JPH0460988B2 - - Google Patents

Description

[Detailed description of the invention]

Piperazine derivatives having a lower alkoxycarbonyl group or a hydroxymethyl group on one of the carbon atoms are described in Helv.Chim.Acta, 45 , 2383-2402.
(1962). These piperazine derivatives are taught to be useful as anthelmintics, antihistamines, and psychotropic agents. N-aryl-4-(4,4-
Diarylbutyl)-1-piperazine alkanamides are described in US Pat. No. 3,267,104. The piperazine alkanamides are taught to be useful as coronary vasodilators, local anesthetics, central nervous system stimulants, and anticarrageenan agents. N-aryl-piperazine acetamides, optionally substituted with methyl or phenyl groups in the piperazine moiety, are described in CA 90 , 168, 547 as useful intermediates in the preparation of analgesics. The compounds of the invention are distinguished from the previously mentioned known compounds by the nature of the substituents on the piperazine moiety and by their pharmaceutical properties. According to the invention, the formula where R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; X is hydroxy lower alkyl, lower alkyloxy lower alkyl, aminocarbonyl, mono(lower alkyl) aminocarbonyl, di(lower alkyl) aminocarbonyl , carboxyl, lower alkoxycarbonyl, (aminocarbonyl) lower alkyl, and (hydroxy lower alkyl) aminocarbonyl; m is an integer of 1 or 2; R ² is hydrogen and lower alkyl; a member selected from the group consisting of; R ³ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, halo,
trifluoromethyl, lower alkylcarbonyl,
Aminocarbonyl, lower alkyloxycarbonyl, cyano, amino, mono(lower alkyl)amino, di(lower alkyl)amino, (lower alkylcarbonyl)amino and (aminocarbonyl)
independently selected from the group consisting of amino, with the proviso that
R ³ and/or R ⁴ can also be nitro, and R is of the formula (In the formula, Ar ₁ and Ar ₂ are each an aryl group)
group and formula -Alk-Q ...(b) (wherein Alk is an alkanediyl group or a lower alkenediyl group, provided that the lower alkanediyl group may be substituted with a hydroxy or lower alkyl group; and Q is aryl, aryloxy, diarylmethoxy, 2,2-diarylethenyl, diarylmethylcarbonyl, arylcarbonyl, monoarylaminocarbonyl, diarylaminocarbonyl, diarylmethyl (the methyl moiety in this diarylmethyl group is cyano, mono-lower alkyl) arylamino (the amino moiety may be substituted with an aryl, arylcarbonyl, lower alkylcarbonyl or arylsulfonyl group); 2,3-dihydro-2
-oxo-1H-benzimidazol-1-yl (this group may be substituted with halo in the 5- or 6-position), 10H-phenothiazine-10
-ylcarbonyl (this group may be substituted with a halo atom), 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-
purin-7-yl, 1-aryl-1,3-dihydroisobenzofuran-1-yl, and 2,2
-diaryl-1,3-dioxolan-4-yl); where aryl is a member selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl and pyridinyl; , wherein said substituted phenyl has 1 to 2 substituents each independently selected from the group consisting of halo and (halo-substituted phenyl)carbonyl,
Stereoisomers and pharmaceutically acceptable acid addition salts thereof are provided. In the above definitions, the term "halo" is inclusive of fluoro, chloro, bromo and iodo and the term "lower alkyl" refers to straight and branched chain saturated hydrocarbons having from 1 to 6 carbon atoms. groups such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl, etc., and "lower alkanediyl" used in the definition of Alk is 1-
"Lower alkenediyl" includes straight and branched alkenediyl chains having 6 carbon atoms, and as used in the definition of Alk, "lower alkenediyl" includes straight and branched alkenediyl chains having 2 to 6 carbon atoms. Contains chains. Preferred compounds within the scope of the invention are those in which R is of formula (b)
where Q is diarylmethyl and Alk is a 1,3-propanediyl group. Particularly preferred compounds within the scope of the invention are R
is a group of formula (b), where Q is diarylmethyl, Alk is l,3-propanediyl, X is aminocarbonyl, m is 1, and R ¹ and R ² is a compound in which both are hydrogen. The most preferred compounds within the scope of the invention are 3-
(aminocarbonyl)-4-[4,4-bis(4-
fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1-piperazine acetamide,
A compound selected from the group consisting of stereoisomers thereof and pharmaceutically acceptable acid addition salts thereof. Compounds of formula () are generally prepared by reacting a suitably substituted piperazine of formula () with a reagent N-
Alkylation or by N-alkylation of a suitably substituted piperazine of formula () with a reagent of formula (). In the above reaction diagram, R, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , m and X are as defined above;
and W is a reactive leaving group, e.g. halo, e.g.
chloro, bromo and iodo, or sulfonyloxy groups, such as methylsulfonyloxy,
Represents 4-methylphenylsulfonyloxy, etc. The reactions of N-alkylation of () with () and N-alkylation of () with () are:
Generally, a suitable reaction-inert solvent, e.g.
Lower alkanols, e.g., methanol, ethanol, propanol, butanol, etc.; aromatic hydrocarbons, e.g., benzene, methylbenzene, dimethylbenzene, etc.; ethers, e.g.,
It can be carried out in 1,4-dioxane, 1,1'-oxybispropane, etc.; ketones, such as 4-methyl-2-pentanone; N,N-dimethylformamide; nitrobenzene; etc., or mixtures of such solvents. The presence of a suitable base, such as an alkali metal or alkaline earth metal carbonate or hydrogencarbonate, e.g. potassium carbonate, sodium bicarbonate, etc., an amine, e.g. N,N-diethylethanamine, etc., pyridine, etc. It is advantageous to remove free acid during the reaction. When W is other than iodo, a small amount of a suitable alkali metal or alkaline earth metal iodide, such as sodium or potassium iodide, may act as a reaction promoter. Slightly higher temperatures are appropriate to increase the reaction rate, and preferably the reaction is carried out at the reflux temperature of the reaction mixture. Compounds of formula () are generally prepared by combining piperazine of formula () or the corresponding carbonyl-oxidized form of a piperazine of formula () with a reagent of formula () or () using known reductive amination methods, e.g. can also be prepared by reacting the reaction components together in a suitable reducing medium, for example in the environment of catalytic hydrogenation, by stirring and optionally heating. The compound of formula () together with a suitably substituted benzene derivative of formula () for the amide of formula (),
in a suitable reaction-inert solvent, if necessary.
It can also be prepared by stirring and heating in the presence of a suitable catalyst such as cuprous chloride, boron trifluoride, etc. Compounds of formula () are prepared by combining a carboxylic acid derivative of formula () in which R ⁶ is hydroxy, lower alkyloxy, aryloxy, amino, chloro, bromo or iodo with an amine of formula () and a suitable solvent;
For example, the reaction components are stirred together in alkanols, such as methanol, ethanol, etc.; ethers, such as 1,4-dioxane, tetrahydrofuran, etc.; N,N-dimethylformamide; 4-methyl-2-pentanone, etc.; If necessary, it can also be produced by reaction by heating. Compounds of formula () can be prepared by N-alkylating diamines of formula () with reagents of formula (XI) or by N-alkylating diamines of formula (XII) following the same procedures described above for the reaction of () with (). They can even be prepared by N-alkylation with reagents of formula (). In the reaction diagrams below, the 1,2-ethanediyl group in () or (XI) and (XII) or () is substituted with a group having the meaning of R ¹ . In (XI) and (), W' has the same meaning as described above for W. Compounds of formula () can be prepared by formula () following the same procedure described above for the reaction of () with ().
) is alkylated with an amine of formula () or an amine of formula () is alkylated with an amine of formula ().
) can also be produced by alkylation with an amine. Depending on the nature of X, the compounds of formula () can be converted into each other according to known functional group rearrangement methods. Some functional group rearrangements are illustrated in Reaction Scheme 1, where the group is represented by D. The carboxylic acid functionality can be converted to an ester or amide functionality according to known methods, for example by stirring the starting carboxylic acid with a suitable alcohol or a suitable amine and, if necessary, heating. can be changed to The carboxylic acid functionality can also be converted to an ester functionality by reacting the starting carboxylic acid with a suitable alkyl halide in the presence of a base such as sodium methoxide. Ester and amide functions can be converted to carboxylic acid functions by stirring the starting amide or ester into an acidic or alkaline aqueous medium and, if necessary, heating. The ester functionality is obtained by subjecting the starting ester to a suitable reaction in the presence of a suitable amine in an inert solvent.
The amide functionality can be converted by stirring and, if necessary, heating. The aminocarbonyl functionality can be converted to a mono- or di-(lower alkyl)aminocarbonyl functionality, and the lower alkylaminocarbonyl functionality can be converted from a starting aminocarbonyl compound or lower alkylaminocarbonyl compound to a suitable lower alkyl halide. It can also be converted into the di(lower alkyl)aminocarbonyl function by stirring and, if necessary, heating, according to known N-alkylation methods. Carboxylic acid and ester functional groups can be reduced according to known reduction procedures, e.g. metal hydrides,
It can be converted to an alcohol functional group using diborane or the like. The alcohol functionality can be converted to a carboxylic acid functionality according to known alcohol to carboxylic acid oxidation methods using, for example, potassium permanganate, chromium trioxide, silver oxide, and the like. The alcohol functionality may be modified according to known methods, for example by reacting the starting alcohol with a suitable alkyl halide in the presence of a suitable base, such as sodium hydride, in a suitable reaction in an inert solvent. Can be done. The ester functionality can be converted into an alcohol functionality according to known ether-cleavage methods, for example by reacting the starting ether with a strong Lewis acid, such as boron trifluoride. Depending on the nature of R, R ¹ , R ² and R ³ , compounds of formula () can be prepared according to known functional group transfer methods.
can change each other. For example, compounds in which at least one of R ³ and R ⁴ is a nitro group can be prepared by catalytic reduction in the presence of a catalyst, such as platinum on charcoal, according to known methods for reducing the nitro group to an amine group. It can be converted into an amine derivative. Compounds of formula () can be prepared using a suitable acid, such as an inorganic acid, such as a hydrohalic acid, such as chlorine,
or organic acids such as acetic acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid , 3-phenyl-2-propanoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino They can be converted to therapeutically active non-toxic acid addition salts by treatment with acids such as -2-hydroxybenzoic acid. Conversely, the salt form can be converted to the free base form by treatment with alkali. As is clear from formula (), the compounds of the invention have at least one asymmetric carbon atom in their structure. That is, the piperazine carbon atom has an X group. This asymmetric center can be represented in the R- and S-configurations, and the R- and S-designations are described by RSCahn. C. Ingold and V. Prelog,
Angew.Chem.Int.Ed.Engl., 5 385, 511 (1966)
This corresponds to the rules described in . After all, compounds of formula () can exist in the form of two different enantiomers, which can be obtained by, for example, converting a mixture of enantiomers into their acid addition salts with an optically active acid, Stereomeric salts can be separated from each other by, for example, separating by selective crystallization and liberating the pure enantiomers by treatment with alkali. When R ¹ is other than hydrogen and/or when the radicals R and CmH ₂ m have one or more asymmetric centers, each of these asymmetric centers is present in the R- and S-configuration and the formula The compounds of () can have different diastereochemical forms, which can be separated by physical separation methods, such as selective crystallization and chromatographic techniques, e.g., countercurrent partitioning, column chromatography, etc. , can be separated from each other. When R ¹ is other than hydrogen, substituent X and R ¹
are engaged to the piperazine ring in a cis or trans relationship with each other, in which case the compound of formula () is designated as "cis" or "trans". Compounds of formula () in which R is a group (b) and Alk is a lower alkenediyl group may be characterized by the designations "E" and "Z", said E- and Z-configurations being J .Org.Chem., 35 , 2849−
2868 (1970). Stereochemically pure stereochemically isomers can also be derived from the corresponding pure stereochemically isomeric appropriate starting materials when the reaction occurs stereospecifically or highly stereoselectively. In most compounds and starting materials, the stereochemical configuration is not determined experimentally. In those cases, without further reference to the actual stereochemical configuration, stereochemical isomers are designated "A" for the first isolated and the second isolated for the stereochemical isomer. is displayed as “B”. Stereochemical isomers of compounds of formula () are naturally included within the scope of the present invention. Some of the intermediates and starting materials used in the above preparation are known, others can be prepared according to known methods of making similar compounds, and for some of them the synthetic method is This will be explained later. intermediate (-a) of formula () having an X group in the 2-position of the piperazine ring; intermediate (b) of formula () having an X group in the 3-position of the piperazine ring; The intermediates (-a) of formula () having an X group in the - position and the intermediates (-b) of formula () having an can be derived from a suitably substituted piperazine of formula () as described, where P ¹ and P ² each represent a protecting group. Intermediates of formulas (-a) and (-b) are
(), () with the formula LW (where L is R or L ₁ as defined in Reaction Scheme 2) and the known N- It can be derived by reacting according to an alkylation method and subsequently removing the protecting group in () thus obtained according to known methods. Intermediates of formulas (-b) and (-a) are
From (), () the secondary amine functional group is protected with ^P2 group, () thus obtained protecting group of ()
P ¹ is removed and () so formed (XI) is given the formula LW (where L is L ₁ or R) and the known react according to the N-alkylation method, and () the protecting group of (XII) thus obtained
P ^{2 can be induced by removing P 2} according to known methods. Suitable protecting groups include, for example, an optionally substituted phenylmethyl group, an optionally substituted lower alkylcarbonyl or arylcarbonyl group, and the like. As can be seen in the reaction step () → (XI), the protecting groups P ¹ and
P ² should be chosen so that P ¹ can be eliminated without affecting P ² . Suitable protecting groups are, for example, hydrogenolyzable groups as the P ² group, such as the phenylmethyl group, and hydrolyzable groups, such as the trifluoroacetyl group, as the P ¹ group. Piperazine () used as a starting material in Reaction Diagram 2 can be produced according to known methods. For example, (-a) piperazine () in which P ¹ is a phenylmethyl group can be prepared by appropriately substituted piperazine (
) by reacting with reagent (),
Alternatively, a suitably substituted piperazine () can be reacted with benzaldehyde according to known reductive amination reactions, i.e. the reaction components are brought together in the presence of a suitable catalyst, e.g. platinum on charcoal, for a suitable reaction. It can be prepared by stirring and heating in an inert solvent under a hydrogen atmosphere. Starting piperazine ()
can be prepared from the corresponding piperazine () according to known catalytic hydrogenation reaction methods or according to the same method as described above for the preparation of () starting from () and (XI) or (XII) and (). Di(phenylmethyl)piperazine () (which can be prepared by reacting () with () or ())
By hydrogenolyzing reaction with (),
Can be guided. In reaction diagram 3, () or ()
and 1 in () or (),
The 2-ethylenediyl group is substituted with a group having the meaning of R ¹ . X is a group of the formula -( _CH2 ) _p- (CO) _q -ZH, where Z is O or ^NR7 , said ^R7 is hydrogen or lower alkyl, and p is 0 or 1; , and q is 0 or 1, provided that p and q are 1 and Z is ^NR7 , then q is 1, intermediates of formulas (-b) and (-a), said intermediates is the formula (-b-1) or (-
Represented by a-1) is piperazine (XI)
From, () (XI) and the carbonyl derivative (
XII), where R ⁸ and R ⁹ are each, independently of each other, hydrogen or lower alkyl, in a suitable reaction-inert solvent, such as methoxyethanol, optionally with a suitable base. Stir, and if necessary, heat () in the presence of () thus obtained ()
LW, where L is L ₁ or R, is reacted with a reagent of () and () starting from () according to the known N-alkylation method described above for the preparation of (), and () is thus It can also be produced by hydrolyzing () obtained in an acidic aqueous medium. Intermediates of formula () can be prepared according to the same method as described in US Pat. No. 3,714,159. Expression (), (), (), starting from expression ()
(XII), production of intermediates of () and (),
The reaction diagram is shown in Figure 4. Intermediates of formulas (), (), () and () can be prepared by converting () into amines (), () according to the known N-alkylation methods described above for the preparation of () starting from () and (). ,
It can be derived from () by reacting with () and _NH3 . Intermediates of formula () and () are prepared by replacing () with an amine of formula () or () with N
-It can also be produced by alkylation. Intermediates of formulas () and (XII) and also intermediates of formulas () and () are
It can be produced by alkylation with L), (L), (L) and (L). In reaction diagram 4, (L), (), (L)
and/or the 1,2-ethanediyl group in (XII) can be substituted with a group having the meaning of R ¹ . Intermediates of formula () are suitable acid halides (L
) can be produced by N-alkylating with aniline (). Intermediates of formulas () and () are ()
can be derived from () by reacting with ammonia or an amine (L) according to known N-alkylation methods. Rearrangement of functional groups as described in reaction diagram 1 is
It can also be carried out for all intermediates which have a group X in their structure. Compounds of formula (), their pharmaceutically acceptable acid addition salts and stereoisomers, increase the oxygen tension ( _pO2 ) of coronary sinus blood when administered intravenously or orally to vertebrates. The increase in pO ₂ is evidenced by experimental data obtained in coronary sinus pO ₂ tests in anesthetized dogs.
The study was published in The Journal of Pharmacology
and Experimental Therapeutics, 152 , (2),
265-274 (1966). Coronary sinus _pO2 in anesthetized dogs A cardiac catheter was advanced into the coronary sinus of anesthetized dogs and Gleichmann-Lubbers of the Clark electrode housed in a constant blood flow chamber. make use of,
Coronary sinus blood oxygen tension (pO ₂ , mmHg) was measured. The pO ₂ value was read on a calibrated scale of an optical checkmeter. Aortic blood pressure, respiratory rate and electrocardiogram were recorded during the experiment. Animals absorbed spontaneously. 30
After a control period of minutes, steady state was usually achieved. At this point, the dose of active compound was given by slow intravenous injection. Subsequently, other active compounds were injected at the end of each new steady state period of 10 minutes or more. Tables 1 and 2 show the most recent effective intravenous dose (mg/Kg body weight) at which the pO ₂ in the coronary sinus increased by 100% compared to the control value (column 1) and the duration of action at the lowest effective dose (column 1). 2) is shown. The data shown in Tables 1 and 2 are for illustrative purposes and are not intended to limit the scope of the invention.

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[Table] Compounds of formula (), their pharmaceutically acceptable acid addition salts and stereoisomers, when administered intravenously or orally, have a positive effect on the outcome of complete warm ischemia in the canine heart. Shows protective effect. A test that reveals said protection is “Myocardial
Protection and Exercise Tolerance: the Role
of Lidoflazine, a New Antianginal
Agent.”, Royal Society of Medicine
International Congress and Symposium
Series No. 29 , p. 89-95 (1980). Protection against myocardial ischemia of application in dogs Experiments were carried out on adult anesthetized beagles ranging in weight from 9 to 15 Kg. Systemic blood pressure was measured via the left femoral artery using a JF Millar tip manometer. A Swann-Ganz thermodilution catheter was introduced through the right femoral vein and placed in the pulmonary artery, and cardiac output was measured by thermodilution and central nerve pressure through the adjacent lumen. . A cannula was placed in the other femoral vein to facilitate infusion of room temperature saline. A cannula was inserted into the right femoral artery and the femoral artery was connected to the cardiopulmonary bypass arterial line. The heart was exposed through a right thoracostomy and suspended in a pericardial crddle. The right atrium was connected to the venous line of the heart-lung machine by cannulation. Left ventricular pressure was measured after inserting a JF Miller tip manometer into the pulmonary vein. For cardiopulmonary bypass, two interlocking roller pumps, a bubble oxygenator, and a heat exchanger were used. 2000 ml of fresh heparinized blood from the donor dog was injected into the heart-lung machine. During the experiment, serial blood samples were taken to monitor pO ₂ , pCO ₂ and PH. At the beginning of coronary bypass,
During the cessation of ischemia and throughout the subsequent 30 minute reperfusion period, the left ventricle was opened via the apical cannula. Experimental Design: (a) Intravenous Route of Administration Approximately 25 minutes after intravenous administration of the active compound, the animals were placed on complete cardiopulmonary bypass at 37°C by firmly pressing the ascending aorta for 60 minutes. At the onset of complete ischemia, an amount of active compound was added to the whole blood content. Myocardial temperature was kept constant at 37°C during the entire period of complete ischemia. Coronary arteries were reperfused for 30 minutes while the heart was empty and stopped. After 10 minutes of perfusion, the heart was defibrillated. At the end of reperfusion,
Dogs were removed from cardiopulmonary bypass and functional parameters were recorded until the end of the experiment. Column 1 of Table 3 indicates the lowest effective intravenous dose of compound (mg/Kg body weight) at which the dog's heart returned to normal function after 60 minutes of complete ischemia, while column 2
indicates the total amount of compound added to the whole blood content. (b) Oral route of administration The experimental procedure is identical to that described for the intravenous route of administration, except that the active compound is administered orally and not administered intravenously or added to the whole blood content. I didn't. Table 3
Column 3 indicates the lowest effective oral dose of compound (mg/Kg body weight) at which the dog's heart returned to normal function after 60 minutes of total ischemia. The data shown in Table 3 is for illustrative purposes and is not intended to limit the scope of the invention.

[Table] Looking at their pharmacological activity, the compounds of formula () improve the blood perfusion of the cardiac muscle tissue, and also improve the effects of ischemia, anoxia or hypoxia in a more or less short period of time. The subject compounds are useful for partially or completely protecting the heart from myocardial disease caused by episodes of By administering it, it can be used for the treatment and prevention of patients suffering from angina pectoris and patients at the stage before or after myocardial infarction. The subject compounds can be formulated into a variety of pharmaceutical forms for purposes of administration. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, as the active ingredient, in base or acid addition salt form, is intimately mixed with a pharmaceutically acceptable carrier. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in a single dose form suitable for oral, rectal administration or parenteral injection. For example, any of the conventional pharmaceutical vehicles can be used in preparing compositions for oral administration. Examples of such vehicles are water, glycols,
or, in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually consists of sterile water, at least in large part, although other ingredients can be included, such as to facilitate solubility. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable solutions can also be prepared, in which case suitable liquid carriers, suspensions, and the like can be used. The acid addition salts of () are clearly more suitable in the preparation of aqueous compositions since they are better in aqueous solution than the corresponding base forms. Because of the ease of administration and uniformity of administration,
It is advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form. As used herein, dosage unit form means physically discrete units suitable for single administration, each unit containing a predetermined amount calculated to produce the desired therapeutic effect. Contains the active ingredient together with any required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets,
wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, etc., and separate multiples thereof. The following formulations are examples of typical pharmaceutical compositions in dosage unit form suitable for systemic administration to patients according to the present invention. Oral Drops The following formulation contains 5 mg/ml of active ingredient (AI).
ml of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,
10 of an oral infusion solution containing 6-dichlorophenyl)-1-piperazine acetamide. AI...50g 2-hydroxypropanoic acid...2.5ml Methyl 4-hydroxybenzoate...18g Propyl 4-hydroxybenzoate...2g Pyrogen-free water...Enough amount to make 10 Methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate are dissolved in approximately 5 mL of boiling pyrogen-free water. After cooling to about 50℃, add 2-hydroxypropanoic acid while stirring.
Then we added AI. The solution was cooled to room temperature and made up to the required volume with pyrogen-free water. The solution was sterilized by filtration (USP p.811) and placed in a sterile container. Injectable Solutions The oral infusion solutions described above can be used as injectable solutions. Capsules each containing 20 mg of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1 as active ingredient (AI). - 10 000 hard gelatin capsules containing piperazine acetamide were made from the following composition. AI...200g Lactose...1000g Starch...300g Talc...300g Calcium stearate...10g A homogeneous mixture of active and auxiliary ingredients was prepared and filled into two pieces of hard gelatin capsules. Tablets each containing 25 mg of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1 as active ingredient (AI). - 5000 compressed tablets containing piperazine acetamide were prepared from the following formulation. AI...125g Starch...150g Dibasic calcium phosphate hydrate...650g Calcium stearate...35g The finely ground ingredients were mixed well and granulated with 10% starch paste. The granules were dried and compressed into tablets. Oral Suspension The following formulation contains 15 mg of 3-(aminocarbonyl) per teaspoon (5 ml) as the active ingredient (AI).
-4-[4,4-bis(4-fluorophenyl)
butyl]-N-(2,6-dichlorophenyl)-1
- provides 5 of an oral suspension containing piperazine acetamide. AI...15.0g Sucrose...300.0g Dioctyl sodium sulfosuccinate...0.5g Bentonite...22.5g Methylparaben...7.5g Propylparaben...1.5g Defoaming AF emulsion...0.15g Propylene glycol...52.0g FD&C Yellow #5...0.1g Sodium diclamate...50.0g Sodium saccharin...5.0g Orange flavoring agent...7.5g Superpurified water...Amount for 5 Dissolve parabens in propylene glycol and add half of this solution. of sodium cyclamate, sodium saccharin and sucrose in water. Bentonite was suspended in hot (approximately 85°C) water and stirred for 60 minutes. Bentonite solution was added to the former solution. The sulfosuccinate was dissolved in a portion of water and the AI was suspended in the resulting solution. Dilute the defoaming AF emulsion with a minimum amount of water to a lotion consistency and add
Mix well. Add the latter suspension of AI to the former mixture and mix well. FD&C Yellow #5 dissolved in a small amount of water was then added, orange flavor added and made up to the required volume with water. Stir everything to make a homogeneous mixture. The mixture was passed through a colloid mill and filled into suitable containers. In view of the pharmaceutical activity of the subject compounds, according to the invention, an effective amount of a compound of formula (), a pharmaceutically acceptable acid addition salt or stereoisomer thereof, is mixed with a pharmaceutical carrier. A method for improving blood perfusion of the cardiac musculature by systemic administration, and for preventing myocardial diseases caused by more or less brief episodes of ischemia, anoxia or hypoxia. It is clear that a method of protecting the heart is provided. The following examples further illustrate the invention.
All parts are by weight unless otherwise noted. Example A Intermediate Preparation Example A mixture of 20 parts of 2-chloroethanol, 3 parts of sulfuric acid and 16 parts of benzene was heated on a water bath.
Then 35 parts of 4-
Fluoro-α-(4-fluorophenyl)benzene methanol was added dropwise. After the addition was complete, the whole was stirred and refluxed for 4 hours. After cooling, the reaction mixture was poured into water. The benzene layer was separated, dried over calcium chloride and evaporated. The residue was vacuum distilled to obtain 35 parts of 1,1'-[(2-chloroethoxy)methylene]bis[4-fluorobenzene]; boiling point 164-166°C/1.5mmHg; ^n20D : _1.5462 ;
^d2020 _: 1.2290 (intermediate 1). Example 11.7 parts of (5-fluoro-2-hydroxyphenyl)(4-fluorophenyl)methanone and 45 parts of N,N-dimethylformamide are added to a stirred mixture and cooled to about 5°C (ice bath). While doing so, nitrogen was bubbled through. Then 2.4 parts of a 50% suspension of sodium hydride was added in portions and a high degree of foaming occurred. When completed, 23.6 parts of 1-bromo-
3-chloropropane was added while still cooling to 5°C. The whole was heated to 40°C and stirred at this temperature for 1 hour. After cooling to 5 °C, the reaction mixture was heated to 400 °C.
of water, and the product was diluted with 180 parts of benzene.
Extracted twice. The extracts were dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified upon trituration in petroleum ether. After cooling to 0°C, the product was filtered and dried to yield 10.7 parts (69%) of [2-
(3-chloropropoxy)-5-fluorophenyl](4-fluorophenyl)methanone, melting point 60
°C (intermediate 2) was obtained. Example A mixture of 16 parts of 1-cyclopropyl-2,2-diphenylethanone and 300 parts of hydrochloric acid was stirred and refluxed for 4 hours. The reaction mixture was cooled and extracted with 2,2'-oxybispropane. Wash the extract with water and dilute sodium bicarbonate,
When dried, filtered and evaporated, 17 parts of 5-
Chloro-1,1-diphenyl-2-pentanone (intermediate 3) was obtained as a residue. Example To a stirred solution of 21.9 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanamine in 160 parts of 2-propanone was added 11.66 parts of sodium carbonate. Then 12.43 parts of 2-chloroacetyl chloride were added dropwise at a temperature below 30°C (cooling in an ice bath was necessary). When complete, continue stirring for 1 hour at room temperature;
The mixture was further kept under reflux for 2 hours. After cooling to room temperature, the sodium carbonate was filtered and washed with 2-propanone. The liquid was evaporated and the residue was recrystallized from 2,2'-oxybispropane, yielding 20.6 parts of N-
[Bis(4-fluorophenyl)methyl]-2-chloroacetamide, melting point 127.6°C (Intermediate 4) was obtained. Example 10.6 in 68 parts of N,N-dimethylformamide
Add 2.1 parts of N-(4-fluorophenyl)-4-methylbenzenesulfonamide to a stirred solution of 2.1 parts.
A 50% dispersion of sodium hydride was added dropwise.
The temperature rises to 35°C. After stirring for 20 minutes, the whole was cooled in an ice bath (approximately 15°C) and 12.6 parts of 1
-Bromo-3-chloropropane was added rapidly.
Stirring was continued first for 20 minutes at room temperature, then for 3 hours at 75°C, and then overnight at room temperature. The reaction mixture was poured onto ice water and the product was extracted with methylbenzene. The extract was washed three times with water, dried and evaporated. The residue was crystallized from petroleum ether. The product was filtered and recrystallized from 2,2'-oxybispropane to yield 11.37 parts (83.2%) of N-(3-chloropropyl)-N-(4-fluorophenyl)-4.
-Methylbenzenesulfonamide (intermediate 5) was obtained. Following the same procedure and starting from 4-fluoro-N-(4-fluorophenyl)benzamide,
The following compounds were obtained analogously: N-(3-chloropropyl)-4- as residue
Fluoro-N-(4-fluorophenyl)benzamide. Example 25 parts of 1,3-isobenzofurandione and
Fifty parts of aluminum chloride were added in portions to the stirred mixture with 108.5 parts of fluorobenzene.
When completed, slowly heat the whole thing to reflux,
Stirring was then continued for 1.50 hours at reflux temperature. The reaction mixture was cooled and poured onto a mixture of crushed ice and 60 parts of concentrated hydrochloric acid. The product was extracted twice with dichloromethane. The combined extracts were dissolved in sodium hydroxide solution.
Washed with 10%. The aqueous phase was separated, washed with 2,2'-oxybispropane and acidified with concentrated hydrochloric acid while cooling. The whole was stirred for 1 hour at room temperature. The precipitated product was filtered and dissolved in benzene. The solution was azeotropically distilled to dryness. The solid residue was stirred in hexane. The product was filtered and dried under vacuum at about 50°C to give 33.5 parts (80.7%) of 2-(4-fluorobenzoyl)benzoic acid, melting point 129.2°C (Intermediate 7). To 1190 parts of 1,1'-oxybisethane were added 50 parts of lithium aluminum hydride all at once. Then, in 875 parts of 1,1'-oxybisethane
A solution of 213.7 parts of 2-(4-fluorobenzoyl)benzoic acid was added dropwise so that the mixture was maintained at the reflux temperature. Once completed, stir first.
Continued for 30 minutes at room temperature, then continued under reflux for 2 hours, and continued overnight at room temperature. The reaction mixture was cooled to 0°C and successively added with 50 parts of water, 50 parts of
A 15% sodium hydroxide solution and 150 parts of water were added dropwise, all at 0°C. The reaction mixture was filtered through Hyflo and washed well with 1,1'-oxybisethane. The organic phase was separated, washed with water, dried, filtered and evaporated. Crystallization of the residue from a mixture of benzene and hexane gave 170.4 parts of α-(4-fluorophenyl)-1,2-benzenedimethanol, mp ±7.5°C (Intermediate 8). 200 parts α-(4-fluorophenyl)-1,2
- Benzenedimethanol and 2.295 parts phosphoric acid 60%
The mixture was stirred at 100°C for 3 hours. Stirring was continued overnight at room temperature. The reaction mixture was poured onto water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, 10% sodium carbonate and water again, dried, filtered and evaporated. If the residue remains, 57 parts of 1-
(4-Fluorophenyl)-1,3-dihydroisobenzofuran, boiling point 108°C/0.2mmHg (Intermediate 9)
was gotten. Example Stirred and cooled (2-propane/CO ₂ −
Bath) 1 part of iron chloride () was added to 1080 parts of ammonia, and then 7.7 parts of sodium was added in portions under a nitrogen atmosphere. After stirring for 20 minutes,
A solution of 64.5 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran in 105 parts of 1,1'-oxybisethane, while still cooling, is
added. A solution of 75 parts of 2-(3-bromopropoxy)tetrahydro-2H-pyran in 37 parts of 1,1-oxybisethane was then added dropwise. When complete, stirring was continued for 2 hours in a 2-propane/ _CO2 bath under nitrogen atmosphere. Without cooling and in the absence of nitrogen, 490 parts of 1,1'-oxybisethane were slowly added dropwise and stirring was continued overnight at room temperature. 225 parts of saturated ammonium chloride solution were added dropwise, followed by 200 parts of water. Separate the layers;
The aqueous phase was then extracted twice with 1,1'-oxybisethane. The combined organic phases were washed with water, dried and
and evaporated. The residue was purified by column chromatography on silica gel with trichloromethane and methanol (99.5:0.5 vol) as eluent.
The mixture was used for purification. The second fraction was collected, the residue was evaporated and 39.6 parts of 1-(4-fluorophenyl)-1,3-dihydro-1-[3-
(tetrahydro-2H-pyran-2-yloxy)
Propyl]isobenzofuran (intermediate 10) was obtained as a residue. 39.6 parts of 1-(4-fluorophenyl)-1,3
-dihydro-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]isobenzofuran was dissolved in 9.8 parts of a 0.1 molar solution of hydrochloric acid and 788 parts of ethanol, and the whole was stirred and refluxed for 1 hour. . The solvent was evaporated and the residue was taken up in methylbenzene and water. The organic phase was separated, washed with water, filtered and evaporated.
The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24.2 parts of 1-(4-fluorophenyl)-
1,3-dihydroisobenzofuran-1-propanol (intermediate 11) was obtained as a residue. To a stirred solution of 24.2 parts of 8 parts of pyridine and 90 parts of trichloromethane was added 12.1 parts of thionyl chloride. When completed, the whole was slowly heated to 50°C and stirring was continued at this temperature for 3 hours. The reaction mixture was poured onto ice water. The organic phase is separated, washed with sodium bicarbonate solution (10%), dried and evaporated to give 20 parts of 1-(3-
chloropropyl)-1-(4-fluorophenyl)
-1,3-dihydroisobenzofuran (intermediate)
12) was obtained as a residue. Example 70 parts of 4-fluorobenzeneacetonitrile
It was heated to 120°C, 83 parts of bromine was added dropwise, and stirring was continued for 30 minutes. The resulting reaction mixture was added dropwise to a stirred mixture (room temperature) of 85 parts of aluminum chloride and 200 parts of fluorobenzene (exothermic reaction: temperature rises to 50° C.). After stirring for 30 minutes at 50° C., the reaction mixture was poured onto a mixture of crushed ice and 75 parts of hydrochloric acid solution. The product was extracted with methylbenzene. The extract was dried and evaporated. The residue was crystallized twice from 2-propanol to give 51 parts of 4
-Fluoro-α-(4-fluorophenyl)benzeneacetonitrile, melting point 63.5°C (Intermediate 13) was obtained. 22.9 parts of 4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile, 23.6 parts of 1-
bromo-3-chloropropane and 0.4 parts N,
To a stirred and cooled (ice bath) mixture of N,N-triethylbenzene aluminum chloride,
600 parts of 50% sodium hydroxide solution were added at a temperature below 30°C. When finished, stir
It lasted for 3 hours at 50-60°C. Methylbenzene and water were added and the layers were separated. Dry and filter the organic phase;
Evaporated. The residue was evaporated once more at 100°C for 30 minutes to remove traces of 1-bromo-3-chloropropane, yielding 29 parts (95%) of α-(3-chloropropyl)-4-fluoro-α-(4 -fluorophenyl)benzeneacetonitrile (intermediate 14) was obtained as a residue. A mixture of 3 parts of α-(3-chloropropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile, 92 parts of concentrated sulfuric acid, 50 parts of water and 50 parts of acetic acid was stirred for 24 hours. It refluxed.
The reaction mixture was concentrated to about 100 parts and the product was extracted with methylbenzene. The extract was washed with water, filtered and evaporated. The residue was suspended in petroleum ether. The product was filtered and crystallized from 2,2'-oxybispropane to yield 1.41 parts of 3,3-bis(4-
Fluorophenyl)tetrahydro-2H-pyran-2-one, melting point 122.4°C (Intermediate 15) was obtained. 5.8 parts of 3,3-bis(4-fluorophenyl)
A mixture of tetrahydro-2H-pyran-2-one and a solution of hydrobromic acid in 30 parts of glacial acetic acid was stirred at room temperature for one week. The reaction mixture was poured onto water. The precipitated product was filtered and dissolved in 2,2'-oxybispropane. Wash the organic phase with water,
Dry, filter and evaporate. The residue was boiled in a mixture of 42 parts of 2,2'-oxybispropane and 42 parts of petroleum ether. The product is filtered and crystallized from 2,2'-oxybispropane to yield 1.27 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid, mp 161°C. (Intermediate 16) was obtained. 29.5 parts of α-(3
28.8 parts of thionyl chloride was added to the stirred solution of -bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid, and the whole was stirred and refluxed for 3 hours. Evaporation of the reaction mixture gave 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetyl chloride (Intermediate 17) as a residue. A mixture of 30 parts α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzene acetyl chloride, 9.3 parts ethanol and 90 parts methylbenzene was stirred overnight at room temperature. The reaction mixture was evaporated, the residue was taken up in ethanol and the ethanol was evaporated again. The residue was taken up in 2,2'-oxybispropane.
The whole was washed with saturated sodium bicarbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel with trichloromethane and hexane (50:
50 volume) mixture was used for purification. The pure fractions were collected and the eluent was evaporated, leaving 19.6 parts of ethyl α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzene acetate (Intermediate 18). It was done. EXAMPLE To a stirred and cooled (ice bath) mixture of 50 parts of fluorobenzene and 4.1 parts of 4-(4-fluorophenyl)-4-hydroxycyclohexanone was added portionwise 11 parts of aluminum chloride.
Once complete, stirring continued for 2 hours while still cooling. The reaction mixture was decomposed by pouring it onto a mixture of crushed ice and hydrochloric acid solution. The product was extracted with methylbenzene. Add the extract until it becomes neutral.
Washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.3 parts (75.9%) of 4,4-bis(4-fluorophenyl)-1-cyclohexane (intermediate
19) was obtained as a residue. Example 10 parts of bis(fluorophenyl)methanone,
A mixture of 22.1 parts of 3-chloro-1,2-propanediol, 0.2 parts of 4-methylbenzenesulfonic acid hydrate and 90 parts of methylbenzene was stirred and refluxed for 23 hours using a water separator. The reaction mixture was poured onto alkaline water. Upon stirring, the layers separated. The organic phase is washed with alkaline water, dried and evaporated to give 14 parts (100%) of 2,
2-bis(4-fluorophenyl)-4-(chloromethyl)-1,3-dioxolane (intermediate 20) was obtained as a residue. Example XI To a stirred suspension of 112 parts of 2,3-dibromobutanamide in 880 parts of acetonitrile was added 91 parts of N,N-diethyl enamine and the whole was stirred at room temperature for 4 hours. The precipitate that formed was filtered off.
112 parts of N,N'-bis(phenylmethyl) in the solution
-1,2-ethanediamine and 45.5 parts of N,N-diethylethanamine were added and stirring continued for 2.50 hours. The whole was further stirred at reflux temperature for 36 hours. The reaction mixture was cooled and filtered. The liquid was evaporated in vacuo. The residue was heated in 675 parts of methylbenzene. The mixture was filtered and the liquid was evaporated. The oily residue was purified by ram chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol to yield 11 parts of 1,4-bis(phenylmethyl)-
2-piperazine acetamide, melting point 113.8°C (Intermediate 21) was obtained. Example XII A mixture of 55.2 parts of methyl 2-pyrazine carboxylate, 48.9 parts of 2-aminoethanol and 360 parts of ethyl acetate was allowed to stand overnight at room temperature.
The precipitated product was filtered and washed with ethyl acetate,
When dried, 54.5 parts (80%) of N-(2-hydroxyethyl)-2-pyrazinecarboxamide,
A melting point of 125°C (intermediate 22) was obtained. Example A mixture of 53.7 parts of N-(2-hydroxyethyl)-2-pyrazinecarboxamide, 20 parts of calcium oxide and 500 parts of 2-methoxyethanol is mixed with 5 parts of palladium on charcoal catalyst at normal pressure and room temperature. Hydrogenated using 10%. After the calculated amount of hydrogen has been absorbed, the catalyst is filtered and the liquid is evaporated, leaving 55.4 parts (100%) of N-(2-hydroxyethyl)-2-piperazinecarboxamide (intermediate 23) as a residue. Obtained. Following the same hydrogenation procedure, the following products were similarly obtained: N,N-dimethyl-2-piperazinecarboxamide, as an oily residue (intermediate 24), N-methyl-2-piperazinecarboxamide, as a residue (intermediate 25), N-(1-methylethyl)-2-piperazinecarboxamide, as a residue (intermediate 26), and trans-3-methyl-2-piperazinecarboxamide, melting point 165 °C ( intermediate 27). Example A dispersion of 29.8 parts of sodium hydride in a stirred mixture of 60.5 parts of α-methyl-1,4-bis(phenylmethyl)-2-piperazinomethanol and 180 parts of N,N-dimethylformamide. 50%
was added little by little in a nitrogen atmosphere below 35°C. The mixture was cooled and stirred at room temperature for 3 hours. After cooling to 10°C, 9.4 parts of iodomethane was added dropwise at about 20°C. The reaction mixture was poured onto water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried and evaporated leaving 45.2 parts (71.5%) of 2-(1-methoxyethyl)-1,4-bis(phenylmethyl)piperazine (intermediate 28) as a residue. Obtained. Following the same procedure and using iodomethane or bromomethane as alkylating agents, the following products were obtained: 2-(methoxymethyl)-1,4-bis(phenylmethyl)piperazine, as residue (intermediate
29), and 2-(ethoxymethyl)-1,4-bis(phenylmethyl)piperazine, as a residue (intermediate
30). Example A mixture of 117 parts of 2-(methoxymethyl)-1,4-bis(phenylmethyl)piperazine and 400 parts of methanol is heated with hydrogen using 5 parts of 10% palladium on charcoal catalyst at normal pressure and temperature. It became. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. After evaporation of the residue, 38.6
(78.8%) of 2-(methoxymethyl)piperazine, boiling point 75-80°C (intermediate 31) was obtained. Following the same hydrogenation procedure, the following products were similarly obtained: 2-(ethoxymethyl)piperazine as residue (intermediate 32), α-methyl-2-piperazine methanol (intermediate 33), 2- Piperazine acetamide, mp 152°C (intermediate 34), and 2-(1-methoxyethyl)piperazine, residue (intermediate 35). Example To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 2.2 parts of benzaldehyde, 2.6 parts of 2 parts
- Piperazine carboxamide and 120 parts of methanol were added. The whole was hydrogenated at normal pressure and room temperature using two parts of 5% catalyst on charcoal.
After the calculated amount of hydrogen has been absorbed, it passes through the catalyst,
The liquid was evaporated. The solid residue was boiled in 64 parts of acetonitrile. The mixture was filtered and the liquid crystallized at room temperature. The product was filtered and dried to yield 2.4 parts (55%) of 4-(phenylmethyl)-2.
-Piperazinecarboxamide, melting point 168.3℃
(Intermediate 36) was obtained. Following the same reductive amination procedure, the following product was similarly obtained: 4-(phenylmethyl)-2-piperazine methanol (E)-2-butenedioate (1:2), mp.
189.8℃ (intermediate 37), 3-(methoxymethyl)-1-(phenylmethyl)
Piperazine, as residue (intermediate 38), N,N-dimethyl-4-(phenylmethyl)-2
-piperazinecarboxamide, as residue (intermediate 39), 3-(ethoxymethyl)-1-(phenylmethyl)
Piperazine, as residue (Intermediate 40), α-Methyl-4-(phenylmethyl)-2-piperazine methanol, mp 100.3°C (Intermediate 41), 4-(phenylmethyl)-2-piperazine acetamide, mp 110.1°C ( Intermediate 42), (A)-3-(1-methoxyethyl)-1-(phenylmethyl)piperazine, as residue (intermediate
43), (B)-3-(1-methoxyethyl)-1-(phenylmethyl)piperazine, as a residue (intermediate
44), and ethyl 4-(phenylmethyl)-2-piperazinecarboxylate, as residue (intermediate 45). Example 13.2 parts of 4-(phenylmethyl)-2-piperazinecarboxamide, 18.5 parts of 1,1'-(4-chlorobutylidene)bis[4-fluorobenzene],
A mixture of 14.8 parts of sodium carbonate, 0.1 parts of potassium iodide and 4-methyl-2-pentanone was stirred and refluxed for 72 hours using a water separator. The reaction mixture was cooled to room temperature, filtered and the liquid was evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. Collect pure fractions,
The eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered and dried to yield 17.7 parts (63.6%) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(phenylmethyl)-2-piperazinecarboxamide;
A melting point of 79.2°C (intermediate 46) was obtained. Following the same N-alkylation procedure, the following products were similarly obtained: 1-[4,4-bis(4-fluorophenyl)
Butyl]-4-(phenylmethyl)-2-piperazine methanol ethanedioate (1:2), melting point
158.4°C (intermediate 47), ethyl 4-(diphenylmethyl)-2-piperazinecarboxylate, melting point 95.1°C (intermediate 48), 4-(3-phenyl-2-propenyl)-2-piperazinecarboxamide, melting point 149.6 °C (intermediate 49), 1-[4,4-bis(4-fluorophenyl)
butyl]-N,N-dimethyl-4-(phenylmethyl)-2-piperazinecarboxamide, residue (intermediate 50), and ethyl 1-[4,4-bis(4-fluorophenyl)butyl]-4 -(phenylmethyl)-2-piperazinecarboxylate as residue (intermediate 52). Example 14.8 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(phenylmethyl)-2-
A mixture of piperazine carboxamide and 200 parts of methanol was hydrogenated using 2 parts of 10% palladium on charcoal catalyst at normal pressure and room temperature. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane to yield 7.9 parts (66.4
%) of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide,
A melting point of 113.6°C (intermediate 53) was obtained. Following the same hydrogenation procedure, the following product was similarly obtained: 1-[4,4-bis(4-fluorophenyl)
butyl]-2-piperazine methanol (intermediate
54), 1-[4,4-bis(4-fluorophenyl)
butyl]-N,N-dimethyl-2-piperazinecarboxamide, as an oily residue (intermediate 55), 1-[4,4-bis(4-fluorophenyl)
butyl]-2-(methoxymethyl)piperazine, as residue (intermediate 56), and ethyl 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxylate, as residue ( intermediate 57). Example To a stirred and cooled (10° C.) solution of 7.8 parts of 3-(methoxymethyl)-1-(phenylmethyl)piperazine in 150 parts of trichloromethane, 10
8.4 parts of trifluoroacetic anhydride were added dropwise over a period of minutes. An exothermic reaction occurs and the temperature rises to 25 °C (cooled with ice water). When complete, stirring was continued for 3 hours at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95:5 by volume) as eluent. The first fraction was collected, the eluent was evaporated, and 9.2 parts (83%) of the 2-
(methoxymethyl)-4-(phenylmethyl)-1-
(trifluoroacetyl)piperazine (intermediate 58)
was obtained as a residue. A mixture of 9.2 parts of 2-(methoxymethyl)-4-(phenylmethyl)-1-(trifluoroacetyl)piperazine and 120 parts of methanol was mixed with 2 parts of 10% catalyst supported on charcoal at normal pressure and room temperature. was used for hydrogenation. After the calculated amount of hydrogen has been absorbed,
After passing through the catalyst and evaporating the liquid, 6.05 parts (92
%) of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine (Intermediate 59) was obtained as a residue. 6.05 parts of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine, 5.25 parts of N,N-
To a stirred mixture of diethylethanamine and 36 parts of N,N-dimethylformamide was added 11 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene]. Stir at 75℃ for 4 hours.
It lasted for hours. The reaction mixture was cooled and poured onto 400 parts of water. The product was extracted twice with 140 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered, and evaporated to yield 11.5 parts (94%) of 4-
[4,4-bis(4-fluorophenyl)butyl]
-2-(methoxymethyl)-1-(trifluoroacetyl)piperazine (intermediate 60) was obtained as a residue. 11.5 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-2-(methoxymethyl)-1-
A mixture of (trifluoroacetyl)piperazine and 60 parts of 6N hydrochloric acid solution was stirred and refluxed overnight. The reaction mixture was cooled and washed with 70 parts of 1,1'-oxybisethane. The acidic aqueous was alkylated with ammonium hydroxide. 70 parts of the product,
Extracted twice with 1'-oxybisethane. Drying the combined extracts and evaporating the liquid yields 6.7 parts (72
%) of 1-[4,4-bis(4-fluorophenyl)butyl]-2-(methoxymethyl)piperazine (intermediate 61) was obtained as a residue. Example 11.7 parts of 2-methoxy-5- in 50 parts of acetic acid
To the stirred and cooled (trifluoromethyl)benzeneamine solution (about 10°C) was added dropwise 7.7 parts of acetyl chloride at a temperature below 20°C. After stirring for 30 minutes, a solution of 24.8 parts of sodium acetate in 62 parts of water was added dropwise (exothermic reaction). When complete, stirring was continued for 30 minutes at room temperature. The precipitated product is filtered, washed with a little water and dried.
15.5 parts (93.3%) of 2-chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]acetamide, melting point 94.7 DEG C. (intermediate 62) were obtained. In a similar manner, the following products were also obtained: 3-chloro-N-(2,6-dichlorophenyl)propanamide, m.p. 143°C (intermediate 63), 2-chloro-N-(5 -fluoro-2-methylphenyl)acetamide, melting point 110.1°C (intermediate
64), and 2-chloro-N-(5-chloro-2-methylphenyl)acetamide, melting point 138.5°C (intermediate
65). Example XI To a stirred solution of 49.2 parts of 2-methoxy-5-methylbenzenamine and 270 parts of methylbenzene is added 22.5 parts of 2-chloroacetyl chloride with cooling (ice bath) at 10-20°C dripped. When complete, stirring was continued for 1.50 hours at room temperature.
Added 200 parts of water. The organic phase was separated, washed with water, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered and dried to yield 28.2 parts (66%) of 2-chloro-
N-(2-methoxy-2-methylphenyl)acetamide, melting point 83.9°C (Intermediate 66) was obtained. In a similar manner, the following products were also obtained: 2-chloro-N-(2,6-dichloro-4-cyanophenyl)acetamide (intermediate 67), N-(4-acetyl-2,6- dichlorophenyl)-2-chloroacetamide (intermediate 68), and 2-chloro-N-(5-chloro-2-methoxy-4-nitrophenyl)acetamide, melting point
130.9°C (intermediate 69). Example XII To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol was added 15 parts of 2-chloro-N-(2-methyl-4-nitrophenyl)acetamide and 400 parts of methanol. The whole was hydrogenated using 2 parts of 5% palladium on charcoal at normal pressure and room temperature. After the calculated amount of hydrogen has been absorbed,
The mixture was filtered through the catalyst and the liquid was evaporated. solid residue,
It was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The product was filtered and dried to give 12 parts (92%) of N-
(4-Amino-2-methylphenyl)-2-chloroacetamide (Intermediate 70) was obtained. Example 36.8 parts of concentrated sulfuric acid were stirred and cooled to 0°C, and 4.2 parts of 2-chloro-N-(2,6-dichloro-4-cyanophenyl)acetamide were added in portions. When complete, stirring was continued in the ice bath for 3 hours. The reaction mixture was left at room temperature overnight and poured onto ice water. The precipitated product was filtered, washed with water, dried and boiled in acetonitrile.
The product was filtered and dried to give 2.7 parts of 3,5-
Dichloro-4-[(2-chloroacetyl)amide]
A benzamide, melting point +260°C (intermediate 71) was obtained. Example 12.8 parts of N ¹ -(2,6-dimethylphenyl)-
A mixture of 4-(phenylmethyl)-1,2-piperazine diacetamide and 120 parts of methanol,
Hydrogenation was carried out using two parts of 10% palladium on charcoal catalyst at normal pressure and room temperature. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. Crystallization of the oily residue from acetonitrile yields 7.7 parts (97.5%) of ^N1- (2,6-dimethylphenyl)-1,2-piperazine diacetamide,
Melting point (intermediate 72) was obtained. Following the same hydrogenation procedure and starting from the corresponding phenylmethyl derivative, the following products were also obtained: N-(2,6-dimethylphenyl)-2-(hydroxymethyl)-1-piperazineacetamide,
Melting point 134.1°C (intermediate 73), 2-(aminocarbonyl)-N-(2,6-dimethylphenyl)-1-piperazineacetamide,
As a solid residue (intermediate 74), ethyl 1-[2-[(2,6-dimethylphenyl]
Amino]-2-oxoethyl]-2-piperazinecarboxylate as residue (intermediate 75), N-(2,6-dimethylphenyl)-2-(methoxymethyl)-1-piperazineacetamide as residue (Intermediate 76), 2-(dimethylaminocarbonyl)-N-(2,
6-dimethylphenyl)-1-piperazineacetamide, as residue (intermediate 77), (A+B)-N-(2,6-dimethylphenyl)
-2-(ethoxymethyl)-α-methyl-1-piperazineacetamide, as residue (intermediate 78), N-(2,6-dimethylphenyl)-2-(ethoxymethyl)-1-piperazineacetamide, As a residue (intermediate 79), N-(2,6-dimethylphenyl)-2-(1-
(B)-N-(2,6-dimethylphenyl)-2-
(1-Methoxyethyl)-1-piperazineacetamide, as residue (Intermediate 81), and (A)-N-(2,6-dimethylphenyl)-2-
(1-Methoxyethyl)-1-piperazine acetamide as residue (Intermediate 82). Example 3 parts of 2- in 16 parts of 2-methoxyethanol
To the stirred warm solution of piperazine carboxamide was added 51.2 parts of 2-propanone. The whole was stirred and refluxed for 20 hours. The reaction mixture was evaporated. Crystallization of the solid residue from acetonitrile yields 2.5 parts (64%) of hexahydro-3,3
-dimethylimidazo[1,5-a]pyridine-1
(5H)-one, melting point 174.2°C (intermediate 83) was obtained. In a similar manner, the following products were also prepared: hexahydro-2,2,3-trimethylimidazo[1,5-a]pyrazin-1(5H)-one as residue (intermediate 84), hexahydro -2-(2-hydroxyethyl)-
3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, mp 95°C (intermediate 85), hexahydro-3,3-dimethyl-2-(1-
methylethyl)imidazo[1,5-a]pyridin-1(5H)-one (intermediate 86), hexahydro-3,3,8-trimethylimidazo[1,5-a]pyridin-1(2H)-one (Intermediate 87), and N-(2,6-dichlorophenyl)hexahydro-3-methyl(2-methylpropyl)-1-oxoimidazo[1,5-a]pyrazine-7 (8H)
- Acetamide, melting point 227.3°C (intermediate 88). Example 2 To a stirred solution of 45 parts of 2-piperazine methanol in 11 parts of warm 2-methoxyethanol was added 675 parts of 2-propanone and stirring was continued at reflux temperature for 27 hours. The reaction mixture was cooled to room temperature over the weekend. The solvent was evaporated and the residue was taken up in methylbenzene. Passage of the mixture yielded 41.4 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine (Intermediate 89). Example 169.8 parts of 1,1'-(4-chlorobutylidene)bis[4-fluorobenzene], 93.5 parts of hexahydro-3,3-dimethylimidazo[1,5-a]
pyrazin-1(5H)-one, 128.3 parts sodium carbonate, 0.1 part potassium iodide and 1200 parts 4
The mixture of -methyl-2-pentanone was stirred and refluxed for 8 hours using a water separator. After cooling at room temperature overnight, the reaction mixture was filtered. The liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was filtered and dried to yield 108 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethylimidazo[1,5-a]pyrazine-1(5H). −
1, melting point 148.4°C (intermediate 90) was obtained. Following the same N-alkylation procedure and using equal amounts of the appropriate starting materials, the following product was also prepared: 7-[4,4-bis(4-fluorophenyl)
butyl]hexahydro-2,3,3-trimethylimidazo[1,5-a]pyrazin-1(5H)-one monohydrochloride (intermediate 91), 7-[4,4-bis(4-fluorophenyl)
butyl]hexahydro-2-(2-hydroxyethyl)-3,3-dimethylimidazo[1,5-a]
pyrazin-1(5H)-one, as a residue (intermediate 92), and 7-[4,4-bis(4-fluorophenyl)
butyl]hexahydro-3,3-dimethyl-2-
(1-methylethyl)imidazo[1,5-a]pyrazin-1(5H)-one, as residue (intermediate
93). Example 30.7 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 11.5 parts of hexahydro-3,3-dimethyl-1H-oxazolo[3,
4-a] A mixture of pyrazine, 14.8 parts of sodium carbonate and 270 parts of N,N-dimethylformamide was stirred at about 70°C for 5 hours. The reaction mixture was cooled to room temperature overnight and the solvent was evaporated. The residue was dissolved in trichloromethane. The organic phase is washed with water, dried, filtered and evaporated to give 34 parts of 7
-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethyl-1H-oxazolo[3,4-a]pyrazine (intermediate 94) was obtained as a residue. Example 40 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-2-(2-hydroxyethyl)-3,3-dimethylimidazo[1,
5-a] A mixture of pyrazin-1(5H)-one, 19 parts of a 10.5N hydrochloric acid solution and 400 parts of water was stirred for 1 hour in a boiling water bath on a Rotavapor. After cooling, the reaction mixture was washed twice with 140 parts of 1,1'-oxybisethane. The aqueous phase was extracted twice with ammonium hydroxide. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using as eluent first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol saturated with ammonia (90:10 by volume). , purified. In a similar manner, the following product was also obtained: 4-[4,4-bis(4-fluorophenyl)
butyl]-N-methyl-2-piperazinecarboxamide, as residue (intermediate 96), 4-[4,4-bis(4-fluorophenyl)
butyl]-2-piperazinecarboxamide, as an oily residue (intermediate 97), 4-[4,4-bis(4-fluorophenyl)
butyl]-N-(1-methylethyl)-2-piperazinecarboxyamito (intermediate 98), and trans-3-(aminocarbonyl)-N-(2,
(6-Dichlorophenyl)-2-methyl-1-piperazine acetamide, melting point 254.6°C (Intermediate 99). Example 34 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethyl-1H-oxazolo[3,4-a]pyrazine and 272
A mixture of 50% and 0.5N aqueous hydrochloric acid solution was stirred and refluxed for 2 hours. Cool the reaction mixture to room temperature,
The product was extracted twice with 1,1'-oxybisethane. The aqueous phase was separated, made alkaline and salted out with sodium carbonate. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 17.0 parts of 4-[4,4
-bis(4-fluorophenyl)butyl]-2-
Piperazine methanol (Intermediate 100) was obtained as an oily residue. Example XI 8.2 parts of 2-chloro-N-(2,6-dimethylphenyl)acetamide, 7.2 parts of hexahydro-
3,3-dimethyl-2-(1-methylethyl)-imidazo[1,5-a]pyrazin-1(5H)-one,
A mixture of 7 parts of N,N-diethylethanamine and 54 parts of N,N-dimethylformamide was added to 75
Stir and heat at °C for 3 hours. After cooling to 0°C, the precipitate was filtered and the liquid was evaporated. residue
Dissolved in 300 parts of trichloromethane. The solution was washed with 50 parts of water, dried, filtered and evaporated. The residue was triturated in 2,2'-oxybispropane. After cooling to 0°C, the product is filtered and dried to give 9.2 parts (72.7%) of N-(2,6-dimethylphenyl)hexahydro-3,3-dimethyl-2
-(1-Methylethyl)-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide, melting point 155 DEG C. (Intermediate 101) was obtained. Following the same N-alkylation procedure and using equal amounts of the appropriate starting materials, the following products were also obtained.

[Table] Example XII 6.6 parts of 2-chloro-N-(5-fluoro-2-
methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,
4-a] A mixture of pyrazine, 6.1 parts of N,N-diethylethanamide and 67.5 parts of N,N-dimethylformamide was stirred and heated at about 70°C for 8 hours. After cooling to room temperature overnight, the reaction mixture was evaporated. Dissolve the residue in trichloromethane. When the solution is washed with water, dried and evaporated,
8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide (Intermediate 121) were left as an oily residue. obtained as. Following the same N-alkylation procedure and using equal amounts of the appropriate starting materials, the following product was also obtained: N-(2,6-dimethyl-4-nitrophenyl)
Tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide, as oily residue (Intermediate 122), N-(2,6-dichlorophenyl)tetrahydro- 3,3-dimethyl-3H-oxazolo[3,
4-a] Pyrazine-7(8H)-acetamide, as an oily residue (intermediate 123), and N-(2-chloro-6-methylphenyl)tetrahydro-3,3-dimethyl-3H-oxazolo[3,4 -a] Pyrazine-7(8H)-acetamide, as an oily residue (Intermediate 124). Example 23.8 parts of N-(2,6-dichlorophenyl)hexahydro-3,3-dimethyl-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide and 256 parts of hydrochloric acid solution 0.5 mixture with N, 2
Stir and reflux for an hour. The reaction mixture was cooled to room temperature overnight, made alkaline, and salted out with sodium carbonate. The product was extracted with trichloromethane. The extract was filtered and the liquid was dried, filtered and evaporated. Crystallization of the residue from acetonitrile yields 13.6 parts (64%) of 3-(aminocarbonyl)-
N-(2,6-dichlorophenyl)-1-piperazineacetamide, melting point 180.4-182.8°C (intermediate
125) was obtained. Following the same hydrolysis procedure and starting from the corresponding imidazo[1,5-a]pyrazine, the following product was also obtained.

【table】

[Table] Example 8.5 parts of N-(5-fluoro-2-methylphenyl)tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide and 105.6 parts of hydrochloric acid The mixture with 0.5N solution was stirred and refluxed for 2 hours. The reaction mixture was cooled to room temperature. The whole was made alkaline with sodium carbonate and salted out. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane.
When the product is filtered and dried, 4.4 parts (59.4%)
N-(5-fluoro-2-methylphenyl)-3
-(Hydroxymethyl)-1-piperazine acetamide, melting point 127.7°C (Intermediate 145) was obtained. Following the same hydrolysis procedure and starting from the corresponding oxazolo[3,4-a]pyrazine, the following product was also obtained: N-(2,6-dimethyl-4-nitrophenyl)
-3-(Hydroxymethyl)-1-piperazineacetamide, melting point 161.8°C (Intermediate 146), N-(2,6-dichlorophenyl)-3-hydroxymethyl)-1-piperazineacetamide, melting point 117.2°C (Intermediate 146) 147), and N-(2-chloro-6-methylphenyl)-3-
(Hydroxymethyl)-1-piperazine acetamide, melting point 116.3°C (Intermediate 148). B Preparation Example of the Final Compound 4.56 parts of N-(2,6-dimethylphenyl)-3
To a stirred mixture of -(methylaminocarbonyl)-1-piperazine acetamide, 3.2 parts of sodium carbonate, and 36 parts of N,N-dimethylformamide was added 6.7 parts of 1,1'-(4-iodobutylidene)bis[ 4-fluorobenzene] was added. Stirring was continued for 1 hour at 75°C. The reaction mixture was cooled and poured onto 400 parts of water. The precipitated product was filtered and dissolved in 360 parts of dichloromethane.
The solution was washed with 100 parts of water, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The whole was evaporated and the oily residue was suspended three times in 1,1'-oxybisethane. The 1,1'-oxybisethane was decanted and the residue was left standing with acetonitrile for 1 hour. The solid precipitate was filtered, washed with warm acetonitrile, and dried to yield 7.44 parts (79.8%) of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6
-dimethylphenyl)-3-(methylaminocarbonyl)-1-piperazine acetamide dihydrochloride,
A melting point of 228.2°C (compound 1) was obtained. Following the same alkylation procedure and using equal amounts of the appropriate starting materials, the following compounds were obtained analogously.

【table】

【table】

【table】

[Table] Example 5 parts of 1,1'-(5-chloropentylidene)bis(4-fluorobenzene), 5 parts of 3-(aminocarbonyl)-N-(2,6-dichlorophenyl)
A mixture of -1-piperazine acetamide, 2.2 parts of sodium carbonate, 0.1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 24 hours. The reaction mixture was cooled and subjected to column chromatography on silica gel (2X) using as eluent first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol (97:3 by volume). It was purified using The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol.
After stirring for 1 hour at room temperature, the salt was filtered and dried to give 1.53 parts of 3-(aminocarbonyl)4-
[4,4-bis(4-fluorophenyl)pentyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamide dihydrochloride-hydrate, melting point
206.2°C (compound 49) was obtained. In a similar manner, the following compound was also prepared: 3-(aminocarbonyl)-N-(2,6-dichlorophenyl)-4-[2-[bis(4-fluorophenyl)methoxy]ethyl] -1-piperazine acetamide, melting point 185.8°C (compound 50) was obtained. Example 7.4 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 5.5 parts of N-(2-chloro-6-methylphenyl)-(3-hydroxymethyl)-1-piperazine acetamide, 4.0 parts N,
N-diethylethanamine and 68 parts of N,N-
The dimethylformamide mixture was stirred at about 70°C for 4 hours. The reaction mixture was cooled to room temperature overnight;
The solvent was evaporated. The residue was taken up in trichloroethane. The organic phase is washed with water, dried and filtered.
Evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified upon trituration in 2,2'-oxybispropane. The product was filtered and dried to yield 3.21 parts (33.1%) of 4-
[4,4-bis(4-fluorophenyl)butyl]
-N-(2-chloro-6-methylphenyl)-3-
(Hydroxymethyl)-1-piperazine acetamide, melting point 149.8°C (Compound 51) was obtained. Following the same N-alkylation procedure and using equivalent amounts of the appropriate starting materials, the following compounds are also prepared.

[Table] Example 2.5 parts of [(2-naphthalenyloxy)methyl]
Oxirane, 3.31 parts of 3-(aminocarbonyl)-
A mixture of N-(2,6-dichlorophenyl)-1-piperazine acetamide, 45 parts of benzene and 20 parts of methanol was stirred first at room temperature for 3 hours and then for a further 30 minutes at reflux temperature. The reaction mixture was cooled and purified by column chromatography on silica gel using trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and acetonitrile. After stirring overnight, straining the salt and drying over the weekend, 1.39 parts (23%) of 3-(aminocarbonyl)-N-(2,6
-dichlorophenyl)-4-[2-hydroxy-3
-(2-naphthalenoxy)propyl]-1-piperazineacetamide dihydrochloride - hydrate, melting point
155.3°C (compound 69) was obtained. In a similar manner, the following compound was also prepared: 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)-2-hydroxybutyl]-N-(2,6- dimethylphenyl)-1-piperazine acetamide, melting point 110.2°C (compound
70). Example 4.3 parts of 4,4-bis(4-fluorophenyl)
Cyclohexanone, 4.35 parts of 3-(aminocarbonyl)-N-(2,6-dimethylphenyl)-1-
A mixture of piperazine acetamide, 1 part of a 4% solution of thiophene in ethanol and 150 parts of 2-methoxyethanol was added at normal pressure and room temperature.
Hydrogenation was carried out using 2 parts of 10% palladium on charcoal. After the hydrogen in the calculation was absorbed, it was passed through a catalyst and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. From the residue, the isomers were separated by HPLS using a mixture of methylbenzene and ethanol as eluent. The fraction containing the B isomer was collected and the eluent was evaporated. The residue was suspended in petroleum ether. The product is filtered, dried and dried under vacuum at 145°C.
1.73 parts of (B)-3-(aminocarbonyl)-4-[4,
4-bis(4-fluorophenyl)cyclohexyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide, melting point 212.1°C (Compound 71)
was gotten. Example L 4.05 parts of 2-chloro-N-(2,6-dichlorophenyl)-acetamide, 5.6 parts of 1-[4,4
-bis(4-fluorophenyl)butyl]-2-
piperazine carboxamide, 2.94 parts N,N-
A mixture of diethylethanamine and 63 parts of N,N-dimethylformamide was stirred at 70°C for 5 hours. The reaction mixture was poured onto ice water. The precipitated product was filtered and dissolved in dichloromethane.
The solution was washed with water, dried, filtered and evaporated.
The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. Pass salt, 1,1'-
When stirred in oxybisethane for 30 minutes, 4.54
3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,
6-dichlorophenyl)-1-piperazineacetamide dihydrochloride hydrate, melting point 182.7°C (compound
72) was obtained. Following the same N-alkyl modification procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared:

【table】

[Table] The following compounds were also prepared in a similar manner:

[Table] Example 24.0 parts of α-methyl-4-(phenylmethyl)-
A mixture of 2-piperazine methanol, 27.3 parts of 2-chloro-N-(2,6-dimethylphenyl)acetamide, 25.4 parts of sodium carbonate, 0.1 part of potassium iodide and 180 parts of N,N-dimethylformamide , stirred at 60 °C for 18 h. The reaction mixture was poured onto water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. Collect pure fractions,
The eluent was evaporated. The residue was crystallized from 1,1'-oxybusethane to yield 35.19 parts (84.8%) of N-(2,6-dimethylphenyl)-2-(1-hydroxyethyl)-4-phenylmethyl)-1 - Piperazine acetamide, melting point 148.8°C (compound
113) was obtained. Following the same N-alkylation procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared:

[Table] Example L 3.7 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide, 2.3 parts of 3-chloro-N-(2,6-dimethylphenyl) ) A mixture of propanamide, 2.3 parts of 3-chloro-N-(2,6-dimethylphenyl)propanamide, 2.1 parts of sodium carbonate, 0.1 part of sodium iodide and 200 parts of 4-methyl-2-pentanone. was stirred and refluxed for 20 hours using a water separator. Cool the reaction mixture to room temperature,
passed. The liquid was evaporated. The oily residue was purified by column chromatography on silica gel with trichloromethane and methanol (95:5) as eluent.
volume) mixture was used for purification. The pure fractions were collected and the eluent was evaporated. The residue is
It solidified upon trituration in 2,2'-oxybispropane. The product was filtered and dried to yield 3.87 parts (70.8%) of 3-(aminocarbonyl)-4-[4,
4-bis(4-fluorophenyl)butyl]-N
-(2,6-dimethylphenyl)-1-piperazinepropanamide, melting point 120.9°C (compound 122) was obtained. Following the same N-alkylation procedure and using equal amounts of the appropriate starting materials, the following compounds were also prepared:

【table】

[Table] Example L 5 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]- Hydrogen chloride gas was passed through the stirred and refluxed mixture of 2-piperazinecarboxylic acid and 200 parts of absolute alcohol over a period of 5 hours. After standing overnight at room temperature, the reaction mixture was evaporated. The residue was taken up in 200 parts of water and made alkaline with sodium hydroxide. The product was extracted twice with 80 parts of 4-methyl-2-propanone. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent.
Purified. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in ethanol and 2-propanol. The solvent was evaporated and the semi-solid residue was dissolved in a mixture of 16 parts of 2-propanone and 2 parts of water. The whole thing evaporated. The solid residue was ground and dried to yield 2.37 parts (40%) of ethyl 1-[4,4-bis(4-fluorophenyl)
Butyl]-4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-2-piperazinecarboxylate dihydrochloride hemihydrate, melting point
118.8°C (compound 154) was obtained. Example L 52 parts of ethyl 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-2
- A mixture of piperazine carboxylate and 600 parts of concentrated hydrochloric acid was stirred in a boiling water bath for 8 hours. The reaction mixture was concentrated to a volume of approximately 200 parts.
Decant the supernatant aqueous phase and add 400 parts of the oily residue to 2
- Dissolved in propanone and 500 parts of water. The whole was neutralized by adding sodium bicarbonate in portions. 2-Propanone was evaporated on a Rotavapor. The aqueous phase was decanted and the residue was triturated in warm 4-methyl-2-pentanone. After cooling, strain the product at 200 ml.
of methanol with heating. The solid product was filtered and crystallized from acetonitrile, and after vacuum drying at 110°C for 3 hours, 16.32 parts of 1-
[4,4-bis(4-fluorophenyl)butyl]
-4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-2-piperazinecarboxylic acid, melting point 186.5°C (compound 155) was obtained. Example L To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 3.4 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl- 4-Nitrophenyl)-2-(hydroxymethyl)-1-piperazine acetamide and 120 parts of methanol were added. The whole was hydrogenated using 2 parts of 5% palladium on charcoal catalyst at normal pressure and room temperature. After the calculated amount of hydrogen has been absorbed,
The catalyst was filtered and the liquid was evaporated. oily residue,
It was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified upon cooling in a 2-propanone/CO ₂ bath. When the product is dried, it contains 1.73 parts (54
%) of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-2-(hydroxymethyl)-1-piperazine acetamide, melting point 85.2℃ (Compound 156)
was gotten. In a similar manner, the following compound was also prepared: 3-(aminocarbonyl)-N-(4-amino-
2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazine acetamide, melting point 114.4°C (compound 157), N-(4-amino-2,6 -dimethylphenyl)
-4-[4,4-bis(4-fluorophenyl)
Butyl]-3-(hydroxymethyl)-1-piperazine acetamide, melting point 81.3°C (compound 158), N-(4-amino-2-methylphenyl)-4-
[4,4-bis(4-fluorophenyl)butyl]
-3-[(methylamino)carbonyl]-1-piperazineacetamide, melting point 86.2°C (compound 159), 3-(aminocarbonyl)-N-(4-amino-
2,6-dichlorophenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide dihydrochloride dihydrate, melting point 196.3°C
(Compound 160), and 2-(aminocarbonyl)-N-(4-amino-
5-chloro-2-methoxyphenyl)-4-[4,
4-bis(4-fluorophenyl)butyl]-1
- Piperazine acetamide, melting point 189.3°C (Compound 161). Example L 3 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl- 4-nitrophenyl)-2-[(methylamino)
Carbonyl]-1-piperazine acetamide and 120 parts of methanol were added. The whole was hydrogenated using two parts of 10% catalyst on charcoal at normal pressure and room temperature. After the calculated amount of hydrogen has been absorbed,
The mixture was filtered through the catalyst and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane and 2.14 parts of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl) )butyl]-2-[(methylamino)carbonyl]-1-piperazine acetamide, melting point
111.7°C (compound 162) was obtained. In a similar manner, the following compound was also prepared: N-(4-amino-2,6-dimethylphenyl)
-4-[4,4-bis(4-fluorophenyl)
Butyl]-3-[(methylamino)carbonyl]-1
- Piperazine acetamide, melting point 88.7°C (compound
163), and 3-(aminocarbonyl)-N-(4-aminophenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide-
Hydrate, melting point 90.1°C (compound 164). Example L 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4
-bis(4-fluorophenyl)butyl]-1-
A mixture of piperazine acetamide, 8 parts 2-propanone, 1 part thiophene in 4% ethanol solution was hydrogenated using 2 parts palladium on charcoal catalyst at normal pressure and room temperature. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered and dried to give 4.5 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-[2,6
-dimethyl-4[(1-methylethyl)amino]phenyl]-1-piperazineacetamide-hydrate,
A melting point of 100.7°C (compound 165) was obtained. Example L 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4
-bis(4-fluorophenyl)butyl]-1-
A mixture of piperazine acetamide, 1 part 5% solution of thiophene in ethanol, 3 parts poly(oxymethylene) and 120 parts methanol was hydrogenated using 2 parts 10% palladium on charcoal catalyst at normal pressure and room temperature. did. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. The residue was taken up in dilute hydrochloric acid solution and the whole was washed with 2,2'-oxybispropane. The aqueous phase was made alkaline and extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered and crystallized from 2-propanol, yielding 2.86 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-[4-(dimethylamino) )−
2,6-dimethylphenyl]-1-piperazineacetamide trihydrochloride hydrate, melting point 194.5°C (compound 166) was obtained. In a similar manner, the following compound was prepared: 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-[4-(dimethylamino)phenyl]- 1-Piperazine acetamide hydrate, melting point 96.3°C (Compound 167). Example L 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl) in 70 parts of acetic acid A solution of 1.62 parts of potassium isocyanate in 20 parts of water was added dropwise to the stirred solution of [butyl]-1-piperazine acetamide. When completed,
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 purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile to yield 2.55 parts of 3-(aminocarbonyl)-N-[4
-[(aminocarbonyl)amino]-2,6-dimethylphenyl]-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazine acetamide, melting point 142.5°C (compound 168) was obtained. It was done. Example L 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4
-bis(4-fluorophenyl)butyl]-1-
A mixture of piperazine acetamide, 1.82 parts of propanoic anhydride and 90 parts of methylbenzene was added to 20
Stir and reflux for an hour. Water was added to the reaction mixture and the layers were separated. The organic phase was washed with sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent.
The first fraction was collected and the eluent was distilled. The residue was suspended in 2,2'-oxybispropane. The product was filtered and crystallized from acetonitrile to yield 1.38 parts of N-[4-[[2-[3-aminocarbonyl)-4-4,4-bis(4-fluorophenyl)butyl]-1- piperazinyl [acetyl]
Amino]-3,5-dimethylphenyl]propanamide hydrate, melting point 136°C (compound 169) was obtained. Example L 4 parts of 3-(aminocarbonyl)-4-[3,3
A mixture of -bis(4-fluorophenyl)-2-propenyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide and 120 parts of methanol was heated on 2 parts of charcoal at normal pressure and room temperature. Hydrogenation was carried out using 10% supported palladium catalyst. After the calculated amount of hydrogen had been absorbed, it was passed through the catalyst and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered and dissolved in acetonitrile. The solution was filtered and the liquid was evaporated. The residue was crystallized in 2,2'-oxobispropane. After filtering and drying the product, 2.21
3-(aminocarbonyl)-4-[3,3-bis(4-fluorophenyl)propyl]-N-
(2,6-dimethylphenyl)-1-piperazine acetamide, melting point 143.2°C (compound 170) was obtained. Example L 4.45 parts of 5-chloro-1,1-diphenyl-2
-pentanone, 9.94 parts of 3-(aminocarbonyl)
A mixture of -N-(2,6-dichlorophenyl)-1-piperazineacetamide and 90 parts of N,N-dimethylformamide was stirred at 60°C for 48 hours and evaporated. The residue was taken up in water and made alkaline with ammonia. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the residue was evaporated. The residue was taken up in 2,2'-oxybispropane and allowed to stand for 10 days. Filter the product and air dry it to 0.32
part (3.7%) of 3-(aminocarbonyl)-N-
(2,6-dichlorophenyl)-4-(4-oxo-5,5-diphenylpentyl)-1-piperazine acetamide hydrate, melting point 91.6°C (compound
171) was obtained. Example L 3.3 parts of ethyl 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-[(2,6-dichlorophenyl)amino]-2-oxoethyl]-2
- A mixture of piperazine carboxylate and 60 parts of a 12N hydrochloric acid solution was stirred in an oil bath at 100°C for 8 hours. Addition of 2-propanone resulted in a solution. Adjust the pH to 5 with sodium bicarbonate,
2-propanone was distilled. A viscous oil was maintained in the water. Decant the aqueous phase and add 24 parts of the viscous oil to 4 parts.
-Methyl-2-pentanone with heating. The solid product was filtered and boiled in 120 parts of acetonitrile. After cooling for a while, the less pure product was filtered out and the liquid was cooled. The product was filtered and dried to yield 0.31 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-
[(2,6-dichlorophenyl)amino]-2-oxoethyl]-2-piperazinecarboxylic acid, melting point
204.3°C (compound 172) was obtained. Example L 3 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1 in 24 parts of ethanol -To a stirred solution of piperazine acetamide was added 0.94 parts of (+)- in 24 parts of ethanol.
A solution of 2,3-dihydroxybutanedioic acid was added. The whole was evaporated and the oily residue was dissolved in warm 4-methyl-2-pentanone. After cooling to 0°C, the product was filtered and dissolved in 2-propanone. 0.2 part of 2,3-dihydroxybutanedioic acid was added and 4-methyl-2-pentanone was added and the product precipitated. After filtering and drying it, 0.8 parts of (+)-3-(aminocarbonyl)-4
-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide [R-(R ^* ,R ^* )]-2,
3-dihydroxybutanedioate (2:3)-
A hydrate, melting point 78.1°C (compound 173) was obtained. Example L 3 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl) in 80 parts of 2-propanone - A solution of 1-piperazine acetamide,
Added to a solution of 1.9 parts (Z)-2-butenedioate in 40 parts 2-propanone. Crystallization occurred slowly. The product was filtered and recrystallized twice from 2-propanol and once from 2-propanone to yield 1.56 parts (39%) of 3-(aminocarbonyl)-
4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-
Piperazine acetamide (Z)-2-butenedioate (1:2)-hydrate, melting point 119.6°C (compound
174) was obtained.

Claims (1)

[Claims] 1 formula where R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; X is hydroxy lower alkyl, lower alkyloxy lower alkyl, aminocarbonyl, mono(lower alkyl) aminocarbonyl, di(lower alkyl) aminocarbonyl , carboxyl, lower alkoxycarbonyl, (aminocarbonyl) lower alkyl, and (hydroxy lower alkyl) aminocarbonyl; m is an integer of 1 or 2; R ² is hydrogen and lower alkyl; a member selected from the group consisting of; R ³ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, halo,
trifluoromethyl, lower alkylcarbonyl,
Aminocarbonyl, lower alkyloxycarbonyl, cyano, amino, mono(lower alkyl)amino, di(lower alkyl)amino, (lower alkylcarbonyl)amino and (aminocarbonyl)
independently selected from the group consisting of amino, with the proviso that R ³
and/or R ⁴ can also be nitro; and R is of the formula (In the formula, Ar ₁ and Ar ₂ are each an aryl group)
a group of the formula -Alk-Q...(b) [wherein Alk is an alkanediyl group or a lower alkenediyl group, provided that the lower alkanediyl group may be substituted with a hydroxy or lower alkyl group; and Q is aryl, aryloxy, diarylmethoxy, 2,2-diarylethenyl, diarylmethylcarbonyl, arylcarbonyl, monoarylaminocarbonyl, diarylaminocarbonyl, diarylmethyl (the methyl moiety in this diarylmethyl group is cyano, mono-lower alkyl) arylamino (the amino moiety may be substituted with an aryl, arylcarbonyl, lower alkylcarbonyl or arylsulfonyl group); 2,3-dihydro-2
-oxo-1H-benzimidazol-1-yl (this group may be substituted with halo in the 5- or 6-position), 10H-phenothiazine-10
-ylcarbonyl (this group may be substituted with a halo atom), 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-
Purin-7-yl, 1-aryl-1,3-dihydroisobenzofuran-1-yl and 2,2-yl
diaryl-1,3-dioxolan-4-yl]
wherein aryl is a member selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl and pyridinyl, said substituted phenyl being a member selected from the group consisting of halo and (halo-substituted phenyl); A compound having one to two substituents each independently selected from the group consisting of carbonyl, stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof. 2. A compound according to claim 1, wherein R is a group of formula (b), where Q is diarylmethyl and Alk is a 1,3-propanediyl group. 3 R is a group of formula (b), where Q is diarylmethyl, Alk is 1,3-propanediyl, X is aminocarbonyl, m is 1, and R ¹ and Both R ² are hydrogen. A compound according to claim 1. 4 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,
6-dichlorophenyl)-1-piperazine acetamide, stereoisomers thereof and pharmaceutically acceptable acid addition salts thereof. 5 Formula of effective amount where R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; X is hydroxy lower alkyl, lower alkyloxy lower alkyl, aminocarbonyl, mono(lower alkyl) aminocarbonyl, di(lower alkyl) aminocarbonyl , carboxyl, lower alkoxycarbonyl, (aminocarbonyl) lower alkyl and (hydroxy lower alkyl) aminocarbonyl; m is an integer of 1 or 2; R ² is hydrogen and lower alkyl; R ³ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, halo,
trifluoromethyl, lower alkylcarbonyl,
Aminocarbonyl, lower alkyloxycarbonyl, cyano, amino, mono(lower alkyl)amino, di(lower alkyl)amino, (lower alkylcarbonyl)amino and (aminocarbonyl)
independently selected from the group consisting of amino, with the proviso that R ³
and/or R ⁴ can also be nitro; and R is of the formula (In the formula, Ar ₁ and Ar ₂ are each an aryl group)
a group of the formula -Alk-Q...(b) [wherein Alk is an alkanediyl group or a lower alkenediyl group, provided that the lower alkanediyl group may be substituted with a hydroxy or lower alkyl group; and Q is aryl, aryloxy, diarylmethoxy, 2,2-diarylethenyl, diarylmethylcarbonyl, arylcarbonyl, monoarylaminocarbonyl, diarylaminocarbonyl, diarylmethyl (the methyl moiety in this diarylmethyl group is cyano, mono-lower alkyl) arylamino (the amino moiety may be substituted with an aryl, arylcarbonyl, lower alkylcarbonyl or arylsulfonyl group); 2,3-dihydro-2
-oxo-1H-benzimidazol-1-yl (this group may be substituted with halo in the 5- or 6-position), 10H-phenothiazine-10
-ylcarbonyl (this group may be substituted with a halo atom), 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-
Purin-7-yl, 1-aryl-1,3-dihydroisobenzofuran-1-yl and 2,2-yl
diaryl-1,3-dioxolan-4-yl]
wherein aryl is a member selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl and pyridinyl, said substituted phenyl being a member selected from the group consisting of halo and (halo-substituted phenyl); Each dosage unit contains a compound having 1 to 2 substituents independently selected from the group consisting of carbonyl, stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof. in the form of a dosage unit for improving the blood perfusion of the cardiac musculature and/or for protecting the heart from diseases of the myocardium caused by more or less brief episodes of ischemia, anoxia or hypoxia. , partially or completely, a pharmaceutical composition for protection. 6. A pharmaceutical composition according to claim 5, wherein 6R is a group of formula (b), where Q is diarylmethyl and Alk is a 1,3-propanediyl group. 7 R is a group of formula (b), where Q is diarylmethyl and Alk is 1,3-propanediyl, X is aminocarbonyl, m is 1, and R ¹ and 6. A pharmaceutical composition according to claim 5, wherein ^R2 are both hydrogen. 8 The compound of formula () is 3-(aminocarbonyl)
-4-[4,4-bis(4-fluorophenyl)
butyl]-N-(2,6-dichlorophenyl)-1
- The compound according to claim 5, which is a compound selected from the group consisting of piperazine acetamide, stereoisomers thereof and pharmaceutically acceptable acid addition salts thereof. 9 formula where R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; X is hydroxy lower alkyl, lower alkyloxy lower alkyl, aminocarbonyl, mono(lower alkyl) aminocarbonyl, di(lower alkyl) aminocarbonyl , carboxyl, lower alkoxycarbonyl, (aminocarbonyl) lower alkyl, and (hydroxy lower alkyl) aminocarbonyl; m is an integer of 1 or 2; R ² is hydrogen and lower alkyl; a member selected from the group consisting of; R ³ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, halo,
trifluoromethyl, lower alkylcarbonyl,
Aminocarbonyl, lower alkyloxycarbonyl, cyano, amino, mono(lower alkyl)amino, di(lower alkyl)amino, (lower alkylcarbonyl)amino and (aminocarbonyl)
independently selected from the group consisting of amino, with the proviso that R ³
and/or R ⁴ can also be nitro; and R is of the formula (In the formula, Ar ₁ and Ar ₂ are each an aryl group)
a group of the formula -Alk-Q...(b) [wherein Alk is an alkanediyl group or a lower alkenediyl group, provided that the lower alkanediyl group may be substituted with a hydroxy or lower alkyl group; and Q is aryl, aryloxy, diarylmethoxy, 2,2-diarylethenyl, diarylmethylcarbonyl, arylcarbonyl, monoarylaminocarbonyl, diarylaminocarbonyl, diarylmethyl (the methyl moiety in this diarylmethyl group is cyano, mono-lower alkyl) arylamino (the amino moiety may be substituted with an aryl, arylcarbonyl, lower alkylcarbonyl or arylsulfonyl group); 2,3-dihydro-2
-oxo-1H-benzimidazol-1-yl (this group may be substituted with halo in the 5- or 6-position), 10H-phenothiazine-10
-ylcarbonyl (this group may be substituted with a halo atom), 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-
Purin-7-yl, 1-aryl-1,3-dihydroisobenzofuran-1-yl and 2,2-yl
diaryl-1,3-dioxolan-4-yl]
wherein aryl is a member selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl and pyridinyl, said substituted phenyl being a member selected from the group consisting of halo and (halo-substituted phenyl); 1 to 2 substituents independently selected from the group consisting of carbonyl, a method for producing a compound having the following, stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof, , formula R-W or () in which W is a reactive leaving group, or its corresponding carbonyl-oxidized form, respectively, with the formula or piperazine in a suitable reaction-inert solvent, provided that the carbonyl-oxidized form of the reagent of formula () or () is used as the reagent, in a suitable reducing medium. , if necessary, the obtained compound of formula () is converted into another compound of formula () by a functional group conversion method, and the conversion method includes: (a) a compound of formula () in which X is a carboxyl functional group; The compound () is reacted with a suitable alcohol, ammonia, mono(lower alkyl)amine or di(lower alkyl)amine in a suitable acidic or alkaline medium, or with a suitable lower alkyl halide in an alkaline medium. (b) A compound of formula () in which X is a lower alkyloxycarbonyl, aminocarbonyl, mono(lower alkyl)aminocarbonyl or di(lower alkyl)aminocarbonyl group is hydrated in an acidic or alkaline aqueous medium. (c) A compound of formula () in which X is a lower alkyloxycarbonyl group is reacted with a suitable amine in a suitable solvent inert to the reaction; (d) X is an aminocarbonyl or lower A compound of formula () which is an alkylaminocarbonyl group,
Reacting with a suitable alkyl halide; (e) Reducing a compound of formula () in which X is carboxyl or lower alkoxycarbonyl group with a suitable metal hydride or diborane; (f) A compound of formula (2) in which X is a hydroxyl group; (g) A compound of formula () in which X is a hydroxylmethyl group is reacted with a suitable alkyl halide in the presence of a suitable base; (h) a compound of formula () in which X is a lower alkyloxymethyl group is stirred in a medium containing a suitable Lewis acid; and (i) a compound of formula () in which one of R ³ and R ⁴ is a nitro group;
catalytically hydrogenating the compound in a suitable solvent, and optionally,
Compounds of formula () can be converted into the form of therapeutically active, non-toxic acid addition salts by treatment with a suitable acid, or conversely, said acid addition salts can be converted to the free base form with an alkali. A process characterized in that it changes the shape and/or produces its stereoisomers. 10 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide to 2-chloro-N-(2,6-dichlorophenyl)
3-(aminocarbonyl)-4-[4,
4-bis(4-fluorophenyl)butyl]=N
Claim 9 for producing a compound selected from the group consisting of -(2,6-dichlorophenyl)-1-piperazine acetamide, stereoisomers thereof and pharmaceutically acceptable acid addition salts thereof. The method described in section.