이트 (화합물 69)를 얻었다. 용점 155.3℃The residue was converted to hydrochloride in 2-propanol and acetonitrile. The mixture was stirred overnight, the salt was filtered, dried for 1 week, and dried to form 1.39 parts (23%) of 3- (aminocarbonyl)-

-(2,6-dichlorophenyl) -4- [2-hydroxy-3- (2-naphthaleneoxy) propyl] -1-piperazineacetamide dihydrochloride monohydrate (Compound 69) was obtained. Melting point 155.3 ℃

In a similar way also,

-(2,6-디메틸페닐)-1-피페라진아세트아미드(화합물 70)을 얻었다. 용점 110.2℃3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) -2-hydroxybutyl]-

-(2,6-dimethylphenyl) -1-piperazineacetamide (Compound 70) was obtained. Melting point 110.2 ℃

Example II

-(2,6-디메틸페닐)-1-피페타진아세트아미드, 1부의 4% 리오펜-에탄올용액 및 150부의 2-메톡시에탄올의 혼합물을 2부의 목탄상의 10%팔라듐 촉매로 상압, 상온하에서 수소화하였다. 계산량의 수소를 취하후에 촉매를 여과하고 또 그 여과액은 증발시켰다. 잔류물을 용리액으로 트리클로로메탄과 메탄올의 혼합물 (97 : 3용량으로)을 사용하여 실리카겔칼람 크로마토그라피 방식으로 정제하였다.4.3 parts of 4,4-bis (4-fluorophenyl) cyclohexane is 4.35 parts of 3- (aminocarbonyl)-

A mixture of-(2,6-dimethylphenyl) -1-pipetazineacetamide, 1 part 4% lyophen-ethanol solution and 150 parts 2-methoxyethanol, under normal pressure and room temperature with 10 parts palladium catalyst on 2 parts charcoal Hydrogenated. After taking the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (97: 3 volumes) as eluent.

Purified fractions were recovered and the eluent was evaporated.

-(2,6-디메틸페닐)-1-피페라진 아세트아미드(화합물 71)를 얻었다. 용점 212.1℃Isomers from the residue were separated by HPLC using a mixture of methylbenzene and ethanol (95: 5 volumes) as eluent. The fraction containing the B-isomer was recovered and the eluate was evaporated. The residue was suspended in petroleum ether. The product was filtered, dried and dried in vacuo at 145 ° C., followed by 1.73 parts of (B) -3- (aminocarbonyl) -4- [4,4-bis (4-fluorotophenyl) cyclohexyl]-

-(2,6-dimethylphenyl) -1-piperazine acetamide (Compound 71) was obtained. Melting point 212.1 ℃

Example III

-(2,6-디클로로페닐)-아세트아미드, 5.6부의 1-[4,4-비스(4-플루오토페닐)부틸]-2-피페라진카르복스아미드, 2.49부의

,

-디에틸에탄아민 및 63부의

,

-디메틸포름아미드의 혼합물을 70℃에서 5시간 교반하였다.4.05 parts 2-chloro-

-(2,6-dichlorophenyl) -acetamide, 5.6 parts 1- [4,4-bis (4-fluorotophenyl) butyl] -2-piperazinecarboxamide, 2.49 parts

,

-Diethylethanamine and 63 parts

,

The mixture of -dimethylformamide was stirred at 70 ° C. for 5 hours.

The reaction mixture was poured into ice water. The precipitate product was filtered off and dissolved in dichloromethane.

-(2,6-디클로로페닐)-1-피페라진아세트아미드 디히드로 클로라이드 모노히드레이트 (화합물 72)를 얻었다.The solution was washed with water, dried and filtered and evaporated. The residue was purified by silica gel column and chromatography using a mixture of trichloromethane and methanol (95: 5 volumes) as eluent. The purified fractions were collected and the eluent was evaporated before the residue was converted to hydrochloride in 2-propanone and 2-propanol. The salt was filtered and stirred for 30 minutes in 1,1'-oxybisethane to 4.54 parts of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorotophenyl) butyl]-

-(2,6-dichlorophenyl) -1-piperazineacetamide dihydrochloride monohydrate (Compound 72) was obtained.

Melting point 182.7 ℃

-알킬화 방법으로 동등한 량의 적합한 출발물질을 사용하여 다음 표의 화합물들을 얻었다.same

The compounds of the following table were obtained using equivalent amounts of suitable starting materials by the -alkylation method.

In a similar manner, the following compounds were also obtained.

Example IV

-(2,6-디메틸페닐)-아세트아미드, 25.4부의 탄산나트륨, 0.1부의 요오드화칼륨 및 180부의

,

-디메틸포름아미드의 혼합물을 60℃에서 18시간 교반하였다. 반응혼합물을 물에 붓고 그 생성물을 디클로로메탄으로 추출하였다. 추출물을 수세, 건조, 여과, 증발시켰다. 잔유물을 용리액으로 트리클로로메탄과 메탄올의 혼합물(90 : 10용량으로)을 사용하여 실리카겔칼람 크로마토그라피방식으로 정제하였다. 정제 분류물을 회수하고 용리액을 증발시켰다. 잔유물을 1,1'-옥시비스에탄 중에서 결정화하여, 35.19부(84.8%)의

-(2,6-디메틸페닐)-2-(1-히드록시에틸)-4-(페닐메틸)-1-피페라진아세트아미드(화합물113)를 얻었다. 융점 148.8℃ 동일한

-알킬화방법으로 동등한 량의 적합한 출발 물질을 사용하여 또한 다음표의 화합물을 얻었다 :24.0 parts α-methyl-4- (phenylmethyl) -2-piperazinmethanol, 27.3 parts 2-chloro-

-(2,6-dimethylphenyl) -acetamide, 25.4 parts sodium carbonate, 0.1 parts potassium iodide and 180 parts

,

The mixture of -dimethylformamide was stirred at 60 ° C. for 18 hours. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (90:10 volume) as the eluent. Purified fractions were recovered and the eluent was evaporated. The residue was crystallized in 1,1'-oxybisethane to give 35.19 parts (84.8%) of

-(2,6-dimethylphenyl) -2- (1-hydroxyethyl) -4- (phenylmethyl) -1-piperazineacetamide (Compound 113) was obtained. Melting point 148.8 ℃ same

Using the equivalent amounts of suitable starting materials in the -alkylation process the compounds of the following table were also obtained:

Example V

-(2,6-디메틸페닐)프로판아미드, 2.1부의 탄산나트륨, 0.1부의 요오드화칼륨 및 200부의 4-메틸-2-펜탄온의 혼합물을 물분리기를 사용해서 20시간 교반 환류시켰다. 반응혼합물을 상온으로 냉각하고 여과하였다. 그 여과액을 증발시켰다. 유상 잔유물을 트리클로로메탄과 메탄올의 혼합물(95 : 5용량으로)을 용리액으로 사용하여 실리카겔칼람 크로마토그라피방식으로 정제하였다. 정제분류물을 회수하고 용리액을 증발시켰다. 잔유물을 2,2'-옥시비스프로판에서 분쇄하여 고체화하였다. 그 생성물을 여과, 건조하여 3.87부(70.8%)의 3-(아미노카르보닐)-4-[4,4-비스(4-플루오로페닐)부틸]-

-(2,6-디메틸페닐)-1-피페라진프로판아미드(화합물122)를 얻었다. 융점 120.9℃ 동일한

알킬화 방법으로 동등한 양의 적합한 출발물질을 사용하여 또한 다음표의 화합물을 얻었다.3.7 parts 1- [4,4-bis (4-flfuophenyl) butyl] -2-piperazinecarboxamide, 2.3 parts 3-chloro-

A mixture of-(2,6-dimethylphenyl) propanamide, 2.1 parts sodium carbonate, 0.1 parts potassium iodide and 200 parts 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water separator. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated. The oily residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volumes) as the eluent. Purified fractions were recovered and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane to solidify. The product was filtered and dried to afford 3.87 parts (70.8%) of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-

-(2,6-dimethylphenyl) -1-piperazinepropanamide (Compound 122) was obtained. Melting point 120.9 ℃ same

The alkylation process also gave compounds of the following table using equivalent amounts of suitable starting materials.

Example VI.

5 parts 1- [4,4-bis- (4-fluorophenyl) butyl] -4- [2-[(2,6-dimethylphenyl) amino] -2-oxoethyl] -2-piperazincarboxylic acid And 200 parts of a stirred reflux mixture of anhydrous ethanol was bubbled through gaseous hydrogen chloride for 5 hours.

After standing overnight at room temperature, the reaction mixture was evaporated. The residue was taken up in 200 parts of water and alkalized with sodium hydroxide. The product was extracted twice with 80 parts of 4-methyl-2-pentanone. The mixed extract was dried, filtered and evaporated. The residue was purified twice by silica gel column chromatography using a mixture of trichloromethane and methanol (90:10 volume) as eluent.

Purified fractions were recovered and the eluent was evaporated. The residue was converted to hydrochloride in ethanol and 2-propanol.

The solvent was evaporated and the semisolid residue was dissolved in a mixture of 16 parts 2-propanone and 2 parts water. This whole solution was evaporated. The solid residue was triturated and dried to give 2.37 parts (40%) of ethyl 1- [4, 4-bis- (4-fluorophenyl) butyl] -4- [2-[(2, 6-dimethylphenyl) amino ] -2-oxoethyl] -2-piperazinecarboxylic acid dihydrochloride hemihydrate (Compound 154) was obtained. Melting point 11.8 ℃

Example VII.

52 parts ethyl 1- [4,4-bis- (4-fluorophenyl) butyl] -4- [2-[(2,6-dimethylphenyl) amino] -2-oxoethyl] -2-piperazincar The carboxylate and 600 parts of the concentrated ginseng mixture were stirred for 8 hours in a boiling water bath. The reaction mixture was concentrated to a volume of about 200 parts. The supernatant aqueous phase was poured over and the oily residue was dissolved in 400 parts 2-propanone and 500 parts water and the whole solution was neutralized by dropwise addition of sodium hydrogen carbonate.

2-propanone was evaporated with Rotabapor. The aqueous phase was poured over and the residue was triturated in warm 4-methyl-2-pentanone. After cooling the product was filtered and dissolved while heating in 200 parts of methanol. 250 parts of water was added after cooling, and this whole solution was stirred briefly.

The solid product was filtered and crystallized in acetonitrile and dried under vacuum at 110 ° C. for 3 hours to give 16.32 parts of 1- [4,4-bis- (4-fluorotophenyl) butyl] -4 [2-[(2, 6-dimethylphenyl) amino] -2-oxoethyl] -2-piperazinecarboxylic acid (Compound 155) was obtained. Melting Point 186.5 ℃

Example VIII.

-(2, 6-디메틸-4-니트로페닐)-2-(히드록시메틸)-1-피페라진 아세트아미드와 120부의 메탄올을 첨가하였다.3.4 parts of 4- [4,4-bis- (4-fluorophenyl) butyl]-1 part of a solution obtained by adding 2 parts of thiophene to 40 parts of ethanol.

-(2, 6-dimethyl-4-nitrophenyl) -2- (hydroxymethyl) -1-piperazine acetamide and 120 parts of methanol were added.

The whole solution was hydrogenated at room temperature and atmospheric pressure with 5 parts platinum catalyst on 2 parts charcoal. The catalyst was filtered off after calculating the calculated amount of hydrogen, and the filtrate was evaporated.

The oily residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (at 90:10 volume) as eluent.

Purified fractions were recovered and the eluent was evaporated. The oily residue was solidified by cooling at ₂ -propanone / CO ₂ -weight.

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-2-(히드록시메틸)-1-피페라진아세트아미드(화합물 156)를 얻었다. 융점 85.2℃The product was dried to 1.73 parts (54%)

- (4-amino-2,6-dimethylphenyl) -4- [4, 4-bis (4-fluorophenyl) butyl] -2- (hydroxymethyl) -1-piperazine acetamide (compound 156) Got. Melting point 85.2 ℃

-(4-아미노2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오토페닐)부틸]-1-피페라진아세트아미드(화합물 157), 융점 11.4℃ :In a similar manner also 3- (aminocarbonyl)-

-(4-amino2, 6-dimethylphenyl) -4- [4,4-bis (4-fluorotophenyl) butyl] -1-piperazineacetamide (Compound 157), melting point 11.4 占 폚:

-(4-아미노-2, 6-디메틸페닐)-4[4, 4-비스(4-플루오로페닐)부틸]-3-(히드록시메틸)-1-피페하진아세트아미드(화합물 158), 융점 81.3℃ :

-(4-amino-2, 6-dimethylphenyl) -4 [4,4-bis (4-fluorophenyl) butyl] -3- (hydroxymethyl) -1-piperazinacetamide (Compound 158), Melting Point 81.3 ° C:

-(4-아미노-2-메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-3-[(메틸아미노)카르보닐]-1-피페라진아세트아미드(화합물 159), 융점 86.2℃ :

-(4-amino-2-methylphenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -3-[(methylamino) carbonyl] -1-piperazineacetamide (Compound 159) Melting point 86.2 ° C .:

3- (aminocarbonyl) -N- (4-amino-2, 6-dichlorophenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazineacetamide dihydrochloro Laid dihydrolate (compound 160), melting point: 196.3 ° C: and

3- (aminocarbonyl) -N- (amino-5-chloro-2-methoxyphenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinacetamide (compound 161) and melting points of 189.3 ° C were obtained.

Example IX

-[2-[(2, 6-디메틸-4-니트로페닐)-2-[(메틸아미노) 카르보닐]-1-피페라진아세트아미드와 120부의 메탄올을 첨가하였다.3 parts 4- [4,4-bis- (4-fluorophenyl) butyl]-1 part of a solution obtained by adding 2 parts thiophene to 40 parts ethanol.

-[2-[(2, 6-dimethyl-4-nitrophenyl) -2-[(methylamino) carbonyl] -1-piperazinacetamide and 120 parts of methanol were added.

This whole solution was hydrogenated at normal temperature and atmospheric pressure with 10 parts palladium catalyst on 2 parts charcoal. After taking the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated.

The residue was purified by silica gel column chromatography using a mixture of trichloromethane and ethanol (95: 5 volumes) as eluent.

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스-(4-플루오로페닐)부틸]-2-[(메틸아미노)카르보닐]-1-피페라진아세트아미드(화합물 162)를 얻었다. 융점 111.7℃Purified fractions were recovered and the eluent was evaporated. The residue was suspended in 2, 2'-oxybispropane to give 2.14 parts

-(4-amino-2, 6-dimethylphenyl) -4- [4, 4-bis- (4-fluorophenyl) butyl] -2-[(methylamino) carbonyl] -1-piperazineacetamide (Compound 162) was obtained. Melting Point 111.7 ℃

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-3-[(메틸아미노)카르보닐]-1-피페라진 아세트 아미드 (화합물 163), 융점 88.7℃ : 및In a similar way also,

-(4-amino-2, 6-dimethylphenyl) -4- [4, 4-bis (4-fluorophenyl) butyl] -3-[(methylamino) carbonyl] -1-piperazine acetamide ( Compound 163), melting point 88.7 ° C .: and

-(4-아미노페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드 모노히드레이트(화합물 164), 융점 90.1℃들을 얻었다.3- (aminocarbonyl)-

-(4-aminophenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazineacetamide monohydrate (Compound 164), melting points of 90.1 占 폚 were obtained.

Example X

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드, 8부의 프로판온, 1부의 4%티오펜-에탄올 용액과 120부의 메탄올의 혼합물을 2부의 목탄상의 10%백금 촉매로 상온 상압하에서 수소화 하였다.55 parts of 3- (aminocarbonyl)-

-(4-amino-2, 6-dimethylphenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinacetamide, 8 parts propanone, 1 part 4% thiophene A mixture of ethanol solution and 120 parts of methanol was hydrogenated at room temperature and atmospheric pressure with 10 parts of platinum catalyst on 2 parts of charcoal.

After taking the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2, 2'-oxybispropane.

[(2, 6-디메틸-4-(1-메틸에틸)-아미노페닐-1-피페라진아세트아미드 모노히드레이트(화합물 165)를 얻었다. 융점 100.7℃The product was filtered off and dried to give 4.5 parts of 3- (aminocarbonyl) -1-4- [4,4-bis- (4-fluorophenyl) butyl]-

[(2, 6-dimethyl-4- (1-methylethyl) -aminophenyl-1-piperazinacetamide monohydrate (Compound 165) was obtained.

Example X I

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드, 1부의 5%티오펜-에탄올용액, 3부의 폴리(옥시메틸렌) 및 120부의 메탄올의 혼합물을 2부의 목탄상의 10%팔라듐 촉매로 상온, 상압하에서 수소화하였다. 계산량의 수소를 취한 후에 촉매를 여과하고 그 여과액을 증발시켰다.5.5 parts of 3- (aminocarbonyl)-

-(4-amino-2, 6-dimethylphenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinacetamide, 1 part 5% thiophene-ethanol solution, 3 A mixture of negative poly (oxymethylene) and 120 parts methanol was hydrogenated at room temperature and atmospheric pressure with a 10% palladium catalyst on 2 parts charcoal. After taking the calculated amount of hydrogen the catalyst was filtered off and the filtrate was evaporated.

The residue was taken up in dilute hydrochloric acid solution and the whole solution was washed with 2.2-oxybispropane. The aqueous phase was alkalized and extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was converted to hydrochloride in acetonitrile and 2-propanol.

-4-(디메틸아미노)-2, 6-디메틸페닐-1-피페라진 아세트아미드 트리히드로클로라이드 모노히드레이트(화합물 166)를 얻었다. 융정 194.5℃ 유사한 방법으로 또한, 3-(아미노카르보닐)-4-[4, 4-비스(4-플루오로페닐)부틸-

-[4-(디메틸아미노)페닐]-1-피페라진아세트아미노 모노히드레이트(화합물 167)를 얻었다. 융점 96.3℃The salt was filtered off and crystallized in 2-propanol to give 2.86 parts of 3- (aminocarbonyl) -4- [4,4-bis (4-fluorephenyl) butyl-

4- (dimethylamino) -2,6-dimethylphenyl-1-piperazine acetamide trihydrochloride monohydrate (Compound 166) was obtained. Melting tablets 194.5 ° C. In a similar manner, 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl-

-[4- (dimethylamino) phenyl] -1-piperazineacetamino monohydrate (Compound 167) was obtained. Melting Point 96.3 ℃

Example XII

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4-비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드를 철가한 교반용액에 20부의 물에 62부의 이소시안산칼륨을 용해시킨 용액을 적가하였다. 적가 종료후, 상온에서 30분간 계속 교반하였다.5.5 parts 3- (aminocarbonyl)-to 70 parts acetic acid

20 parts of water to 62 parts of stirring solution with-(4-amino-2, 6-dimethylphenyl) -4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazineacetamide A solution in which potassium isocyanate was dissolved was added dropwise. After completion of the dropwise addition, stirring was continued for 30 minutes at room temperature.

After standing overnight at room temperature, the reaction mixture was evaporated.

Water was added to the residue and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated.

The residue was eluted using a mixture of trichloromethane and methanol (at 90:10 volume) as an eluent by gel chromatography.

Purified fractions were recovered and the eluent was evaporated.

-[(4-[(아미노카르보닐)-아미노]-2, 6-디메틸페닐]-4-[4, 4-비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드(화합물 168)를 얻었다. 융점 142.5℃The residue was crystallized in acetonitrile to give 2.55 parts of 3- (aminocarbonyl)-

-[(4-[(aminocarbonyl) -amino] -2, 6-dimethylphenyl] -4- [4, 4-bis (4-fluorophenyl) butyl] -1-piperazineacetamide (Compound 168 Melting point: 142.5 ° C

Example XIII

-(4-아미노-2, 6-디메틸페닐)-4-[4, 4비스(4-플루오로페닐)부틸]-1-피페라진아세트아미드, 1.82부의 무수프로판산 및 90부의 메틸벤젠의 혼합물을 20시간 교반, 환류시켰다.5.5 parts of 3- (aminocarbonyl)-

-(4-amino-2, 6-dimethylphenyl) -4- [4,4bis (4-fluorophenyl) butyl] -1-piperazineacetamide, a mixture of 1.82 parts propanoic anhydride and 90 parts methylbenzene Was stirred for 20 hours and refluxed.

Water was added to the reaction mixture and the layers were separated.

The organic phase was washed with sodium carbonate solution and water, dried and filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (as an eluent: 5 to 5 volumes) as eluent.

The first fractions were recovered and the eluate was evaporated.

The residue was suspended in 2, 2'-oxybispropane.

-[4-[[2-[3-아미노카르보닐-4-[4, 4-비스(4-플루오로페닐)부틸[-1-피페라진일]아세틸]아미노]-3, 5-디메틸페닐]-프로판아미드 모노히드레이트(화합물 169)를 얻었다. 융점 136℃The high product was filtered to crystallize in acetonitrile and 1.38 parts

-[4-[[2- [3-aminocarbonyl-4- [4, 4-bis (4-fluorophenyl) butyl [-1-piperazinyl] acetyl] amino] -3, 5-dimethylphenyl ] -Propanamide monohydrate (Compound 169) was obtained. Melting point 136 ℃

Example XIV

-(2, 6-디메틸페닐)-1-피페라진아세트아미드와 120부의 메탄올의 혼합물을 2부의 목탄상의 10%팔라듐 촉매로 상온, 상압하에서 수소화 하였다.4-part 3- (aminocarbonyl) -4- [3, 3-bis (4-fluorophenyl) -2-propenyl]-

A mixture of-(2, 6-dimethylphenyl) -1-piperazineacetamide and 120 parts of methanol was hydrogenated at room temperature and atmospheric pressure with a 10% palladium catalyst on 2 parts charcoal.

After taking the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (90:10 volume) as the eluent.

Purified fractions were recovered and the eluent was evaporated.

The residue was suspended in 2, 2'-oxybispropane.

The product was filtered off and dissolved in acetonitrile.

The solution was filtered and the filtrate was evaporated.

The residue was crystallized in 2, 2'-oxybispropane.

-(2, 6-디메틸페닐)-1-피페라진아세트아미드(화합물170)를 얻었다. 융점 143.2℃The product was filtered and dried to afford 2.21 parts of 3- (aminocarbonyl) -4- [3, 3-bis (4-fluorophenyl) propyl]-

-(2, 6-dimethylphenyl) -1-piperazineacetamide (Compound 170) was obtained. Melting point 143.2 ℃

Example XV

-(2, 6-디클로로페닐)-1-피페라진아세트아미드와 90부의 N, N-디메틸포름아미드의 혼합물을 60℃에서 48시간 교반하면서 증발시켰다.4.45 parts 5-chloro-1, 1-diphenyl-2-pentanone, 9.94 parts 3- (amino carbonyl)-

A mixture of-(2, 6-dichlorophenyl) -1-piperazineacetamide and 90 parts of N, N-dimethylformamide was evaporated with stirring at 60 ° C. for 48 hours.

The residue was taken up in water and alkalized with ammonia.

The product was extracted twice with dichloromethane.

The combined extracts were washed with water, dried and filtered and evaporated. The residue was purified twice by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volumes) as eluent.

Purified fractions were recovered and the eluent was evaporated.

The residue was taken up in 2, 2'-oxybisphan and left for 10 days.

(2, 6-디클로로페닐)-4-(4-옥소-5, 5-디페닐펜닐)-1-피페라진아세트아미드 모노히드레이트(화합물 171)를 얻었다. 융점 91.6℃The product was filtered and air dried to give 0.32 parts (3.7%) of 3- (aminocarbonyl)-

(2, 6-dichlorophenyl) -4- (4-oxo-5, 5-diphenylphenyl) -1-piperazineacetamide monohydrate (Compound 171) was obtained. Melting Point 91.6 ℃

Example XVI

With 3.3 parts of ethyl 1- [4,4-bis (4-fluorophenyl) butyl] -4- [2-[(2,6-dichlorophenyl) amino] -2-oxoethyl] -2-piperazine carboxylic acid A mixture of 60 parts of 12N hydrochloric acid solution was stirred for 8 hours at 100 ° C. in an oil bath.

2-propanone was added to give a solution.

The pH was evaporated to 5 with sodium hydrogen carbonate and the viscous oil was taken with warming to 24 parts 4-methyl-2-pentanone.

The solid product was filtered off and boiled in 120 parts of acetonitrile.

After brief cooling the less purified product was filtered and the filtrate was cooled.

The product was filtered and dried to give 0.31 parts of 1- [4,4-bis (4-fluorophenyl) butyl] -4- [2-[(2,6-dichlorophenyli) amino] -2-oxoethyl]- 2-piperazincarboxylic acid (Compound 172) was obtained. Melting point 204.3 ℃

Example XVII

-(2, 6-디메틸페닐)-1-피페라진아세트아미드를 첨가한 교반용액에 24부의 에탄올에 0.94부의(+)-2, 3-디히드록시부탄디올산을 용해 시킨 용액을 첨가하였다.3 parts 3- (amino carbonyl) -4 [4,4-bis94-fluorophenyl) butyl] -24 parts ethanol

To a stirred solution to which-(2, 6-dimethylphenyl) -1-piperazineacetamide was added, a solution obtained by dissolving 0.94 parts of (+)-2 and 3-dihydroxybutanediol acid in 24 parts of ethanol was added.

This whole solution was evaporated and the oily residue was dissolved in warm 4-methyl-2-pentanone.

After cooling to 0 ° C. the product was filtered off and dissolved in 2-propanone.

The product precipitates when 0.2 part of 2, 3-dihydroxybutanediol acid is added and 4-methyl-2-pentanone is added.

-(2, 6-디메틸페닐)-1-피페라진아세트아미드[R-(R^*, R^*)]-2, 3-디히드록시부탄디오에이트(2 : 3)모노히드레이트(화합물 173)를 얻었다. 융점 78.1℃This was filtrated to dry 0.8 parts (+)-3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-

-(2, 6-dimethylphenyl) -1-piperazinacetamide [R- (R ^* , R ^* )]-2, 3-dihydroxybutanedioate (2: 3) monohydrate (Compound 173) Got. Melting Point 78.1 ℃

Example XXIII

-(2, 6-디메틸페닐)-1-피페라진아세트아미드를 첨가한 용액을 40부의 2-프로판온에 1.9부의 (Z)-2-부텐디오에이트를 용해에 서서히 결정화하면서 첨가하였다.3 parts 3- (aminocarbonyl) -4- [4,4-bis (4-fluorophenyl) butyl]-to 80 parts 2-propanone-

A solution to which-(2, 6-dimethylphenyl) -1-piperazineacetamide was added was added to 40 parts of 2-propanone, while 1.9 parts of (Z) -2-butenedioate was slowly crystallized for dissolution.

-(2, 6-디메틸페닐)-1-피레라진아세트아미드(Z)-2-부텐디오에이트(1 : 2)모노히드레이트(화합물 174)를 얻었다. 융점119.6℃The product was filtered and recrystallized twice in 2-propanol and once in 2-propanone to yield 1.56 parts (39%) of 3- (aminocarbonyl) -4-4, 4-bis (4-fluorophenyl) butyl -

-(2, 6-dimethylphenyl) -1-pyrazineacetamide (Z) -2-butenedioate (1: 2) monohydrate (compound 174) was obtained. Melting Point 119.6 ℃

Claims (6)

A process for preparing a compound of formula (I ''), a pharmaceutically acceptable acid addition salt or stereochemically isomer by reacting a compound of formula (V) with a compound of formula (IV) in an inert solvent in the presence of a base.

In the above formula, X is hydroxy C _1-4 alkyl, C _1-4 alkyloxy, C _1-4 alkyl, aminocarbonyl, mono-, or di (C _1-4 alkyl) aminocarbonyl, carboxyl , C _1-4 alkyloxycarbonyl or (hydroxy C _1-4 alkyl) aminocarbonyl, m is an integer of 1 or 2, R ² is hydrogen or C _1-4 alkyl, R ³ , R ⁴ And R ⁵ is hydrogen, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, halo, trifluoromethyl, C _1-4 alkylcarbonyl, aminocarbonyl, cyano, amino, mono-di (C _1-4 alkyl) amino, (C _1-4 alkylcarbonyl) amino or (aminocarbonyl) amino, or (amino carbonyl) amino, R ⁴ may also be nitro, and Alk is C _{1 -6} alkanediyl, Q is dihalophenylmethyl, phenyl or phenylmethyl and W is halo. The compounds of the "by hydrogenation from aliphatic alcohol under the char present, R ⁴ is an amino of general formula (I palladium compound-of-the-charcoal or platinum) in accordance with claim 1, R ⁴ is nitro in the formula (I)" , Pharmaceutically acceptable acid addition salts or stereochemical isomers thereof. The compound of claim 1 wherein R⁴The compound of formula (I ″) is amino in alkylation with alkanal or alkanone in aliphatic alcohol in the presence of hydrogen and palladium-charcoal, R⁴Gaddie (C_1-4A process for preparing a compound of general time (I ″), a pharmaceutically acceptable acid addition salt or a stereochemical isomer thereof, which is alkyl) amino. According to claim 1, to R ⁴ are Amano of the acylating formula (I ") of anhydrous alkanoic acid (Alkanoic acid anhydride) in an alkali metal isocyanate, or an aromatic hydrocarbon trouble in water a compound of the reaction, R ⁴ a 'C _1-4 Alkylcarbonylamino or aminocarbonyl aminoyl A method for preparing a compound of formula (I ″), a pharmaceutically acceptable acid addition salt or granular isomer thereof. The compound of general formula (I '') according to claim 1, wherein the compound of general formula (I ') wherein X is C _1-4 alkyloxycarbonyl is hydrolyzed with a hydrohalic solution so that X is carboxyl. , Pharmaceutically acceptable acid addition salts or stereochemical isomers thereof. The compound of formula (I '') according to claim 1, wherein the compound of general formula (I ") wherein X is a carboxyl group is reacted with alkanol in the presence of a hydrohalicacid, where X is C _1-4 alkyloxycarbonyl. ), A pharmaceutically acceptable acid addition salt or stereochemical isomer thereof.