CS246099B2 - Method of piperazine derivatives production - Google Patents

Description

The present invention relates to compounds, compositions and suitable methods of treating humans who are. affected by a block of calcium intake. In particular, it relates to those compounds wherein the piperazine is bonded via one nitrogen to the aryloxy or arylthio moiety of the molecule via a hydroxypropylene or alkanoyloxypropylene chain and through another nitrogen to the acetanilide moiety, and which are suitable for this purpose.

A large number of compounds are known to affect various physiological systems related to adrenergic controls. Compounds similar to the compounds of the invention are disclosed in Belgian Patent No. 806,380 (US Patent 3,944,549) and include 1- (1,4-benzodioxan-2-ylmethyl) -4- (2,6-dimethylphenylacetanilido) piperazine; Stankeviciene et al.

in Mater. Mezhvug. Nauchv. Conf. Kaunos. Copper. Inst., 25 (1976), published in 1977, pp. 322-323 (Chem. Abstr., 90, 54907c (1976); and French Patent No. 2,267,104). 3,360,529, 3,496,183, 3,829,441,

879 401, 3 944 549, 4 059 821, 4 302 469,

315 939, 4,335,126 and 4,353,901,

Calcium blocking compounds have been used to control the symptoms of cardiovascular diseases such as myocardial infarction, congestive heart failure, cardiac angina and arrhythmia. The present invention relates to a group of cardioselective compounds that are useful in the treatment of these cardiovascular diseases.

The present invention provides a process for the preparation of piperazine derivatives of formula (I)

OH

W-Ar CHfO CH "H ¹ of

N, N-CW-C-N-zAr ² · O (I) in which

Ar ² represents a group of the general formula

in which

R ^1, R ^2, R ^3, R ⁴ and R ⁵ are independently hydrogen, C _V4 alkyl, C _M alkoxy, cyano, trifluoromethyl, halogen, C. ₄ alkylthio, C ^ alkylsulfinyl, C ^ alkylamldovou group optionally N-substituted by C ₁ Series. ₄ alkyl, or C ₄ alkylsulfonyl, with the proviso that when R ¹ is methyl, R ⁴ is other than methyl, or R ² and R ³ together form -OCH 2 O-, Ar ¹ represents a group of formula

in which

R ⁸ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ independently of one another are hydrogen, C 1-4 acyl, aminocarbonylmethyl, optionally substituted phenyl or naphthyl, when R ⁶ and R ⁷ together form a group of the formula - C = CH -CH = CH-, cyano, Ci.4alkyl, C ₄ alkoxy, trifluoromethyl, halogen, C _{1st 4} alkylthio, C -alkylsulfinylovou ₄ alkyl, C _M alkylsulfonyl, di-C. ₄ alkylamino, or R ⁷ and R ⁸ together form a group of formula -OCH 2 O-, R ^{and R12} are independently hydrogen or C ^ alkyl and

W represents an oxygen or sulfur atom, stereoisomers thereof, pharmaceutically acceptable esters thereof and acid addition salts thereof.

These cardioselective compounds are useful in the treatment of cardiovascular diseases including arrhythmia, angina and myocardial infarction.

In the description, unless otherwise stated:

"Aminocarbonylmethyl" means a group of the formula

O

-CH2-C II-NH2 "Aryl" means optionally substituted phenyl or naphthyl group where R ⁸ and R ⁷ together form -CH = CH-CH = GH-.

"Cyano" means a group of formula - C = N.

'Di-Ci. ₄ alkylamino "represents a group of formula R ¹³ (R ¹⁴⁾ N- wherein R ¹³ and R ¹⁴ are independently C alkyl _b4.

"Halo" or "halogen" means fluorine, chlorine, bromine or iodine, customary for the substitution of a hydrogen atom by halogen in organic compounds.

"Isomerism" includes compounds that have the same atomic mass and atomic number but differ in one or more physical or chemical properties. Various types of Isomerism include:

- 'stereoisomers', which include chemical compounds having the same molecular weight, chemical composition and formula but different atomic group locations. This means that the same chemical groups are differently oriented in space and so, when pure, have the ability to rotate the plane of polarized light. However, some pure stereoisomers have an optical rotation so small that it is not detectable by current instruments.

- 'optical isomers' include those types of stereoisomers which exhibit rotation, either pure or in solution, relative to the plane of polarized light. In many cases, this is due to the attachment of four different chemical atoms or groups to one carbon atom in the molecule. Isomers may be referred to as D-, L-, DL-; d-, 1- or d, 1-; or R-, S- or R-, S- according to the nomenclature used.

- 'diastereoisomers' are those stereoisomers which are dyssymmetrical but which are not mirror images. Diastereoisomers corresponding to a structural formula must have at least two asymmetric atoms. Compounds having two asymmetric atoms can exist in four diastereomeric forms, i.e. (-j-erythro, (+ -j-erythro, (-j-threo and (+) -threo)).

Certain compounds of formula I wherein R ¹² is hydrogen may have. an asymmetric carbon atom, i.e. a second carbon atom in the propyl group. These compounds can exist in two stereochemical forms, i.e. (+) and (-) or R- and S- and mixtures thereof. Compounds of formula I wherein R ¹² is other than hydrogen may have two asymmetric carbon atoms, i.e., the carbon atom at the 2-position of the propyl group and the carbon atom to which R ¹² is attached. These compounds can exist in four stereochemical forms of (+) -erythro-, (+ j-threo, (-j-threo and

24B099 (-) - erythro and mixtures thereof. The Cahn-Prelog convention refers to these four isomers as R-R, R-S, S-R, and S-S, thereby capturing the stereochemistry of each of the asymmetric carbon atoms. The R and S designations will be used in this description. It is to be understood that the invention encompasses both individual stereoisomers and mixtures thereof.

"Structure of Formula I" means generic formulas of the compounds of the invention. The chemical bonds referred to as (f) in formula I represent non-specific stereochemistry at the asymmetric carbon atom, i.e. at the 2-position of the propyl or chain, i.e. the carbon atom to which the hydroxyl group - (OH) is attached and the carbon atom to which the substituent is attached. R ¹² between piperazine ring and carbonyl group.

"C _1-4 acyl" means a group of the general formula

O

R ¹⁵ - C - wherein R ¹⁵ is C 1-6 alkyl as defined herein and represents such groups as acetyl, propanoyl, n-butanoyl and the like.

"C _1-4 alkyl" means a straight or branched saturated hydrocarbon chain of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and tert-butyl.

"C 1-6 alkoxy" represents a group -OR where R is C 1-6 alkoxy; _C4 alkyl group, whose meaning is stated in the description.

"C _1-4 alkylthio" means a group of the formula -SR, wherein R is C 1-6 alkyl, the meaning of which is given in the description.

'Cj. ₄ alkylsulfinyl group 'represents a group of the formula

O-S-R wherein R is C 1-4 alkyl, the meaning of which is given in the description.

"Whose. ₄ alkylsulfonyl 'represents a group of the formula

O

II —S — R o

wherein R represents C _1-4 alkyl, the meaning of which is given herein.

"C ₁₄ alkylamide group optionally substituted on a nitrogen atom" means a group of the following general formula

O -N (R ^le j - C-R ¹⁷ wherein R ¹⁶ represents hydrogen or C _M alkyl, and R ¹⁷ represents C _1.4 alkyl which meaning is given in the description.

'Optional' or 'optional' means that the above facts may or may not occur. For example, "optionally substituted phenyl" means that phenyl may or may not be substituted and that the description includes both unsubstituted and substituted phenyl; "Optionally with subsequent conversion of the free base into an acid addition salt" means that said conversion may or may not be carried out in the process of the invention and the invention includes both a process wherein the free base is converted to an acid addition salt as well as a process wherein the salt not ready.

"Pharmaceutically acceptable acid addition salt" includes those salts which retain the biological effects and properties of the free bases and which are not biologically or otherwise undesirable formed with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid and others, and with organic acids such as acetic acid, pronionic acid, glycolic acid, racemic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, ρ-toluenesulfonic acid, salicylic acid and the like.

A "pharmaceutically acceptable ester" of a compound of Formula I that can be used in therapy comprises an alkanoyloxy group of the formula -O-C (= Oj-Z), wherein Z is an alkyl group containing 1 to 12 carbon atoms attached to the other carbon atom in the propylene chain instead of the hydroxyl group, i.e. the hydroxy group is esterified The group Z may be, for example, methyl, ethyl, butyl, hexyl, octyl, dodecyl, etc. Thus, this invention includes both compounds of formula I which are esters and pharmaceutically acceptable salts of these compounds.

A "piperazino" group represents a saturated six-membered ring containing two nitrogen atoms of the following formula:

The compounds of the present invention are named according to the IUPAC nomenclature. Locants ring system substituents in the compounds of the invention are positioned as shown in formula I. For example, if R ¹ and R ⁵ are methyl, R ^Ti is methoxy, R ² to R ⁴ and R ⁷ to R ¹² are hydrogen and W známe7 is a compound of the formula I called 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and has the following formula:

H where * denotes the center or possible center of asymmetry.

This compound can also be referred to as 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (2,6-dimethylphenylcarbamoylmethyl) piperazine or 1- (3- (2-methoxyphenoxy) -2- hydroxypropyl] -4- (2,6-dimethylacetanilido] piperazine For the purposes of the present invention, a designation which is in accordance with the IUPAC nomenclature and which is mentioned first will be used.

Optically active compounds can be labeled differently: for example, the R- and S-sequences of Cohn and Prelog; erythro and threo isomers; D- and L-isomers; d- and 1-isomers; and (+) and (-) - isomers that indicate the direction of rotation of the plane of polarized light induced by the chemical structure, either in pure state or in solution. These designations are well known in the art and described in detail, for example, by B. L. Eliel in the Stereochemistry of Carbon Compounds, published by McGraw Hill Book Company, Inc. of New York in 1962 and the references therein.

In the reaction schemes, it further means:

An "Ar ¹ " aryl group which may be optionally substituted with substituents R ^e to R ¹⁰ as defined above. The attachment to the other part of the molecule is via the carbon atom at the 1-position, i.e. the oxygen or sulfur atom, and the other positions of the aryl group are numbered as follows:

(Ar ¹ ) "Ar ² " means an optionally substituted phenyl group wherein R ¹ to R ⁵ are as defined above and the position designation is as follows:

_R S lAr ² ·)

A preferred embodiment of the invention includes compounds of formula I wherein two substituents from R ¹ to R ⁵ are hydrogen and two substituents from R ⁶ to R ¹⁰ are hydrogen. Their preferred subgroup is compounds wherein W is oxygen in formula I, i.e. O.

A preferred subgroup of these compounds of formula I are those wherein R ² , R ^3, and R ⁴ are hydrogen.

A preferred subgroup are those compounds wherein two substituents R ¹ and R ⁵ are each C _M alkyl, preferably methyl.

Particularly preferred compounds of the invention include those compounds of formula I wherein R ¹ and R ⁵ are each methyl, R ² , R ³ , R ^4, and R ^e to R ¹² are each hydrogen and W is O; i.e. 1- (3-phenoxy-2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

Particularly preferred compounds of the invention include that compound of formula I wherein R ¹ and R ⁵ are each methyl, R ⁶ is methoxy, R ² , R ³ , R ⁴ and R ⁷ to R ¹² are each hydrogen and W is O; i.e. 1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

Particularly preferred are those compounds of formula I wherein R ¹ and R ⁵ are each methyl, R ^e is cyano, R ² , R ³ , R ⁴ and R ⁷ to R ¹² are each hydrogen and W is O, i.e. [3- (2-cyanophenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

Particularly preferred are those compounds of formula I wherein R ^1, R ⁴ and R ⁵ are hydrogen.

Preferred are further those compounds of formula I wherein two substituents R ^a and R ³ which are not hydrogen, are each halogen, in particular chlorine.

A preferred embodiment includes those compounds of formula I wherein most of R ¹ to R ^{5 is} not hydrogen. A presently preferred group of compounds of formula I wherein substituents as is not hydrogen, R is ^{the first} A particularly preferred subgroup of these compounds are those compounds of formula (I) wherein one substituent is lower alkoxy, especially methoxy.

The invention further includes compounds of formula I wherein the two non-hydrogen substituents are R ⁷ to R ⁹ . Preferred subgroups are those compounds wherein R ⁶ and R ¹⁰ are C _1-4 alkoxy, preferably methoxy.

A preferred subgroup of these compounds of formula I are those wherein R ^e represents a cyano or halo, particularly chloro.

A preferred subgroup includes those compounds of formula (I) wherein the non-hydrogen substituent is R ⁸ , which represents a C 1-4 alkoxy group, preferably methoxy, or chloro.

The present invention includes those compounds of formula I wherein R ¹¹ is hydrogen.

The invention includes those compounds of formula I wherein R ¹² is hydrogen.

The invention includes those compounds of formula I wherein R ¹¹ and R ¹² are both hydrogen.

The invention includes those compounds of formula I wherein W is sulfur, i.e. S.

A particularly preferred sub-group are those compounds wherein R ¹² is C 1-4 alkyl, preferably methyl, and R ¹¹ and R ¹² are each C 1-4 alkyl, preferably methyl. Particularly preferred sulfur-containing compounds are:

1- [3- (phenylthio) -2-hydroxypropyl] -4 - [(phenyl) aminocarbonyl-1-ethyl] piperazine and

1- [3- Phenylthio} -2-hydroxypropyl] -4- (N-methyl-N-phenylaminocarbonyl-2-ethyl) -piperazine.

Particularly preferred are those compounds of the invention wherein R ^b , R ⁷ , R ^a , R ⁹ and R ¹⁰ are each hydrogen. Particularly preferred is that subgroup of compounds wherein R ¹ to R ¹⁰ are each hydrogen.

Further particularly preferred compounds are those wherein R ¹¹ is hydrogen. Of this subgroup, those presently preferred are those compounds wherein R ¹ to R ^1U hydrogen. Preferred are compounds wherein R ¹¹ is also hydrogen.

Especially preferred from those compounds wherein ^R11 is hydrogen are the following compounds:

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (phenylaminocarbonylmethyl) piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methoxyphenoxyphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dichlorophenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-ethylsulfinylphenoxy) -2-hydroxypropyl] -4 - [(phenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4 - [(3,4-methylenedioxyphenyl aminocarbonylmethyl) piperazine or

1- [3- (1-naphthyl) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

Also preferred are those compounds of the invention wherein R ^and R ¹² are methyl; presently preferred among these is: 1- (3- (2-methoxyphenoxy) -3-hydroxypropyl] -4- [(2,6-dimethylphenyl -N- (methyl) aminocarbonyl-1-ethyl] piperazine.

Pharmaceutical compositions used to treat one or more cardiovascular diseases, such as arrhythmia, myocardial infarction and angina, in mammals, particularly humans, comprise a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof in admixture with pharmaceutically acceptable excipients.

A method of treating cardiovascular diseases such as arrhythmia, myocardial infarction and angina in mammals, particularly humans, comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention also relates to the optical isomers of the (+) and (-) and R- and S-isomers and mixtures thereof, and the present invention includes the individual isomers and all possible mixtures thereof.

Furthermore, pharmaceutically acceptable esters and acid addition salts, especially mono- and dihydrochlorides, and mixtures thereof, are also included.

Compounds of formula (I) may be prepared according to the following scheme. In this scheme, X represents a leaving group such as a halogen or a sulfonyl ester group, preferably halogen.

τ Ci-CH-CH — CW, (A) O

O

II o /

Sheet? CH-CH, HN NH? -CH-CCt + H-N-Ar? ^t18J (Ai (CJ (D) o R ¹¹ u I

Ar-CH ^C-CH ^N NH ⁺ A-CH-CN-Ar ^ _c , RK IE II (F)

OR ¹¹ η i

Ar ¹ - CH 2 -C - CH 2 --N - CH 2 CN - Ar 1 ^J R 3 (tl

The compounds of formula (I) are prepared by Ar ² , R ¹ to R ¹² and W have the above-described process of the invention known by the reaction of the compounds. A and G. The substituents Ar ¹ , compound B + compound F

O d 44 ^ - _CH -ch ₂ * HK n-ch-cn-ahil · * (A (G)

OH

O R li i

A r ¹ - W - C HxCh - Ch - N - CH - CNA r Z ω ^Λ1

Compounds of formula F are obtained by reacting compounds of formula C and compounds of formula D as described in the previous reaction scheme.

Compounds of formula G are prepared from the corresponding compounds of formula F by reaction with piperazine (formula B) by a method well known in the art, similar to the reaction of compounds of formulas E and F to give compounds of formula I. In these procedures, in both cases, the halide is mixed with an excess of piperazine or substituted piperazine, in particular about 3 to 5 mol excess, preferably about 4 molar excess, in a polar organic solvent such as ethanol or propanol, preferably ethanol or a mixture of ethanol and water (50:50), and heated to 50 to 100 ° C, preferably to the boiling point of the solvent used for 1 to 4 hours, preferably about 2 hours. The product of formula G can then be isolated by conventional methods.

The coupling reaction in the process of the invention is carried out by a conventional method. The compounds of formulas A and G are preferably mixed in equimolar amounts in an aprotic organic polar solvent such as dimethylformamide, tetrahydrofuran and the like, preferably dimethylformamide. The reaction mixture is heated to about 50 to 100 ° C, preferably to about 60 to about 70 ° C, and then the temperature is raised to about 70 to 110 ° C, preferably 85 to 95 ° C, and allowed to react for about 1 to about 70 ° C. 24 hours, preferably overnight. The condensed product of formula I is then isolated by conventional methods.

Isolation and purification of compounds and intermediates can be accomplished, if desired, by separation and purification, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, or thick layer chromatography, or using various combinations of these procedures. Specific procedures for these isolation and purification methods are given in the Examples below. However, other equivalent separation and isolation procedures may be used.

Salt products can also be isolated by conventional methods. For example, the reaction mixture may be evaporated to dryness and the salt further purified by conventional methods.

The compounds of formula I described herein may exist as a mixture of optical isomers, since two asymmetric carbon atoms are possible. Therefore, the compounds of the invention can be prepared either as optically active substances or as a racemic mixture. Without further specification, the compounds described herein have all racemic form. However, the scope of the invention is by no means limited to a mixture of racemic forms, but encompasses all individual possible optical isomers.

If desired, the racemic intermediates of the compounds of formula A, A ', C, E, F or G or the final compounds, i.e. formula I prepared by the process of the invention, may be resolved into their optical antipodes by conventional splitters known in the art. (i.e., traction crystallization) of diastereomeric salts formed in the reaction, for example racemic compounds of formula I or intermediates of formula A, A ', C, E, F or G with an optically active acid. Examples of such optically active acids are optically active forms of camphor-10-sulfonic acid, α-bromocapro-sulfonic acid, camphoric, methoxyacetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid and the like. and, if necessary, a base such as cinchonidine, brucine and the like. The separated pure diastereomeric salts may be purified by standard procedures to obtain optical isomers of compounds of Formula I or intermediates of Formulas A, A ‘, C, E, F or G.

Compounds of formula I may be isolated as the free bases, but it is more convenient to isolate these compounds as acid addition salts. These salts are prepared in a conventional manner, i.e. by reacting the free base with a suitable organic or inorganic acid, for example one of the aforementioned pharmaceutically acceptable acids. A base of formula I dissolved in a non-reactive solvent such as an alcohol such as methanol or ethanol, or an ether such as diethyl ether or the like is acidified with an acid dissolved in a similar solvent. The acidic solution is added until precipitation of the salt is complete. The reaction is carried out at a temperature of from 20 to 50 ° C, preferably at room temperature. If desired, the salt can be converted to the free base by the action of a base such as potassium or sodium carbonate, or ammonium, potassium or sodium hydroxide.

The free base compounds of formula (I) may be converted to acid addition salts by treatment with suitable organic or inorganic acids such as phosphoric, racemic, hydrochloric or sulfuric acids and the like. Typically, the free base is dissolved in a polar organic solvent such as ethanol or methanol and acid is added to the solution. The temperature is maintained between about 0 to about 100 ° C. A precipitate of the resulting acid addition salt precipitates or is displaced from the solution by a less polar solvent.

The acid addition salts of the compounds of formula I may be decomposed to the corresponding bases by treatment with a suitable base such as potassium carbonate or sodium hydroxide, conveniently in the presence of an aqueous solvent and at a temperature between about 0 to 100 ° C. The free base is isolated by conventional procedures, such as extraction with an organic solvent.

The pharmaceutically acceptable esters of the compounds of formula I and the pharmaceutically acceptable acid addition salts of these esters are prepared by treating them with an excess of about 1.1 to about 2 equivalents of the corresponding acid anhydride or acyl halide in the presence of a catalyst such as pyridine under temperature conditions of about -10 to about. + 10 ° C for about 0.5 to about 12 hours; these conditions are known in the art and are described in the examples (see, for example, the appropriate sections of Morrison and Boyd, supra, and Fieser and Fiesr, Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, published in 1967). Suitable esters, for example, include acetates, propionates, butanoates, hexanoates, octanoates, dodecanoates, and the like. The pharmaceutically acceptable acid addition salts of the esters of the compounds of formula I are prepared as described in Examples 6, 8 or 9 below.

Salts of compounds of formula (I) may be resolved using different solubility and volatility or by treatment with a suitable ion exchange resin. This one. the conversion is carried out at a temperature between about 0 ° C and the boiling point of the solvent used as the medium in said process.

In conclusion, the compounds of formula I of the present invention are prepared by reacting unsubstituted or substituted 1- (aryloxy) or 1- (arylthio) -2,3-epoxypropane (formula A 1 and N-substituted-pb perazine (formula G), ( which can also be prepared by reacting a 2-haloalkylcarboxylic halide (formula Cj) with unsubstituted or substituted aniline (formula D) to form a compound of formula F that reacts with piperazine (formula B).

Alternatively, compounds of Formula I are prepared by converting salts of compounds of Formula I to the free base by treatment with a stoichiometric excess of base.

Alternatively, the free base of the compounds of Formula I is converted to a pharmaceutically acceptable acid addition salt using a stoichiometric excess of an acceptable acid;

Alternatively, a salt of a compound of Formula I is converted to another salt of a compound of Formula I using a stoichiometric excess of another acceptable acid.

The compounds of the invention exhibit the effect of blocking calcium uptake and causing β-blockade, in animal experiments, using in vitro experiments and animal cell cultures: See, for example, Kent et al. Federation Proceedings, Vol. 40, p. 724 (1981), Killam et al., Federation Proceedings, Vol. 42, p. 1244 (1983) and Cotten et al., Journal ^; Pharm. Exp. Therap., Vol. 121, p. 183-190 (1957) The compounds are effective in animal experiments against cardiovascular diseases such as arrhythmia, angina and myocardial infarction, and are useful in the treatment of cardiovascular diseases, particularly myocardial infarction, angina, and arrhythmias mammals, especially humans.

Administration of the active compounds - and the salts described herein - can be accomplished by a procedure suitable for conventional administration of therapeutic agents. These procedures include oral, parenteral, transdermal, suhcutaneous and other various procedures. A preferred method of administration is oral, except that the patient is not capable of self-medication. Parenteral administration may be necessary in these cases.

Depending on the desired route of administration, the preparations may be in solid, semi-solid or liquid form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, usually- and preferably in unit dosage form, suitable for administration of an accurate dose. The formulations may include excipients and active compounds of formula (I) or pharmaceutically acceptable salts thereof in conventional pharmaceutical practice, and may optionally contain other active ingredients, pharmaceutical excipients, diluents and the like.

Amounts of active ingredient administered; samožřěj-. I care about the patient's condition, his. weight; route of administration and assessment. However, the antibody varies in the range from 0.1 to 10 mg / kg / day, preferably 0.5 to 5 mg / kg / day. the weight of 70 kg is from 7 to 700 mg / day, preferably > 35 to 350 mg / day;

Since all of these effects (antiinfarct, Inhibiceangin β'βη · thiaryrhythmia) are caused by a simple mechanism (calcium blockade effect) of doses (and administration forms), they are generally suitable and advantageous for these. use.

For solid preparations, conventional non-toxic solids may be used which include, for example, mannitol, lactose; starch., - · stearate: magnesium, · sodium saccharide; talc, cellulose, glucose, sucrose, magnesium carbonate, and similar substances of appropriate quality to meet pharmaceutical requirements. The active compounds mentioned above may be; formulated as suppositories, for example using; polyalkylene glycols, for example propylene glycol, as carriers. Liquid pharmaceutical preparations can be prepared, for example, by dissolving, dispersing, etc., the active compounds mentioned above and optionally a pharmaceutical adjuvant in an excipient such as water, a saline solution, aqueous dextrose, glycerol, ethanol and the like; thereby forming a solution or suspension. If desired, the pharmaceutical preparations may also contain - also a small amount of nontoxic excipients such as glidants or emulsifying agents such as pi-I modifying agents and the like, such as: sodium acetate, sorbitan imonourate, tri- »ethanolamine, sodium acetate, triethanolamine oleate; etc. Methods for preparing such dosage units are known, or for workers skilled in the art, · - VI-from> nsfpříklad-Remington 's Pharmaceutical Sciences. & ΝΜ ^·! Publishing- Company, Eastan, Pennsylvania, 15th Edition, 1975. Preparations or formulations intended for administration always. they contain a certain amount of active ingredients, i.e., an amount effective to alleviate the symptoms of the subject being treated.

For oral administration, pharmaceutically acceptable non-toxic preparations are formed by - incorporating the active ingredient in any of the conventional pharmaceutical excipients such as; is τπ »ηnital, lactose, starch, - magnesium stearate ¹ ,, sodium saccharine cephalosporin, talc; cellulose, glucose, sucrose, magnesium carbonate, and the like; in the form of solutions, suspensions, tablets, pills, capsules, powders, support aids and the like. These compositions may contain 10-95% of the active ingredient, preferably 1-70%.

Parenteral administration is generally characterized by injection, either snbcutaneously, intra246099 muscularly, or intravenously. Injections may be prepared in conventional forms either as solutions of solids or as suspensions, solids suitable for solutions or suspensions in liquid form, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. If desired, the pharmaceutical compositions to be administered may also contain small amounts of nontoxic excipients such as wetting or emulsifying agents, pH buffering agents and the like such as sodium acetate, sorbitan monolaurate, triethanolamine oleate and the like.

Recent parenteral administration involves the implantation of a system that releases the active agent slowly or in a retention manner so that a constant dose level is maintained. See, for example, U.S. Patent No. 3,710,795, which is incorporated herein by reference.

The following preparations and examples serve to illustrate the invention. These are to be understood as not limiting the invention in any way.

Preparation A (Preparation of Compounds of Formula Aj

and)

To a 2-methoxyphenol (76 gj dissolved in about 60 ml water and 200 ml dioxane containing 29 g sodium hydroxide) was slowly added a large excess of epichlorohydrin (80 g). The solution was stirred at reflux for 3 hours. Evaporation of the dry extract followed by distillation of the residue gave the product, 1- (2-methoxyphenoxy) -2,3-epoxypropane.

(b)

The procedure is as in paragraph aj, but the 2-methoxyphenol is replaced by a stoichiometric amount of the following:

2-Methylphenol

3-methylphenol,

4-Methylphenol

4-n-Butylphenol

2-methoxyphenol,

4-methoxyphenol,

2-isopropoxyphenol,

2-n-butoxyphenol,

2-chlorophenol,

4-chlorophenol,

4-bromophenol,

2,4-dimethylphenol,

2.4- dichlorophenol,

4-Methyl-5-chlorophenol

3.4.5- trichlorophenol,

3.4.5- trimethoxyphenol,

3-Methyl-4-chloro-5-methoxyphenol

3-methyl-4,5-dichlorophenol,

2,3,4,5-tetrabromophenol,

3,6-dimethyl-4,5-dichlorophenol,

4-Trifluoromethylphenol

4-methylthiophenol,

4-n-butylthiophenol,

4-methylsulfinylphenol,

4-n-Butylsulphinylphenol

4-methylsulfonylphenol,

4-n-Butylsulfonylphenol

2-cyanophenol,

2-acetylphenol,

4-n-butanoylphenol,

4- (Ν, Ν-dimethylamino) phenol,

4- (N, N-di-n-butylamino) phenol,

1-naphthol, thiophenol or

4-methylphenylthiol;

the following epoxy compounds of formula A are obtained

1- (2-Methylphenoxy) -2,3-epoxypropane

1- (3-Methylphenoxy) -2,3-epoxypropane

1- (4-Methylphenoxy) -2,3-epoxypropane

1- (4-n-Butylphenoxy) -2,3-epoxypropane

1- (2-methoxyphenoxy) -2,3-epoxypropane,

1- (4-Methoxyphenoxy) -2,3-epoxypropane

1- (2-isopropoxyphenoxy) -2,3-epoxypropane, 1- (2-n-butoxyphenoxy) -2,3-epoxypropane,

1- (2-chlorophenoxy) -2,3-epoxypropane, 1- (4-chlorophenoxy) -2,3-epoxypropane,

1- (4-bromophenoxy) -2,3-epoxypropane,

1- (2,4-Dimethylphenoxy) -2,3-epoxypropane

1- (2,4-dichlorophenoxy) -2,3-epoxypropane, 1- (4-methyl-5-chlorophenoxy) -2,3-epoxypropane, 1- (3,4,5-trichlorophenoxy) -2, 3-epoxypropane,

1- (3,4,5-trimethoxyphenoxy) -2,3-epoxypropane, 1- (3-methyl-4,5-dichlorophenoxy) -2,3-epoxypropane,

1- (3-Methyl-4-chloro-5-methoxyphenoxy) -2,3-epoxypropane

1- (2,3,4,5-tetrabromophenoxy) -2,3-epoxypropane, 1- (3,6-dimethyl-4,5-dichlorophenoxy) -2,3-epoxypropane,

1- (4-Trifluoromethylphenoxy) -2,3-epoxypropane, 1- (4-methylthiophenoxy) -2,3-epoxypropane,

1- (4-n-Butylthiophenoxy) -2,3-epoxypropane

1- (4-methylsulfinylphenoxy) 2,3-epoxypropane, 1- (4-n-butylsulfinylphenoxy) -2,3-epoxypropane, 1- (4-methylsulfonylphenoxy) -2,3-epoxypropane, 1- (4- n-butylsulfonylphenoxy) -2,3-epoxypropane, 1- (2-cyanophenoxy) -2,3-epoxypropane,

1- (2-acetylphenoxy) -2,3-epoxypropane, 1 - [(4-n-butanoylphenoxy)) - 2,3-epoxypropane,

1- [4- (Ν, Ν-dimethylamino) phenoxy] -2,3-epoxypropane,

1- (1-naphthoxy) -2,3-epoxypropane

1- (phenylthio) -2,3-epoxypropane or 1- (4-methylthio) -2,3-epoxypropane.

These compounds have sufficient purity for use in the reaction of the invention,

C)

In the same manner as in paragraph a) of this preparation, but replacing the epichlorohydrin with a stoichiometric amount of S-epichloro246099 hydrin, R-1- (2-methoxyphenoxy) -2,3-epoxypropane is obtained in good yield.

(d)

In the same manner as in paragraph c) of this preparation, but replacing said 2-methoxyphenol with a stoichiometric amount of substituted phenol, the corresponding R-substituted phenoxy-epoxy compounds of formula A are obtained.

θ)

In the same manner as in paragraph a) of this preparation, but replacing the stoichiometric amount of R-epichlorohydrin with epichlorohydrin, the corresponding (S) -1- (2-methoxyphenoxy) -2,3-epoxypropane is obtained in good yield.

F)

In the same manner as in paragraph 2 of this preparation, but replacing epichlorohydrin and 2-methoxyphenol with an equivalent amount of R-epichlorohydrin and substituted phenol, the corresponding (S1-1-substituted phenoxy-2,3-epoxypropane in good yield) is obtained.

G)

In the same way as in aj, bj, cj, dj, e) or fj, but substituting 2-methoxyphenol with an optionally substituted phenylthiol derivative, the corresponding R-, S- or R, S1- (optionally substituted phenylthio) -2 is obtained, 3-epoxypropane.

Preparation

Preparation of [(2,6-dimethylphenyl) aminocarbonylmethyl] chloride (compound of formula F)

and)

2,6-Dimethylaniline (96 g, 793 mol) and triethylamine (TEA) (96 g, 130 mol) were dissolved in one liter of methylene chloride, cooled in ice, and chloroacetyl chloride (89.5 g, 800 mol) was added slowly. The mixture was stirred for four hours to give a very dark color, then washed with dilute hydrochloric acid and concentrated in vacuo, hexane was added to the product precipitate, and the crude [(2,6-dimethylphenyl) aminocarbonylmethyl] chloride product was filtered, washed and dried. 130 g of product are obtained in a purity sufficient for use in the process according to the invention.

(b)

Repeating the above procedure but replacing the stoichiometric amount of the following with 2,6-dimethylanilip;

aniline,

2-chloroaniline,

3-chloroaniline,

4-chloroaniline,

2-bromoaniline,

3-bromoaniline,

4-bromoaniline,

2-fluoroaniline,

3-fluoroaniline,

4-fluoroanlline,

2-methylaniline,

3-methylaniline,

4-methylaniline,

4-n-butylaniline,

2-methoxyaniline,

3-methoxyaniline,

4-methoxyaniline,

4-n-butoxyaniline,

2-Trifluoromethylaniline

3-Trifluoromethylaniline

4-Trifluoromethylaniline

2.6- dichloraniline,

3,5-dimethoxyaniline,

3.4- methylenedioxyaniline,

2-chloro-5-methylaniline,

4-methylthioaniline,

4-methylsulfinylaniline,

4-methylsulfonylaniline,

4-n-butylthioaniline,

4-n-butylsulphinylaniline,

4-n-butylsulfonylaniline,

3.4- difluoraniline,

4-chloro-3-trifluoromethylaniline,

4-fluoro-3-trifluoromethylaniline,

2.5- diethoxyaniline,

2.4.5- trichloroaniline,

3.4.5- trimethoxyaniline,

2.4.5.6- tetrachloraniline,

2.3.4.6- tetramethylaniline,

2.3.4.5.6- pentachloranllin,

3-chloro-2,4,6-trimethylaniline,

2-cyanoaniline,

4-acetamidoaniline,

4- (N-methylacetamido) aniline,

4- (N-n-butylacetamido) aniline,

N-methylaniline,

N-n-butylaniline,

N-methyl-2,6-dimethylaniline or N-n-butyl-2,6-dimethylaniline, gives the following substituted chloro; dy formula F:

(phenylaminocarbonylmethyl) chloride, [(2-chlorophenyl) aminocarbonylmethyl] chloride, [(3-chlorophenyl) aminocarbonylmethyl] chloride, [(4-chlorophenyl) aminocarbonylmethyl] chloride, [(2-bromophenyl) aminocarbonylmethyl] chloride, [(3 -bromophenyl) aminocarbonylmethyl] chloride, [(4-bromophenyl) aminocarbonylmethyl] chloride, [(2-fluorophenyl) aminocarbonylmethyl] chloride, [(3-fluorophenyl) aminocarbonylmethyl] chloride, [(4-fluorophenyl) aminocarbonylmethyl] chloride, ((2-methylphenyl) aminocarbonylmethyl] chloride, [(3-methylphenyl) aminocarbonylmethyl] chloride, [(4-methylphenyl) aminocarbonylmethyl] chloride, [(4-n-butylphenyl) aminocarbonylmethyl] chloride, [(2- methoxyphenyl) aminocarbonylmethyl] chloride, [(3-methoxyphenyl) aminocarbonylmethyl] chloride, [(4-methoxyphenyl) aminocarbonylmethyl] chloride, [(4-n-butoxyphenyl) aminocarbonylmethyl] chloride, [(2-trifluoromethylphenyl) aminocarbonylmethyl] chloride, [ (3-trifluoromethylphenyl) aminocarbonylmethyl] chloride; (4-trifluoromethyl) chloride; ylphenyl) aminocarbonylmethyljchloride, [(2,6-dichlorophenyl) aminocarbonylmethyl] chloride, [(3,5-dimethoxyphenyljammocarbonylmethyl) chloride, [(3,4-methylenedioxyphenyl) aminocarbonylmethyl] chloride, [(2-chloro-5-methylphenyl) aminocarbonylmethyl] ] chloride, [(4-methylthiophenyl) aminocarbonylmethyl] chloride, [(4-methylsulfinylphenyl) aminocarbonylmethyl] chloride, [(4-methylsulfonylphenyl) aminocarbonylmethyl] chloride, [(4-n-butylthiophenyl) aminocarbonylmethyl] chloride, [(4-n- butylsulfinylphenyl) aminocarbonylmethyl] chloride, [(4-n-butylsulfonylphenyl) aminocarbonylmethyl] chloride, [(3,4-difluorophenyl) aminocarbonylmethyl] chloride, [(4-chloro-3-trifluoromethylphenyl) aminocarbonylmethyl] chloride, [(4-fluoro-3-trifluoromethylphenyl) aminocarbonylmethyl] chloride, [(2,5-diethoxyphenyl) aminocarbonylmethyl] chloride, [(2,4,5-trichlorophenyl) aminocarbonylmethyl] chloride, [(3,4 , 5-trimethoxyphenyl) aminocarbonylmethyl] chloride, [(2,4,5,6-tetrachlorophenyl) aminocarbonylmethyl] chloride, [( 2,3,4,6-tetramethylphenyl) aminocarbonylmethyl] chloride, [(2,3,4,5,6-pentachlorophenyl) aminocarbonylmethyl] chloride, [(3-chloro-2,4,6-trimethylphenyl) aminocarbonylmethyl] chloride, [(2-cyanophenyl) aminocarbonylmethyl] chloride, [(4-acetamidophenyl) aminocarbonylmethyl] chloride, [(4-N-methylacetamidophenyl) aminocarbonylmethyl] chloride, [(4-N-butylacetamidophenyl) aminocarbonylmethyl] chloride, [N-methyl -N- (phenyl) aminocarbonylmethyl] chloride, [Nn-butyl-N- (phenyl) aminocarbonylmethyl] chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonylmethyl] chloride or [Nn-butyl-N- (2 (6-dimethylphenyl) aminocarbonylmethyl] chloride, in sufficient purity for use in the process of the invention.

C)

Repeating the procedure in a), replacing chloroacetyl chloride with a stoichiometric amount of 2-chloropropanoyl chloride,

2-chloro-n-butanoyl chloride, or 2-chloro-n-hexanoyl chloride, the following substituted chlorides of formula F are obtained:

[(2,6-dimethylphenyl) aminocarbonyl-1-ethyl] chloride, [(2,6-dimethylphenyl) aminocarbonyl-1-n-propyl] chloride or [(2,6-dimethylphenyl) aminocarbonyl-1-n-pentyl] chloride.

(d)

Repeating the procedure in paragraph a, except that a stoichiometric amount of aniline is used instead of 2,6-dimethylaniline,

N-methyl-2,6-dimethylaniline or N-n-butyl-2,6-dimethylaniline and instead of chloroacetyl chloride 2-chloropropanoyl chloride, the corresponding compounds are obtained:

(phenylaminocarbonyl-1-ethyl) chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-ethyl] chloride, or [N-butyl-N- (2,6-dimethylphenyl aminocarbonyl-1-ethyl)] chloride.

E)

Repeat the procedure in a) except that a stoichiometric amount of aniline is used instead of 2,6-dimethylaniline

N-methyl-2,6-dimethylaniline or N-n-butyl-2,6-dimethylaniline and instead of chloroacetyl chloride 2-chloro-n-hexanoyl chloride, the following corresponding compounds are obtained:

[(phenyl) aminocarbonyl-1'-pentyl] chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1'-pentyl] chloride, or [Nn-butyl-N- (2,6-dimethylphenyl) aminocarbonyl- 1'-pentyl] chloride.

Preparation C

Preparation of 1 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine (Compound of Formula Gj

and)

The crude [(2,6-dimethylphenyl aminocarbonylmethyl) chloride prepared in Preparation B (50 g, 0.25 mol) and piperazine (86 g, 1 mol) were dissolved in 500 ml of ethanol. The product is obtained by adding aqueous ammonia to the residue and extracting with methylene chloride. Extraction with methylene chloride is carried out three times, the fractions are combined, washed with water and evaporated to almost dryness. After addition of ether, the product crystallizes and is filtered. ether and then evaporated and the residue triturated with hexane to give pure material, 1 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine, and the product obtained is of sufficient purity to be used in the process of the invention.

(b)

Repeating the procedure in a), substituting [(2,6-dimethylphenyl-aminocarbonylmethyl) chloride for the stoichiometric amount of the following compounds: phenylaminocarbonylmethyl chloride, [(4-chlorophenyl) aminocarbonylmethyl] chloride, [(4-methylphenyl) aminocarbonylmethyl] chloride , [(4-methoxyphenyl) aminocarbonylmethyl] chloride, [(3-chlorophenyl) aminocarbonylmethyl] chloride, [(2,6-dichlorophenyl) aminocarbonylmethyl] chloride, [(2,4,6-trimethylphenyl aminocarbonylmethyl) chloride, [(3 , 5-dimethoxyphenyl aminocarbonylmethyl] chloride, [(2,4,6-trimethylphenyl aminocarbonylmethyl) chloride, [(3,5-dimethoxyphenyl) aminocarbonylmethyl] chloride, [(4-methylthiophenyl) aminocarbonylmethyl] chloride, [(4-n -butylthiophenyl] aminocarbonylmethyl] chloride, [(4-methylsulfinylphenyl) aminocarbonylmethyl] chloride, [(4-n-butylsulfinylphenyl) aminocarbonylmethyl (chloride, [(4-methylsulfonylphenyl) aminocarbonylmethyl] chloride, [(4-n-butylsulfonylphenyl) aminocarbonylmethyl] chloride thyl] chloride, [(4-trifluoromethylphenyl) aminocarbonylmethyl] chloride, [(2-chloro-5-methylphenyl) aminocarbonylmethyl] chloride, [(3,5-difluorophenyl) aminocarbonylmethyl] chloride, [(4-chloro-3-trifluoromethylphenyl) ) aminocarbonylmethyl (chloride, [(4-fluoro-3-trifluoromethylphenyl (aminocarbonylmethyl) chloride, ((2,6-diethoxyphenyl) aminocarbonylmethyl] chloride), [(3-bromo-4-ethylphenyl) aminocarbonylmethyl] chloride, [( 4-n-butylphenyljaminocarbonylmethyl] chloride, ((4-isobutylphenyl) aminocarbonylmethyl] chloride, [(3,4,5-trimethoxyphenyl) aminocarbonylmethyl (chloride, ((2,3,4,5-tetrachlorophenyl) aminocarbonylmethyl) chloride , [(2,3,4,5,6-pentachlorophenyl (aminocarbonylmethyl) chloride, [(2-cyanophenyl (aminocarbonylmethyl) chloride, ((4-acetamidophenyl) aminocarbonylmethyl] chloride, ((4-N-methylacetamidophenyl) aminocarbonylmethyl) ] chloride, [(4-Nn-butylacetamidophenyl) aminocarbonylmethyl] chloride, [N-methyl-N- (phenyl) aminocarbonylmethyl] chloride, [Nn-butyl-N- (phenyl) aminocarbonyl] 1-methyl] chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonylmethyl] chloride, [N-butyl-N- (2,6-dimethylphenyl (aminocarbonylmethyl) chloride), [(2,6-dimethylphenyl) aminocarbonyl-1] -ethyl] chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-ethyl] chloride, [N-butyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-ethyl] chloride, [ (2,6-dimethylphenyl-aminocarbonyl-1'-pentyl) chloride, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1'-pentyl] chloride, or [N-butyl-N- [2,6-dimethylphenyl] ) aminocarbonyl-1'-pentyl (chloride), the following plperazines are obtained:

1- (phenylaminocarbonylmethyl) piperazine

1 - ((4-chlorophenyl) aminocarbonylmethyl] piperazine,

1 - [(4-methylphenyl) aminocarbonylmethyl] piperazine,

1 - [(4-methoxyphenyl aminocarbonylmethyl) piperazine,

1 - [(3-chlorophenyl) aminocarbonylmethyl] piperazine,

1 - [(2,6-dichlorophenyl) aminocarbonylmethyl] piperazine,

1 - [(2,4,6-trimethylphenyl) aminocarbonylmethyl] piperazine,

1 - [(3,5-dimethoxyphenyl) aminocarbonylmethyl] piperazine,

1 - [(4-methylthiophenyl) aminocarbonylmethyl (piperazine,

1 - [(4-n-butylthiophenyl) aminocarbonylmethyl] piperazine,

1 - [(4-methylsulfinylphenyl) aminocarbonylmethyl] piperazine, η 7 1 - [(4-n-butylsulphinylphenyl) aminocarbonylmethyl] piperazine,

1 - [(4-n-butylsulfonylphenyl) aminocarbonylmethyl] piperazine, 1 - [(4-methylsulfonylphenyl) aminocarbonylmethyl] piperazine,

1 - (, (4-Trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1 - [(2-chloro-5-methylphenyl) aminocarbonylmethyl] piperazine,

1 - [(3,5-difluorophenyl) aminocarbonylmethyl] piperazine, [{4-chloro-3-trifluoromethylphenyl) aminocarbonylmethyl] piperazine, [(4-fluoro-3-trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1 - [(2,6-diethoxyphenyl) aminocarbonylmethyl] piperazine,

1-1 (3-bromo-4-ethylphenyl) aminocarbonylmethyl] piperazine,

1 - [(4-n-butylphenyl) aminocarbonylmethyl] piperazine,

1 - [(4-isobutylphenyl) aminocarbonylmethyl] piperazine,

1 - [(3,4,5-trimethoxyphenyl) aminocarbonylmethyl] piperazine,

1 - [(2,3,4,5-tetrachlorophenyl) aminocarbonylmethyl] piperazine, 1 - [(2,3,4,5,6-pentachlorophenyl) aminocarbonylmethyl] piperazine, [(2-cyanophenyl) aminocarbonylmethyl] piperazine, [( 4-acetamidophenyl) aminocarbonylmethyl] piperazine, [(4-N-methylacetylamidophenyl) aminocarbonylmethyl] piperazine, [(4-N-butylacetamidophenyl) aminocarbonylmethyl] piperazine,

1- [N-methyl-N- (phenyl) aminocarbonylmethyl] piperazine

1- [N-n-butyl-N- (phenyl) aminocarbonylmethyl] piperazine

1- [N-methyl-N- (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine

1- [N-butyl-N- (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine, [(2,6-dimethylphenyl) aminocarbonyl-1-ethyl] piperazine, [N-methyl-N- (2,6- dimethylphenyl-aminocarbonyl-1-ethyl] piperazine, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-ethyl] piperazine, [N-butyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-ethyl ] piperazine, [(2,6-dimethylphenyl) aminocarbonyl-1'-pentyl] piperazine, [N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1'-pentyl] piperazine or [Nn-butyl-N- (2) (6-dimethylphenyl) aminocarbonyl-1H-pentyl] piperazine of sufficient purity for use in the process of the invention.

Example 1

Preparation of 1- [3- [2-methoxyphenoxy] -2-hydroxypropyl] -4 - [[2,6-dimethylphenyl aminocarbonylmethyl] piperazine

and)

1- [2-Methoxyphenoxy) -2,3-epoxypropane [2.0 g] from Preparation A and 4 - [(2,6-dimethylphenyl aminocarbonylmethyl) piperazine (2.5 g) were dissolved in 20 mL of methanol and The solution was heated at reflux for 2 h, evaporated and chromatographed on silica gel using 5% methanol / methylene chloride as eluent to add excess hydrochloric acid in methanol to form the dihydrochloride salt which was recrystallized from methanol / methylene chloride. ether and isolated as a white powder, yield 3 g, mp 164-166 ° C / hydrate (IH 2 O).

and')

Alternatively, 1- (2-methoxyphenoxy) -2,3-epoxypropane (3.78 g) from Preparation A and 4- (2,6-dimethylphenyl aminocarbonylmethyl) piperazine (4.94 g) were dissolved in isopropanol (25 mL). The solution was heated to reflux for 3 hours. The hot solution was filtered and acidified with a solution of hydrogen chloride in methanol. The mixture is heated on a steam bath and crystallization is induced by scraping the vessel walls. After cooling, the dihydrochloride salt is filtered off to give 7.3 g of product, m.p. 224-225 ° C.

Elementary analysis for:

C24H35N3O4Cl2 (0.5H2O) calculated:

C 56.58, H 7.12, N 8.25;

<5,] ri r π 6-t as b J found:

% C, 56.38;% H, 7.27;

¹ H NMR (DMSO-D 6) <δ:

2.19 (S, 6HJ,

3.30 - 3.55 (m, 2H, CH 2 N),

3.78 (s, 3H, OCHa),

3.60 - 3.85 (m, 8H, piperazine CH2),

3.90 - 4.08 (m, 2H, OCH 2),

4.35 (s, 2H, NCII 2 CO). 4.45 (m, 1H, CHOFI),

6.85-7.08 (m, 3H),

7.10 (s, 4H),

10.32 (s, 1H, NH).

Since the 1- (2-methoxyphenoxy) -2,3-epoxypropane of Preparation A (paragraph a) has undefined stereochemistry at the carbon atom at the 2-position of the ring, these compounds and substituted compounds from paragraphs b, c, d below are obtained as mixture of R- and S-forms.

(b)

In the same manner as in paragraph a, except that 1 - ((2,6-dimethylphenyl) aminocarbonylmethyl] piperazine is replaced by a stoichiometric amount of the substituted phenylpiperazine derivative described in Preparation B above, to give the corresponding 1- (3- (2-methoxyphosphine)). enoxy) -2-hydroxypropyl] -4- [substituted phenyl] aminocarbonylmethyl] -piperazine.

Examples of such compounds are:

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [phenylaminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((4-methylphenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - ((4-methoxyphenyl) aminocarbonylmethyl) piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (4-bromophenyl) aminocarbonylmethyl] piperazine, 1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4-j [3] -chlorophenyl Jaminocarbonylmethyl] piperazine

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((2,6-dichlorophenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) 30

-4 - ((2,4,6-trimethylphenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((3,4,5-trimethoxyphenyl) aminocarbonylmethyl) piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methylthiophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-ethylthiophenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4-: (4-methylsulfinylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- (4-n-propylsulfinylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((4-trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - ((2-chloro-5-methylphenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3,5-difluorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - ((2,6-diethoxyphenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - ((3-bromo-4-ethylphenyl) aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-n-butylphenyl) aminocarbonylmethyl] piperazine and

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-isobutylphenyl) aminocarbonylmethyl] piperazine.

C)

In the same manner as in paragraph a, but replacing the epoxide with a stoichiometric amount of one of the substituted phenoxy epoxide derivatives described in Preparation A (paragraph b), the corresponding 1- [3- (substituted phenoxy) -2-hydroxypropyl] -4- [(2, 6-dimethylphenyl) aminocarbonylmethyl] piperazine.

Examples of compounds are:

1- (3- (4-methylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (4-methoxyphenoxy) -2-hydroxypropyl] -4-1 (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine, 1- [3- (4-chlorophenoxy) -2-hydroxypropyl] - 4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (3-methylphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (3-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (3-chlorophenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1-13- (2,4-dimethylphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-acetylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-aminocarbonylmethylphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl} aminocarbonylmethyl] piperazine or

1- (2- (1-naphthoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

(d)

In the same manner as in paragraph and above except that 1 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine is replaced by a stoichiometric amount of any substituted phenylpiperazine derivative described in Preparation C above and 1- (2-methoxyphenoxy-2,3- The epoxypropane is replaced with a stoichiometric amount of any of the substituted phenoxy epoxides described in Preparation A above to give the corresponding 1-1 3- (substituted phenoxy-2-hydroxypropyl) -4 - [(substituted phenyl) aminocarbonylmethyl] piperazines.

Examples of these compounds are given below:

1- (3- (4-methylphenoxy) -2-hydroxypropyl) -4- (phenylaminocarbonylmethyl) piperazine,

1- (3- (4-chlorophenoxy) -2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (3-methylphenoxy) -2-hydroxypropyl) -4 - [(4-methylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-methoxyphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2,4-dimethylphenoxy) -2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (3-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3-chlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dichlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,4,6-trimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methylthiophenoxy) -2-hydroxypropyl) -4 - [(3,5-dimethoxyphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-chlorophenoxy) -2-hydroxypropyl) -4 - [(4-methylthiophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methylphenoxy) -2-hydroxypropyl) -4 - [(4-ethylthiophenyl) aminocarbonylmethyl] piperazine,

- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methylsulfinylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-Trifluoromethylphenoxy) -2-hydroxypropyl) -4 - [(4-n-butylsulfinylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methylphenoxy) -2-hydroxypropyl] -4 - [(4-trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-Methylsulfinylphenoxy) -2-hydroxypropyl] -4 - [(2-chloro-5-methylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-Methylsulfonylphenoxy) -2-hydroxypropyl] -4 - [(3,5-difluorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-n-butylsulfinylphenoxy) -2-hydroxypropyl) -4 - [(2,6-diethoxyphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3-bromo-4-ethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methylphenoxy) -2-hydroxypropyl) -4 - [(4-n-butylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (3-Methoxyphenoxy) -2-hydroxypropyl] ω 5

4 - [(4-isobutylphenyl) aminocarbonylmethyl] (piperazine,

1- [3- (4-n-butylthiophenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl (aminocarbonylmethyl) piperazine),

1- (3- (2-methyl-3,4-dichlorophenoxy) -2-hydroxypropyl) -4 - [[2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2,3,4,5-tetrachlorophenoxy) -2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonyl] piperazine),

1- [3- (2-methyl-5-chlorophenoxy) -2-hydroxypropyl (-4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine),

1- (3- (4-n-butylsulfinylphenoxy) -2-hydroxypropyl (-4 - ((2,6-dimethylphenyl (aminocarbonylmethyl) piperazine),

1- (3- (4-n-butylsulfonylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2,4-dimethylphenoxy) -2-hydroxypropyl (-4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine),

1- (3- (1-naphthoxy (-2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine),

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - ((2,6-dimethylphenyl) aminocarbonyl-1-ethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- [N-methyl-N- (2,6-dimethylphenyl (aminocarbonyl-1-ethyl) piperazine),

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [N-n-butyl-N- (2,6-dimethylphenyl (aminocarhonyl-1-ethyl) piperazine),

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonyl-1-n-pentyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- (N-methyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-n-pentyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [N-n-butyl-N- (2,6-dimethylphenyl) aminocarbonyl-1-n-pentyl (piperazine,

1- (3- (phenylthio) -2-hydroxypropyl) -4-f (phenyl (aminocarbonylmethyl) piperazine),

1- (3- (4-methylphenylthio) -2-hydroxypropyl) -4-1 (phenyl (aminocarbonylmethyl) piperazine),

1- (3- (phenoxy) -2-hydroxypropyl) -4- [phenylaminocarbonylmethyl (piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (4-chlorophenylaminocarbonyimethyl) -piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (4-methylphenyl) aminocarbonylmethyl] piperazine,

^1J [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methoxyphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- [(4-bromophenyl) aminocarbonylmethyl] piperazine,

1- (3- (4-methylthiophenoxy) -2-hydroxypropyl (-4- [phenylaminocarbonylmethyl] piperazine),

1- (3- (2-n-butylthiophenoxy) -2-hydroxypropyl) -4 - ((4-chlorophenyl) aminocarbonylmethyl) piperazine,

1-, 3- (2-methoxyphenylthio-2-hydroxypropyl) -4 - ((4-methylphenyl) aminocarbonylmethyl) piperazine,

1- [3- (2-methylthiophenylthio] -2-hydroxypropyl] -4- (4-methoxyphenyl) aminocarbonyimethyl] piperazine,

1- (3- (2-n-butylthiophenylthio) 2-hydroxypropyl (-4 - ((3-chlorophenyl) aminocarbonylmethyl) piperazine),

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dichlorophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,4,6-trimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy (-2-hydroxypropyl) -4 - [(3,4,5-trimethoxyphenyl) aminocarbonylmethyl (piperazine),

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methylthiophenyl) aminocarbonylmethyl (piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-ethylthiophenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-methylsulfinylphenyl) aminocarbonylmethyl] piperazine,

1-13- (2-methoxyphenoxy) -2-hydroxypropyl] -4 ^j [(4-n-propylsulfonyl inylf phenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-trifluoromethylphenyl) aminocarbonylmethyl] piperazine,

1-1 3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2-chloro-5-methylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3,5-difluorophenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-diethoxyphenyl) aminocarbonylmethyl] piperazine,

1-13- (2-methoxyphenoxy) - [2-hydroxypropyl] -4 - [(3-bromo-4-ethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((4-n-butylphenyl) aminocarbonylmethyl] piperazine

- Γ 3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-isobutylphenyl) aminocarbonylmethyl] piperazine,

E)

Using the same procedure as in paragraph a above except that a stoichiometric amount of R- or one of the substituted R- [1- (phenoxy) -2,3-epoxypropane and 1- (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine was used, replaced by a stoichiometric amount of any of the substituted phenylpiperazine derivatives described in Preparation C above, yielding the corresponding R- [3- (substituted phenoxy) -2-hydroxypropyl] -4 - [(substituted phenyl) aminocarbonylmethyl] piperazines.

F)

Using the same procedure as in paragraph and above. but by replacing 1- (2-methoxyphenyl) -2,3-epoxypropane with a stoichiometric amount of S- or one of the S- [1- (optionally substituted phenoxy)] -2,3-epoxypropane derivatives described above, and also replacing 1- [ (2,6-dimethylphenyl) aminocarbonylmethyl] chloride by stoichiometric amount of any of the substituted phenylaminocarbonyl chloride derivatives described in Preparation B, paragraph b above, yields the corresponding S- [2- (substituted phenoxy) -2-hydroxypropyl] -4 - [(substit. phenyl) aminocarbonylmethyl] piperazines.

Example IA

and)

Preparation of S-1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (2,6-dimethylphenyl aminocarbonylmethyl) piperazine

and)

Preparation of S1- (2-methoxyphenoxy) -2,3-epoxypropane (R) -2,2-Dimethyl-1,3-dioxolane-4-methanol (Aldrich) (10 g) was converted to the tosylate with p-toluenesulfonyl chloride in pyridine by conventional way. The tosylate was added to a solution of 2-methoxyphenol (15 g) and potassium tert-butoxide (13.4 g) in DMF (100 mL), and the resulting mixture was stirred at 70 ° C for 3 h. The cooled mixture was diluted with water and the product isolated by extraction with ether. The product was dissolved in 50 ml of water, 50 ml of acetone and 5 ml of hydrochloric acid, and the resulting mixture was heated to reflux for 30 minutes. The mixture was evaporated under reduced pressure to give a solid, which was washed with ether and filtered. 12 g of diol [α] _D = 9.07 °, CH 3 OH, m.p. 96-97 ° C.

A solution of this diol (11.3 g) in 80 mL of pyridine was cooled to -5 ° C and methanesulfonyl chloride (4.6 mL) was added dropwise. The mixture was added to water and extracted with ether. The ether was washed with 5% hydrochloric acid, water and brine and evaporated, the residue was dissolved in 50 ml THF. Potassium tert-butoxide is added in small portions until thin layer analysis indicates that the reaction is complete. Water was added and extraction with ether gave the crude product, which was purified by silica gel chromatography (50% ether-hexane) to give S-epoxide, 4.9 g ([α] _D = 12.2 °, CH 3 OH).

(b)

S1- [3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4- [2,6-dimethylphenyl aminocarbonylmethyl] piperazine was prepared from S-epoxide by the same procedure as for the racemic mixture in Example 1a above, melting point (as dihydrochloride] 226-230 ° C, ([α] ²⁵ _{D =} 10.3 °, CH 3 OH).

Elementary analysis for:

C24H35N3O4Cl2 calculated:

% G,% 57.60;% H, 7.05;% N / 8.39;

found:

% H, 7.05;% N, 8.22.

4 β ο g g

Π)

Preparation of R-1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine

and)

Preparation of R-1- (2-methoxyphenoxy) -2,3-epoxypropane.

R-1- (2-methoxyphenoxy) -2,3-epoxypropane was prepared as described by Caroon et al. in J. Med. Chem. 24, 1320 (1981).

(b)

R1- [3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine was prepared from R-epoxide in the same manner as described for the racemic compound in Example 2a above, melting point ( as dihydrochloride) 220-222 ° C, (a) / ⁵ = - + 9.84 ° (MeOH);.

Example IB

Preparation of 1- [3- (4-diethylaminophenoxy) -2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl] piperazine

a) 1- (4-Nitrophenoxy) -2,3-epoxypropane was prepared from 4-nitrophenol by the method used in Preparation A (a).

(b)

1- (3- (4-nitrophenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine prepared from 1- [4-nitrophenoxy] -2,3-epoxypropane and 4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine as described in Example 1 (a).

C)

This 4-nitro compound is then reduced to the corresponding 4-amino compound by hydrogenation in the presence of platinum oxide in methanol as the reaction medium. The reaction is complete in one hour, then excess formaldehyde is added and heated in the presence of hydrogen at 40 ° C for two hours. The solvents were then evaporated and the residue was purified by column chromatography (silica gel) eluting with methanol / methylene chloride (1: 9) to give the title compound. The trichloride salt of the title compound was then prepared as described in Example 1 (a), mp 192 ° C.

(d)

Alternatively, the title compound can be prepared by the same procedure, starting from 4-dimethylaminophenol.

Example 2 (Preparation of compounds of formula I)

and)

A solution of 0.70 g of 1 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and 0.71 g of R-1-phenoxy-2,3-epoxypropane in 20 ml of toluene and 20 ml of methanol is heated to reflux. 12 hours. Evaporation and chromatography of the residue on silica gel eluting with 10% methanol-methylene chloride gave 0.5 g of R- (3-phenoxy-2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine which is then dissolved in methanol containing excess HCl and precipitated with ether to give the dihydrochloride salt.

(b)

Using the same procedure as in paragraph above, but substituting 1- (substituted arylaminocarbonyl) piperazine for 4- [(2,6-dimethylphenyl) aminocarbonylmethyl) piperazine from Preparation C, the following compounds were obtained as the dihydrochloride salts:

R-1- (3-phenoxy-2-hydroxypropyl) -4- (phenylaminocarbonylmethyl) piperazine,

R-1- (3-Phenoxy-2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine,

R-1- (3-phenoxy-2-hydroxypropyl) -4 - ((4-methylphenyl) aminocarbonylmethyl] piperazine,

R-1- (3-phenoxy-2-hydroxypropyl) -4 - ((4-methoxyphenyl) aminocarbonylmethyl] piperazine,

R-1- (3-Phenoxy-2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl) piperazine or

R-1- (3-Phenoxy-2-hydroxypropyl) -4 - ((3-chlorophenyl) aminocarbonylmethyl) piperazine.

Example 3

Preparation of salts of compounds of formula I a)

A solution of 0.70 g of 1 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and 0.71 g of 1-phenoxy-2,3-epoxypropane in 20 ml of toluene and 20 ml of methanol was combined and heated to reflux. hours. Evaporation and chromatography of the residue on silica gel with 10% methanol / methylene chloride as eluent gave 0.5 g of 1- [3-phenoxy-2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine, which was then dissolved in methanol containing excess HCl and precipitated with ether to give the dihydrochloride salt, mp 143-5 ° C.

(b)

In the same manner as in paragraph a above, but substituting 1- (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine with the appropriate 1- [substitutionarylaminocarbonyl] piperazine from Preparation C, the corresponding compounds were obtained as the dihydrochloride salts.

Example 4

and)

Similarly, compounds of Formula I are prepared by any of the procedures set forth in Examples 1, 2 or 3, and the following compounds may be prepared as hydrochloride or dihydrochloride salts by the procedure of Examples 3 or 5.

If desired, the following compounds and salts can be converted to the free bases by the procedure of Examples 6 and 9 or to other salts by the procedure of Example 7:

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [phenylaminocarbonylmethyl] -piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-chlorophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- [3- (2-cyanophenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride, di-HCl, mp 213-215 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-methoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy-2-hydroxypropyl) -4 - [(3,4-dichlorophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (phenoxy) -2-hydroxypropyl] -4-4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and the dihydrochloride salt, R-di-HCl m.p. 220-222 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3,5-dimethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (4-chlorophenyl) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl) piperazine and dihydrochloride, R, S-di-HCl, mp 205 ° C,

1- (3- (phenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride, R, S-di-HCl, m.p. 195 ° C,

1- (3- (phenoxy) -2-hydroxypropyl] -4 - [(2,5-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride, R, S-di-HCl m.p. 167 ° C,

1- (3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride, R, S-diHCl mp 210 ° C,

1- (3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4 - [(3,4-dichlorophenyl) aminocarbonylmethyl] piperazine and dihydrochloride, R, S-di-HCl, mp 192 ° C,

1- (3- (2-acetylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and the dihydrochloride salt, R, S-di-HCl m.p. 195 ° C,

1- (3- (4-aminocarbonylmethylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and the dihydrochloride salt, R, S-di-HCl m.p. 148-150 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,5-dimethylphenyl) aminocarbonylmethyl) piperazine and dihydrochloride, R, S-di-HCl, mp 174 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-methoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl, mp 162 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-fluorophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 169 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-bromophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 170 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 155 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(3,4-dimethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 132 ° C,

1- (3- (2-Methoxyphenoxy) -2-hydroxypropyl)

4 - [(4-n-butylphenyl) aminocarbonyl41 methyl] piperazine and dihydrochloride salt, R, S-di-HCl m.p. 180 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] 4 - [(2-methoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 196 ° C,

1- (3- (2-methoxyphenoxy) -2-hydr oxypropyl] -4- [(2,4-dimethylphenyl) aminocarbonyl bonylmethyl] piperazine and dichlorides salt, R, S- di-HCl, mp 202 ^C C

1- (3- (2-isopropoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl [piperazine and dihydrochloride, R, S-di-HCl m.p. 180 ° C,

1- (3- (2-n-butoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl, mp 160 ° C,

1- [3- (1-naphthoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

R, S-di-HCl mp 154-156 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((3-trifluoromethylphenyl) aminocarmonylmethyl] piperazine and dihydrochloride, R, S-di-HCl m.p. 158 ° C,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2-chloro-5-methylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-methylthiophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(4-n-propylsulinylphenyl} aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-chlorophenoxy) -2-hydroxypropyl] -4 - [(3,5-difluorophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-ethylphenoxy) -2-hydroxypropyl) -4- [phenylaminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-diethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(3-bromo-4-ethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (4-methoxyphenoxy) -2-hydroxypropyl) -4- (phenylaminocarbonylmethyl) piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) 246099

-4 - [(2-cyanophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(4-acetamidophenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- [4-N-methylacetamidophenyl] amino-carbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [4-N-n-butylamldophenyl] aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-acetylphenoxy) -1- (3- (4-n-butanoylphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride, methylaminophenoxy) -2 -hydroxypropyl] -4-methylaminophenoxy-2-liydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (2-acetylphenoxy) -1- (3- (4-N, N-di-n-butylaminophenyl) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (5-n-butylphenoxy) -2-hydroxypropyl) -4- (phenylaminocarbonylmethyl) piperazine and dihydrochloride,

1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4- [N-methyl-N- (2,6-diethoxyphenyl) aminocarbonylmethyl] piperazine and dihydrochloride,

1- (3- (phenoxy) -2-hydroxypropyl) -4- [N-methyl-N- (phenyl) aminocarbonyl-1-n-propyl] piperazine and dihydrochloride, di-HCl, mp 210 ° C,

1- (3- (4-chlorophenoxy) -2-hydroxypropyl) -4- (N-methyl-N- (phenyl) aminocarbonyl-1-n-propyl] piperazine and dihydrochloride, di-HCl, mp 190 ° C,

1- (3- (phenoxy) -2-hydroxypropyl) -4- [N-methyl-N- (phenyl) aminocarbonyl-1-ethyl] piperazine and dihydrochloride, di-HCl, mp 168 ° C,

1- (3- (phenoxy) -2-hydroxypropyl] -4 - [(phenyl) aminocarbonyl-1-ethyl] piperazine and dihydrochloride, di-HCl, m.p. 148 ° C,

1- (3- (4-chlorophenoxy) -2-hydroxypropyl) -4- [N-methyl-N- (phenyl) aminocarbonyl-1-ethyl] piperazine and dihydrochloride, di-HCl, mp 210 ^C C

1- (3- (4-chlorophenoxy) -2-hydroxypropyl) -4- [N-methyl-N- (phenyl) aminocarbonyl246099

-1-n-pentyl] piperazine and dihydro chloride, di-HCl, mp 200 ° C,

1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- [4-methylthiophenylaminocarbonylmethyl] piperazine and dihydro chloride,

- [3- (phenylthio) -2-hydroxypropyl] -4- (phenylaminocarbonylmethyl) piperazine and dihydro chloride,

1- [3- (4-Methylphenylthio) -hydroxypropyl] -4- (phenylaminocarbonylmethyl) piperazine and dihydro chloride,

1- [3- (phenylthio) -2-hydroxypropyl] -4- (phenylaminocarbonyl-1-ethyl) piperazine and dihydro chloride, R, S-di-HCl mp 146 ° C, or 1- (3- (phenylthio) -2-hydroxypropyl] -4-N- (methyl) -N- (phenyl) amino-carbonylmethyl] piperazine and dihydro chloride,

R, S-di-HCl, mp 152 ° C.

(b)

Using the same procedure as in (a) except that 1- (2-methoxy) -2,3-epoxypropane is replaced by an equivalent amount of R- or S1- (phenoxy) -2,3-epoxypropane, the corresponding salt is obtained. R- or S- configuration.

C)

Using the same procedure as in aj, but substituting R 1 - (2-methoxyphenoxy) -2,3-epoxypropane with a stoichiometric amount of R 1 or S 1 - (optionally substituted phenylthio) -2,3-epoxypropane gives the corresponding salt of the corresponding R- or S- orientation.

Example 5

Conversion of free base to salt

Dissolve 8.0 g of 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl] piperazine) in methanol and acidify with methanolic hydrochloric acid. with 7.0 g of 1- [3- (2-methoxyphenyyloxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine dihydrochloride salt, mp 175-176 ° C.

In a similar manner, all the compounds of formula I prepared according to Examples 1, 2 or 3 can be converted to the corresponding pharmaceutically acceptable acid addition salts by treatment with suitable acids, for example:

hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, grape acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

Examples 1 and 6

Conversion of salt to the free base

1.0 g of 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethyl) aminocarbonylmethyl] piperazine. The 1HCl was suspended in 50 mL of ether with stirring with an excess of dilute aqueous potassium carbonate solution until the salt was completely dissolved. The organic layer was then separated, washed twice with water, dried over magnesium sulfate and evaporated. 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine was obtained as the free base.

In a similar manner, the acid addition salts prepared according to Example 5 are converted to the corresponding free bases.

Example 1 a d 7

Direct exchange of acid addition salts

1- (3- (2-Methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine acetate (1.0 g) was dissolved in 50 ml of 50% aqueous sulfuric acid and The solution was evaporated to dryness and the product was suspended in ethanol and filtered, air dried and recrystallized from methanol-acetone to give 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4- (2,6- dimethylphenylaminocarbonylmethyl) piperazine 2H2SO4.

Example 8

Preparation of ester and dihydrochloride salt of compounds of formula I

and)

One g of 1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine was dissolved in 25 ml of pyridine and cooled in an ice bath to 0-5 ° C. acetic anhydride (0.6 g) was added and the reaction stirred for 2 h. After addition of 100 mL

246098 water, the reaction mixture was extracted with diethyl ether (2 x 100 mL). The ether extracts were combined, washed twice with 100 ml of water and evaporated to dryness. 1- (3- (2-methoxyphenoxy) -2-acetoxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine was obtained as an oil.

By repeating the procedure (paragraph i of this example using a stoichiometric amount of propionic anhydride, n-butanoic anhydride, n-hexanoic anhydride, n-octanoic anhydride or n-dodecanoic anhydride instead of acetic anhydride, the following piperazines are obtained:

1- (3- (2-methoxyphenoxy) -2-propanoyloxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- [3- (2-methoxyphenoxy) -2-n-butanoyloxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine,

1- (3- (2-methoxyphenoxy) -2-n-hexanoyloxypropyl) -4 - [(2,8-dimethylphenyl aminocarbonylmethyl) piperazine,

1- (3- (2-methoxyphenoxy) -2-n-dodecanoyloxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine or

1- (3- (2-methoxyphenoxy) -2-n-dodecanoyloxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

By repeating the above procedure (paragraph a) of this example, replacing acetic anhydride with a stoichiometric amount of alkyl anhydride and 1- [3- (2-methoxyphenoxy-2-hydroxypropyl) -4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine 1- (3) - (optionally substituted phenyl) aminocarbonylmethyl] piperazine, yielding the corresponding 1- (3- (optionally substituted phenoxy) -2-alkanoyloxypropyl) -4 - [(optionally substituted phenyl jamnocarbonylmethyl) piperazine.

(d)

The compounds described in paragraphs a), bj and c) of this example after treatment with an excess of hydrochloric acid as described in Example 7 afford the corresponding 1- (3- (optionally substituted phenoxy) -2-alkanoyloxypropyl) -4 - [(optionally substituted phenyl) dihydrochlorides aminocarbonylmethyl] piperazine.

In all of the above reactions described in paragraphs aj, bj, c] and dj of this example, the phenoxy compounds may be replaced by optionally substituted thiophenoxy compounds and the stereochemistry of the compounds of Formula I remains unchanged.

Example 9

A solution of 3.5 g of 1- [3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine dihydrochloride in water (50 ml) was adjusted to pH 12 with a hydroxide solution. Methylene3 g of 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine as the free base .

The acid addition salt solution of Examples 5-7 was prepared in the same manner and converted to the corresponding free base

Example 10

The following examples illustrate the preparation of representative pharmaceutical compositions containing the active compound of formula I, i.e. 1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine.

I.V preparation active ingredient 0.14 g propylene glycol 20.0 g

Polyethylene glycol 400 20.0 g

Tween 80 1.0 g

0.9% saline solution 100.0 ml

In Examples 10-16, the active compound is 1- (1- (phenoxy) -2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] plperazine dihydrochloride. This compound may be replaced by another compound. or a pharmaceutically acceptable salt thereof.

Example 11

Ingredient amount per tablet, mg active ingredient 25 maize starch 20 spray-dried lactose 153 magnesium stearate 2

The above ingredients are mixed and compressed into one notch tablets.

Example 12 amount components per capsule, mg active ingredient 100 spray-dried lactose 148 magnesium stearate 2

The ingredients are mixed and filled into hard gelatin capsules.

Example 13

folders amount per tablet, mg active substance 1 cornstarch 50 lactose 145 magnesium stearate 5 The above ingredients are mixed and compressed into one scored tablet. Example 14 folders amount per capsule, mg active substance 108 lactose 15 Dec cornstarch 25 magnesium stearate 2 The ingredients are mixed with gelatin capsules. stuffed into hard Example 15 folders amount per capsule, mg active substance 150 lactose 92 The ingredients are mixed with gelatin capsules. stuffed into hard Example 16 The pH 7 injection buffered formulation has the following composition: folders active substance 0.2 g KH2PO4 buffer (0.4M solution 1) 2 ml KOH (IN) q. to pH 7 water (distilled sterile) q. to 20 ml

Example 17

The prepared oral suspension has the following composition:

folders

active substance fumaric acid sodium chloride 0.1 0.5 2,0 WITH G G methylparaben 0.1 G granulated sugar 25.5 G sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 G flavoring substance 0.035 ml dyes 0.5 mg Distilled water q. to 100 ml

Example 18

Compound:

1- (3- (2-methoxyphenoxy) -2'-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine - was tested for antigenic activity.

Methodology:

It was based on the work of L. Szekeres, J. Pharm. Exp. Ther., Vol. 196, pp. 15-28, 1976, and proceeded as follows:

Single-sex adult beagles (11-16 kgj) were premedicated with acetylpromazine 0.2 mg / kg im and anesthetized with sodium pentobarbital 30 mg / kg iv, intubated, artificially ventilated, and thoracotomy was performed with the left lateral fifth intercostal space. coronary heat (LAD) was loosely ligated with a nylon ligature to prevent blood flow through the anterior ventricle wall.The effect of transient critical stenosis on the deterioration of arterial blood flow below the above-mentioned LAD was generated by transient (time-controlled after 12 minutes) heart rate ranging from 50 to 70 beats / min above spontaneous rhythm, in which case each ischemic insult that was followed by stimulation after one minute was created by totally strangling the loosening loop, with continued closure stimulation continued for another two minutes. they were fed in 8 epicarian electrograms as a result of each ischemic stimulus, and these phenomena were basically reversible within 5 to 10 minutes, during which the heart was allowed to return to spontaneous rhythm. These changes in the S-T region served as an electrophysiological indicator in determining the oxygen debt phase. After the first excessive response, an additional 4 to 5 repeated cycles of stress rhythm were required at 12 minute intervals to produce reproducible recordings. The elevations of the S-T region thus induced were always larger than a simple closure. These tests were performed to determine whether preventive administration of i. At a dose of cumulative drug administered 5 minutes prior to stimulation can prevent the S-T region.

Results:

The test compound at a dose of 5 µg / kg IV gave statistically significant suppression of the elevation of the S-T region.

Cardioselectivity:

In further tests, the compound has been shown to be more selective for the heart muscle than for the vascular wall muscle and has the desired anti-angina properties.

Example 20

Toxicity:

Both the 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl-4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine dihydrochloride and its S-isomer were separately orally administered to rats in seven-day doses up to 250 mg. / kg / day No toxic effects of any of the compounds were noted.

In addition, many modifications may be made to the particular circumstances, material or composition of the substance, the manufacturing process or processes, or the stated objects, spirit and scope of the invention. These modifications can be made while maintaining the essential features of the invention. The present invention is described and characterized by its specific features, but it will be apparent to those skilled in the art that various changes may be made while maintaining the spirit and scope of the invention.

Claims (8)

OBJECT OF THE INVENTION A process for the preparation of piperazine derivatives of the general formula I C' H N, N ~ Ctf-C-Ar pl Q in which Ar ² represents a group of the formula R 6 'R ² ' C,. ₄ alkylsulfinyl, C ₄ alkylamide group optionally N-substituted by C ^ alkyl, or C ₄ alkylsulfonyl, with the proviso that when R ¹ is methyl, R ^'1 is other than methyl, or R ² and R ³ form together the group “OCH2O”, Ar ¹ represents a group of the general formula in mzz R ¹ R ² R ^3, R ⁴ and R ⁵ are independently hydrogen, C _b4 alkyl Ctoalkoxyskupinu, cyano, trifluoromethyl, halogen, C ₄ alkylthio, wherein 246 R ^B, R ^7, R ^8, R ^y and R ^1U are independently hydrogen, Cb4acyl, aminocarbonylmethyl, optionally substituted phenyl or naphthyl, where R ^B and R ⁷ form together a group of formula -C --CH = CH - cyano, C 1-4 alkyl, C 1-4 alkoxy, trifluorinethyl, halogen, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, di-C _1-4 alkylamino or R ⁷ and R ⁸ together form a group of the formula "OCH 2 O", R ¹¹ and R ¹² are each independently hydrogen or C 1, alkyl and W are oxygen or sulfur, their stereoisomers, their pharmaceutically acceptable esters and their acid addition salts, characterized in that a piperazine derivative of the general formula G is reacted OR ^ ¹¹ · ' H N ~ -CH ~ ~ A r '~ R ^{1Z (} G) in which: Ar ² , R ¹¹ and R ¹² are as defined above, with a compound of formula A wherein Ar ¹ and W are as defined above, or optionally converting a salt of a compound of Formula I obtained into the corresponding free base, or converting a free base of a compound of Formula I into a pharmaceutically acceptable acid addition salt, or converting a salt of a compound of Formula I into another pharmaceutically acceptable salt of a compound of formula I, or a compound of formula I or a salt thereof is converted into a pharmaceutically acceptable ester, or the compound of formula I or a salt or ester thereof is isolated as a stereoisomer. 2. A method according to claim 1, characterized by reacting a piperazine derivative of formula G wherein two of the substituents of R sub99 ^1, R ^2, R ^3, R ⁴ or R ⁵ in the formula, Ar ² represent hydrogen and the other substituents in the general formula Ar ² and the substituents R ¹¹ and R ¹² are as defined above. 3. The process of claim 2, wherein the piperazine derivative of formula G is reacted wherein R ^{@ 2} , R ^{@ 3} and R ^{@ 4} in Ar @ ² are hydrogen and other substituents in formula Ar @ ² and R @ 2. ¹¹ and R ¹² are as defined above. 4. Method according to claims 2 and 3 characterized by reacting a piperazine derivative of formula G wherein R ¹ and R ⁵ are each C ^ alkyl, preferably methyl and the other substituents are as defined in point 1. 5. The process of item 1 for the preparation of 1- (3-phenoxy-2-hydroxypropyl) -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and its pharmaceutically acceptable acid addition salts, characterized in that it is reacting 1-phenoxy-2,3-epoxypropane with 4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and optionally converting the compound obtained into its pharmaceutically acceptable acid addition salt. 6. The process of item 1 for the preparation of 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and its pharmaceutically acceptable acid addition salts, characterized by: by reacting 1- (2-methoxyphenoxy) -2,3-epoxypropane with 4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] plperazine and optionally converting the compound obtained into its pharmaceutically acceptable acid addition salt. 7. The process of item 6 for the preparation of R1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenylsocanonylcarbonylmethyl) piperazine and its pharmaceutically acceptable acid addition salts, The reaction is carried out by reacting R1- (2-methoxyphenoxy) -2,3-epoxypropane with 4 - ((2,6-dimethylphenyl) aminocarbonylmethyl) piperazine and optionally converting the compound to its pharmaceutically acceptable acid addition salt. 8. A process according to item 6 for the preparation of S1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethylphenyl aminocarbonylmethyl) piperazine and its pharmaceutically acceptable acid addition salts, The reaction is carried out by reacting S1- (2-methoxyphenoxy) -2,3-epoxypropane with 4 - [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine and optionally converting the compound into its pharmaceutically acceptable acid addition salt.