Derivatives of piperazine and pharmaceutically acceptable esters and acid additive salt

 

(57) Abstract:

Usage: in medicine in the treatment of diseases of the cardiovascular system. The inventive product - piperazine derivatives of General formula I:

< / BR>
or their pharmaceutically acceptable esters, or their kislotoupornye salt, where R1is hydrogen, lower alkyl or lower alkoxy; R2is hydrogen, lower alkoxy, halogen, trifluoromethyl or alkylthio; R3is hydrogen, lower alkyl, lower alkoxy, halogen or cyano; R4is hydrogen or lower alkoxy; R5is hydrogen or lower Alky; R6is hydrogen, lower Alky, lower acyl, lower alkoxy; R7is hydrogen, lower alkoxy, trifluoromethyl, halogen, or together with R6forms a group; -CH=CH-CH=CH-; R8is hydrogen, lower alkyl, lower alkoxy, halogen, aminocarbonylmethyl, cyano or di/lower/alkylamino; R9and R10each independently hydrogen or lower alkoxy; R11and R12each independently hydrogen or lower alkyl; W is oxygen. Reagent 1: the corresponding piperidine derivative; reagent 2: alkylating agent containing one of the side chains. Reaction conditions: inert solvent at 60 to 150oC for 6-24 h 1 table.

The invention Rel is that nitrogen is associated with a fragment of aryloxy or aaltio link oxypropylene or alkanoyloxy, and through another nitrogen atom with the rest of acetanilide. Such compounds prevent the blockade of receipt of calcium and therefore be useful for treatment of diseases of the cardiovascular system, including disorders of the heart rate, angina at rest and during movement of the body, myocardial infarction.

There are a large number of compounds affecting various physiological systems related to the control of the nerves that produce adrenalinoman substances.

Similar to the compounds of the invention compound is described in Belgium patent 806380 (U.S. patent 3944549) and include 1-(1,4-benzodioxan-2-ylmethyl)-4-(2,6-diphenylmethyl-acetanilide)piperazine, then the following links: HP Stankeviciene and other Mater. International. the scientific. proc. Kaunas, Honey. inst. 25th, 1976, published 1977, pages 322-323 [Chem. Abstr. 90, s (1979)] and French patent 2267104. Further interest in this field references are in U.S. patents 3360529, 3496183, 3829441, 3879401, 3944549, 4059621, 4302469, 4315939, 4335126, 4353901, which are all included in this application as prior art. Compounds that block calcium intake, used to be symptoms of diseases of the cardiovascular system, such as myocardial infarction, nadeane belongs to the group cardioselektivee compounds, suitable for treatment of the diseases of the cardiovascular system.

The invention relates to the production of piperazine of General formula I

< / BR>
or their pharmaceutically acceptable esters or their acid additive salts, where

where

R1hydrogen, lower alkyl or lower alkoxy;

R2hydrogen, lower alkoxy, halogen, trifluoromethyl or alkylthio;

R3hydrogen, lower alkyl, lower alkoxy, halogen or cyano;

R4hydrogen or lower alkoxy;

R5hydrogen or lower alkyl;

R6hydrogen, lower alkyl, lower acyl, lower alkoxy;

R7hydrogen, lower alkoxy, trifluoromethyl, halogen, or together with R6forms a group-CH=CH-CH=CH-;

R8hydrogen, lower alkyl, lower alkoxy, aminocarbonylmethyl, cyano or di(lower)alkylamino, halogen;

R9and R10each independently hydrogen or lower alkoxy;

R11and R12each independently hydrogen or lower alkyl;

W oxygen.

Definition expression:

The expression "aryl" means unsubstituted or substituted phenyl or naftalina group, where R6and R7together form a-CH=CH-CH=CH-.

The expression "cyano" UP>13(R14)N-, where R13and R14, independently of one another represent lower alkyl, as neukazono.

The expression "halogen" means fluorine, chlorine, bromine or iodine, and the expression usually refers to the replacement of the halogen atom of hydrogen in an organic compound.

The expression "isomerism" refers to compounds that have the same atomic mass and number of atoms, but differ in one or more physical or chemical properties.

The expression "stereoisomer" means a chemical compound having the same molecular weight and chemical composition, as well as the same structure, but different grouping of atoms. The fact that certain similar chemical fragments have an excellent spatial orientation, and therefore, in their pure form have the ability to rotate the plane of polarized light. However, the optical rotation of some of the pure stereoisomers is so small that it is not subject to monitoring using current tools.

The expression "optical isomerism" means one type of stereoisomer expressed in the rotation, which gives the isomer in pure form or in solution, plane polarized light is one of the carbon atoms in the molecule. These isomers depending on the system the item is designated as d-, l-, or d,l-pair, or D-,L - or D,L-pair, or R-,S-or R,S-pair.

The expression "diastereoisomer" means stereoisomers that some or all of them dissymmetries, but they are not a mirror image of the other. Diastereoisomer corresponding to this structural formula, must have at least two asymmetric atom. The compounds having two asymmetric atoms, usually exists in the form of four diastereoisomeric forms, for example, (-)-Erythro, (+)-Erythro, (-)-threo and (+)-threo.

Certain compounds of formula (I), where R12hydrogen has one asymmetric carbon atom, i.e. a carbon atom 2, sawn fragment. Such compounds exist in two stereochemical forms, i.e. ( + ) and (-) or R - and S -, and mixtures thereof. The compounds of formula (I), where R12has a value other than hydrogen, have two asymmetric carbon atoms, i.e. the carbon atom in position 2, sawn fragment, and the carbon atom that is attached to R12. These compounds are present in four stereochemical forms, i.e., (+)- Erythro, (-)-Erythro, (+)-Treo, (-)-threo and their mixtures. According to the Convention Cana-Prelog carbon. Here are symbol using symbols R and S, including and individual stereoisomers and mixtures thereof.

The expression "the structure of formula (I)" means the overall structure of the proposed compounds. Chemical bonds indicated in the formula (I) through (a) mean nonspecific stereochemical asymmetric carbon atoms, for example, in position 2 through the circuit, i.e. the carbon atom that is attached to the hydroxyl group and the carbon atom that is attached to R12between piperazinyl ring and the carbonyl group.

The expression "lower acyl" means a group having the structure where R15means specified in this application is lower alkyl and includes such groups as, for example, acetyl, propanol, n-butanol etc.

The expression "lower alkyl" means a branched or unbranched saturated hydrocarbon chain containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Symm.-butyl and tert.butyl.

The expression "lower alkoxy" means the group-OR, where R is lower alkyl.

The expression "lower alkylthio" means the group-SR, where R is lower alkyl.

The expression "lower alkylsulfonyl" means a group where R is nissia "N-unsubstituted or N-substituted, alkylamino" means the group having the structure where R16independently represents or lower alkyl, and R17lower alkyl.

The expression "may" indicates what is happening in certain conditions, the process or the optional conditions, and specified preconditions for these processes and conditions. So, for example, possibly substituted phenyl" (unsubstituted or substituted phenyl means phenyl which may be substituted, i.e., unsubstituted or substituted phenyl. The expression "with the possible conversion of the free base salt with acid" means a possible conversion of the free base salt with acid and processes, where it has no place.

The terms "pharmacologically acceptable salt with an acid" means a salt that has biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, obtained with such inorganic acids as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric and other acids, and such organic acids as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, almond, Eugenie "pharmaceutically acceptable ester" of the compounds of formula (I), which usually can be used for therapeutic purposes, include esters, which contain alkanoyloxy group-O-C(=O)-Z, where Z denotes an alkyl group containing 1-12 carbon atoms, which is attached to the carbon atom 2 propylene connection instead of a hydroxyl group, i.e. in this case the hydroxyl group etherification in ester. The group Z may mean, for example, methyl, ethyl, butyl, hexyl, octyl, dodecyl, etc. the Invention also includes compounds of formula (I), which are esters and are pharmaceutically acceptable salts with acids.

The structure of the piperazine derivatives" describes the following six-membered substituted heterocyclic fragment with two nitrogen atoms:

< / BR>
The proposed connection is usually specified according to the system of nomenclature of IUPAC. The position of substituents in the ring system proposed compounds corresponds to the one described above. For example, if R1and R5methyl, R6methoxy, R2, R3, R4, R7-R12is hydrogen, W is oxygen, the compound of formula (I) is designated as 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine as shown below:

< / BR>
Mr. metatitanate)-2-oksipropil]-4-(2,6-dimethylphenylcarbamate)piperazine, or 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-(2,6-dimethylacetanilide)piperazine. Here the connection specified mean according to the IUPAC nomenclature.

Optically active compounds are identified in accordance with a variety of systems of symbols, i.e., as R - and S-isomers according to the rules of Cahn and Prelog, Erythro - and threo-isomers, D and L-isomers, d - and l-isomers, as well as (+)- and (-)-isomers, which indicate the direction of rotation of plane polarized light due to the action of chemical structure, in pure form or in solution. These designations are well known and they are described in detail by E. L. Eliel publication Stereochemistry of Carbon Compounds", published by McGraw Hill Book Company, Inc. New York, 1962 and described in this publication references.

Sequencing reactions mean:

"Arl" aryl fragment, unsubstituted or substituted by the above-mentioned residues R6R10. Communication with other parts of the molecule, i.e., an oxygen atom, or sulfur, is through the carbon atom in position 1, with the numbering of the other provisions aryl group:

< / BR>
"Ar2" unsubstituted or substituted phenyl group, where R1-R5have the above significance, with the numbering of other provisions as follows:

< / BR>
PEL, selected from the group R1-R5represent hydrogen, and two substituent selected from the group R6-R10the hydrogen. A preferred subgroup are those compounds of formula (I), where W is oxygen.

A preferred subgroup are those compounds of formula (I) where the substituents R2, R3and R4the hydrogen.

A preferred subgroup are those compounds where two Deputy R1and R5both signify lower alkyl, in particular methyl.

The preferred compound of this invention include compounds of formula (I), where each of the substituents R1and R5methyl, each of R2, R3, R4and R6-R12hydrogen, and W is O, i.e., 1-(3-phenoxy-2-oksipropil)-4 -[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine.

The preferred compound of the invention include compounds of formula (I), where each of R1and R5methyl, R6methoxy, R2, R3, R4and R7-R12hydrogen, and W is O, i.e., 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[2,6-dimetilfenil))aminocarbonylmethyl]piperazine.

The preferred compound of the invention includes such is connected to the rod, and W is O, i.e., 1-[3-(2-cianfrocca)-2-oksipropil]-4-[(2,6 - dimetilfenil)aminocarbonylmethyl]piperazine.

Preferred forms of execution include the compounds of formula (I) where the substituents R1, R4and R5the hydrogen.

Preferred forms of execution include the compounds of formula (I) where the two do not signify a hydrogen substituent R2and R3means halogen, in particular chlorine.

Preferred forms of execution include the compounds of formula (I) where at least one is not a synonym hydrogen Deputy selected from the group R1-R5. A preferred subgroup includes the compounds of formula (I) where one does not indicate hydrogen Deputy selected from R1. A preferred subgroup includes the compounds of formula (I) where a Deputy is a lower alkoxy, in particular methoxy.

Forms of execution of the invention include compounds of formula (I), where two of not signify a hydrogen substituents, the substituents R7-R9. A preferred subgroup are those compounds where R6and R10lower alkoxy, in particular methoxy.

Preferred forms of execution include the UP>10.

A preferred group includes the compounds of formula (I) where one does not indicate a hydrogen substituent R6lower alkoxy, in particular methoxy.

A preferred subgroup includes the compounds of formula (I), where R6cyano or halogen, in particular chlorine.

A preferred subgroup of the invention include compounds of formula (I) where no meaning hydrogen substituent R8lower alkoxy, in particular methoxy or chlorine.

The invention includes such compounds of formula (I), where R11- hydrogen, where R12hydrogen, where R11and R12- hydrogen.

The preferred nowadays subgroups include such compounds, where R12lower alkyl, in particular methyl, and R11and R12lower alkyl, in particular methyl.

Preferred compounds of the invention are such compounds where R6, R7, R8, R9, R10the hydrogen. Particularly preferred compounds of this subgroup are compounds where R1-R10do all hydrogen.

Another preferred group of compounds is that group, where R11the hydrogen. Preferred now soedineniya, where R11the hydrogen.

Among the compounds, where R11hydrogen, particular preference is given to compounds selected from the group including:

1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine,

1-[3-(2-methoxyphenoxy)-2-oksipropil]-4- (phenylenecarbonyl)piperazine,

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

1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-([4 - were)aminocarbonylmethyl]piperazine,

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

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

1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(4-triptoreline)aminocarbonylmethyl]piperazine,

1-[3-(2-metilsulfonilmetane)-2-oksipropil]-4 -[(phenyl)aminocarbonylmethyl]piperazine,

1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(3,4 - methylenedioxyphenyl)aminocarbonylmethyl]piperazine,

or

1-[3-(1-naphthyl)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine.

Further preference is given to compounds where R11and R12is methyl;

preferred of them is

1-[3-(2-methoxyphenoxy)-2 oxoprop which also includes optical isomers (+) and (-) and R - and S-isomers and mixtures thereof, covering both the individual isomers and to all possible mixtures thereof.

The invention also relates to pharmaceutically acceptable esters and salts with acids, in particular mono - and diclorhidrato and their mixtures.

Obtaining compounds of formula (I) is possible as described below.

The following sequence of reactions 1 and 2 respectively are complementary processes linking the two "halves" of the compounds of formulas (I) through pieperazinove ring.

The following sequence of reactions X represents tsepliaeva group, for example halogen or complex sulfanilyl ether, preferably halogen. The initial substances for carrying out the following sequence of reactions was prepared as follows:

< / BR>
The sequence of reactions 1.

The compound of formula A', where Ar1has the above value, obtained by reaction of interaction of the corresponding phenol, 2,3-isopropylidene-1-desipramine, by hydrolysis with aqueous acid, the reaction of interaction with methanesulfonamido or toluensulfonate, with subsequent reaction of interaction with sodium hydroxide, as is well known to everyone in specialissue A) receive interaction unsubstituted or substituted phenol or thiophenol with epichlorohydrin in the presence of such strong bases, as TRITON B, trialkylamine, hydroxide, alcoholate or hydrides of alkali metals, for example, hydroxide, methanolate or sodium hydride or potassium. The reaction is carried out in an inert solvent like methanol, ethanol, dimethylformamide, dimethylsulfoxide and the other at room temperature for 20 h [G. Shtacher et al. J. Med. Chem. so 16, No. 5, pages 516 and the following (1973)]

Phenols and thiophenol readily available or otherwise they can easily get the well-known methods. For example, many of substituted phenols available in the trade, including methyl-, dimethyl-, trimethyl-, ethyl-, diethyl-, propyl-, butyl-, methoxy-, dimethoxy-, trimetoksi, ethoxy, diethoxy-, propoxy-, butoxy-, cyano-, chloro-, dichloro-, trichloro-, tetrachloro-, pentachloro-, bromo-, dibromo-, tribromo-, fluorine-, debtor, trifter-, Brahler-, Brompton-, Harper-, methylthio, methylendioxy-phenols and their mixtures, according to Chemical Sources, published by Directories Publishing Company, Inc. Flemington, New Jersey, 1979.

Methylsulfinyl and methylsulfonyl substituted phenols get known methods from the corresponding methylthiophenol, which is available in Commerce or easy to obtain. So, for example, o-methylsulfinylphenyl receive treatment o-methylthiophenol of acetic anhydride is for the purpose of removal of acetyl groups in acidic or basic conditions are o-methylsulfinylphenyl. o-Methylsulfonylbenzoyl receive the processing result of the above ester with hydrogen peroxide or 2-chlormadinone acid in aqueous methanol. After hydrolysis for the removal of acetyl groups get good output o-methylsulfonylbenzoyl. The corresponding m - or p-substituted methylsulfinylphenyl and methylsulfonylbenzoyl get replacement o-methylthiophenol m-methyl - p-methylthiophenol, respectively.

These compounds of formula A can be transformed into compounds of formula D in the sequence of reactions 1 interaction received phenoxy-substituted epoxypropane with piperazine (formula B), by heating in a solvent, dissolving both reagents using known techniques (Caroon et al. as indicated above).

The compounds of formula E is obtained from available in the trading of the relevant derivatives of aniline, substituted aniline or N-substituted aniline of the formula G interaction with haloacrylates as chloride monochloracetic chloride or a-chloropropionyl (compounds of formula).

Many of substituted anilines available in the trade, including methyl-, dimethyl-, trimethyl-, ethyl-, diethyl-, propyl-, butyl-, methoxy-, dimethoxy-, trimetoksi, ethoxy, diethoxy-, propoxy-, butoxy-, Khor, Harper-, methylthio-, methylenedioxy-anilines and mixtures thereof. According to the link above Chemical Sources available in the trade too many N-alkylated aniline derivatives as N-methyl, N-ethyl-, N-propyl and N-butylaniline and substituted anilines.

Replaced by methylsulfinyl or methylsulfonyl anilines get well-known techniques on the basis of available trade corresponding methylthioinosine. For example, o-methylsulfinylphenyl receive treatment o-methylthioinosine with acetic anhydride to obtain the corresponding acetanilide, which is then treated with periodate sodium in methanol. After hydrolysis for the removal of acetyl groups in acidic or basic conditions are o-methylsulfinylphenyl. o-Methylsulfonylamino obtained by processing the above acetanilide hydrogen peroxide or 2-chlormadinone acid in aqueous methanol. After hydrolysis for the removal of acetyl groups get good output o-methylsulfonylamino. The corresponding m - and p-substituted methylsulfonylmethane and methylsulfonylmethane get replacement o-methylthioinosine m-stands and p-methylthioinosine, respectively.

The corresponding ethyl, propyl and butylthiourea p is didom. The corresponding ethyl - propyl - and butylsulfonyl and-sulfonanilide get replacement o-methylthioinosine appropriate ancilliaries on the above techniques.

Many N-alkyl-substituted anilines can be obtained well-known techniques, for example, processing unsubstituted or aryl-substituted anilines on this application haloalkyl as methyl chloride, ethyl chloride, propyl chloride, butyl chloride and the like in an appropriate solvent, e.g. diethyl ether or methylenechloride.

Many a-halogenallylacetic available in the trade, including, for example, chlorocatechol and 2-chloropropionate. 2-Harmaclona acid available in the trade and it can be converted into the acid chloride by the known methods as, for example, the reaction of interaction with thionyl chloride or pentachloride phosphorus. a or 2-chlorine substituted the acid chlorides, which are not easily accessible, you can get accepted methods, such as reaction type Hell-Volhard-Zelinsky, which corresponds alkalicarbonate acid is subjected to interaction with chlorine in the presence of phosphorus (R. T. Morrison and R. N. Boyd, Organic Chemistry, 2nd edition, Ch. 18, page 204 and Chem. Revs. so 7, page 180 (1930).

For the purpose of such re primary amine (as, for example, triethylamine or pyridine, preferably triethylamine) and chlorosilane dissolved in an inert aprotic organic solvent, such as benzene, chloroform, carbon tetrachloride, methylene or methylene chloride, preferably methylene chloride. Aniline and tert.-Amin used in approximately equimolar quantities, and acylchlorides enter in a slight molar excess, i.e., approximately 1.2 or 2, preferably of 1.3-1.5-molar excess compared to aniline. To add allvalid the mixture is cooled to approximately -10 +30oC, preferably in an ice bath. The mixture is maintained at this low temperature for about 0.5 to 8 hours, preferably for 4 h under stirring. The obtained condensed product formula E then emit known techniques.

The compounds of formula (I), where Ar1, Ar2, R1-R12and W have the abovementioned meaning, is produced by interaction of the compounds of formula D with compounds of formula E in the presence of a solvent, such as mixtures of toluene with methanol, ethanol, dimethylformamide, etc. of the Reaction mass is heated to a temperature approximately in the range 60-150oC, preferably priblizitel the by-products isolated and purified, if it is desired, using any suitable technique isolation and purification, for example by filtration, extraction, crystallization, column chromatography, thin-layer or thick-layer chromatography, or by combinations of these techniques. Suitable methods of separation and allocation are illustrated in the following examples. But, of course, you can use other equivalent methods of separation or discharge.

Salt also produce conventional techniques. For example, the reaction mass can evaporate to dryness and the resulting salt can be cleaned by ordinary methods.

The compounds of formula (I) obtained as a result of any of the described sequence of reactions may be in the form of R - or S - isomers (or Erythro - and threo-isomers). So, the proposed connection can be obtained or R-or S-configuration, or mixtures thereof. If the application otherwise indicated, the proposed compounds are a mixture of R - and S-configurations. However, the invention is not limited to the mixture of R - and S-configurations, and also covers all of the individual isomers of the proposed connections.

If desired, the mixture of intermediates used to produce compounds farmpolicy individual isomers of isomeric intermediates compounds of formula (I).

Alternative compounds of formula (I) can be obtained according to the sequence of reactions 2, where Ar1, Ar2, R1-R12and W have the above values.

< / BR>
The compounds of formula E is produced by interaction of the compounds of formula V with a compound of formula G, as described above in the sequence of reactions 1.

The compounds of formula W is obtained from the corresponding compounds of formula E interaction with piperazine (formula B) well-known techniques, the same techniques for the conversion of compounds of formulas D and E in the compounds of formula (I). In both cases, when carrying out this process, the halide is mixed with an excess of piperazine or substituted piperazine, in particular 3-5 molar excess, preferably 4 molar excess, in a polar organic solvent, for example ethanol or propanol, preferably ethanol or ethanol-water (50:50), after which the mixture is heated to a temperature in the range of 50-100oC, preferably to a temperature of reflux distilled solvent, for 1-4 hours, preferably 2 hours, the Product formula W emit conventional techniques.

Then the compounds of formula (I) receive and emit similarly, reaction of compounds of formulas a and B in the last final stage) methods sequences of reactions 1 and 2 is usually carried out in essentially similar ways. Compounds of formulas D and E or formulas a and W combine mainly in equimolar amounts in an aprotic organic polar solvent, for example dimethylformamide, tetrahydrofuran, etc. preferably dimethylformamide. The reaction mass is heated to a temperature in the approximate limits of 50-100oC, preferably 60-70oC, after which the temperature was raised to approximately 70-110oC, preferably 85-95oC, for about 1-24 hours, preferably over night. Then the condensed product of the formula (I) allot ordinary reception.

Due to the possible presence of two asymmetric carbon atoms of the proposed compounds of formula (I) can be in the form of mixtures of optical isomers. So we obtain the connection optically active form or as racemic mixtures.

If the application has not indicated otherwise, all described compounds are racemic form. However, the scope of the invention is not limited to a mixture of racemic forms, and covers all of the individual optical isomers.

If desired, racemic intermediates of the compounds of formulas a, a', B, D, E, or W, or the target product, i.e. of the formula (I) can be divided by natalizia) of the diastereomeric salts, obtained by the interaction between, for example, racemic compounds of formula (I) or the intermediate compounds of formulas a, a', B, D, E or F with an optically active acid. Examples of such optically active acids are the optically active forms of camphor-10-sulphonic, bromocamphor - p-sulphonic, camphor, methoxybutanol, tartaric, malic, diatsetilvinny, pyrrolidone-5-carboxylic acid, etc. and, if necessary, bases, for example, canonizing, bruinooge or other Separated pure diastereomeric salt can then be split conventional techniques in order to obtain the respective optical isomers of the compounds of formula (I) or intermediates of formula a, a', B, D, E or G.

The compounds of formula (I) can be isolated in the form of free bases, but it is usually more convenient to allocate the proposed connection in the form of salts with acid. These salts get in the usual way, i.e. by the interaction of the free base with a suitable organic or inorganic acid, for example, with one of the above-mentioned pharmaceutically acceptable acids. The basis of the formula (I), dissolved in such areagirls solvent, such as alcohol (e.g. methanol or ethanol) or ether (e.g., dietert acid solution to complete the precipitation of the salt. The reaction is carried out at a temperature in the range of 20-50oC, preferably at room temperature. If desired, the salt can be easily converted to the free base, for example, processing in the potassium carbonate or sodium, or ammonium hydroxide, potassium or sodium.

The compounds of formula (I) in the form of the free base can be converted into a salt with the acid by treatment with suitable organic or inorganic acid, such as phosphoric acid, pyruvic acid, hydrochloric or sulfuric acid and other Typical implementation of this method is the dissolution of the free base in a polar organic solvent, for example ethanol or methanol, and added to it the acid. The temperature is kept in the range of about 0-100oC. the Obtained salt with acid spontaneously precipitates, or can select from a solution with a less polar solvent.

Salts of acid compounds of the formula (I) can be disposed on the corresponding free base by treating such suitable base such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, at a temperature in the range of about 0-100othe body.

Pharmaceutically acceptable esters of compounds of formula (I) and pharmaceutically acceptable layers with their acid ester is treated with an excess of approximately 1.1 to 2 equivalents of the appropriate acid anhydride or acylhomoserine in the presence of a catalyst (e.g. pyridine) at a temperature in the range from about -10oC to approximately +10oC for about 0.5 to 12 h, and these conditions the reaction is known and is described in the following examples (relevant sections of the above mentioned publications Morrison and Boyd, and Fieser Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Ins. New York, 1967). Received suitable esters include acetates, propionate, butanoate, hexanoate, octanoate, dodecanoate and other Pharmaceutically acceptable acid additive salts of esters of compounds of formula (I) is then processed according to the following examples 6, 8, or 9.

Salts of compounds of formula (I) can be exchanged with each other using differential solubilities and leucuta, or by processing respectively loaded ion exchange resin. This conversion is carried out at a temperature ranging from about 0oC to the boiling point is used as the solvent environment.


Alternative compounds of formula (I) are obtained as follows:

Subjected to interaction unsubstituted or substituted 1-(aryloxy) or 1-(arieti)-2,3-epoxypropane (formula A) with N-substituted piperazine (formula F) [which according to one variant can be created by combining 2-halogenlithiumcarbeniod of halide (formula V) with unsubstituted or substituted aniline (formula G) in order to obtain the compounds of formula E, which is combined with piperazine (formula B)]

The alternate connection of the formula (I) is obtained by transforming a salt of the formula (I) in free base using a stoichiometric excess of base.

Alternative free base of compounds of formula (I) is transformed into a pharmaceutically acceptable salt of the acid with the use of stoichiometric amount acceptable acid.

Alternative salt of compounds of formula (I) is transformed into another salt of the compounds of formula (I) with a stoichiometric excess of other acceptable acid.

One of the ways of obtaining the proposed compounds are subjected to interaction of the first reactant, which represents a piperazine, wearing one of the side chains of the compounds of formula (I), with the first reagent was one of the foregoing compounds of formula D or W, and the other reagent corresponding compound of formula E or A.

The usefulness and application.

It was shown that the proposed connections provide the blockade of receipt of calcium and b-blockade in the test drugs animal drugs in vitro and when injected into the animal tissue culture [Kent et al. Federation Proceedings, volume 40, pages 724 (1981); Killam et al. Federation Proceedings, T. 42, page 1244 (1983); Cotten et al. Journal Pharm. Exp. Therap. so 121, pages 183-190 (1957)], it Was shown that the proposed compounds are effective in animal models for treatment of diseases of the cardiovascular system, for example, arrhythmia, angina and myocardial infarction. Therefore, these compounds are useful in the treatment of diseases of the cardiovascular system, in particular myocardial infarction, angina at rest and during movement of the body, and arrhythmia in mammals, particularly in humans.

The use of the claimed active compounds and salts by any accepted method of applying therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous application and other system application methods. The preferred method of administration is oral, except in those cases where the pain is Yu parenteral.

Depending on the intended mode of application of the composition can be in the form of solid, semi-solid or liquid preparative forms, for example, in the form of tablets, suppositories, pills, capsules, powders, liquids, suspensions, or other preferably in the form of unit dosage forms suitable for single administration of certain doses. The compositions contain conventional pharmaceutical excipient and an active compound of the formula (I) or its pharmaceutically acceptable salt, and optionally, they may include other medicinal or pharmaceutical agents, carriers, adjuvants, diluents, etc.

The amount of applied active compounds depends, of course, treat the patient, weight, extent of disease, route of administration of drugs and judgement prescribing medicine physician. However, the effective dosage ranges from 0.1 to 10 mg/kg per day, preferably 0.5 to 5 mg/kg per day. Per person weighing 70 kg, this dose equals 7-700 mg per day, or preferably 35-350 mg per day.

Since all steps of the proposed compounds (protivojinfectini action, action against angina at rest and during movement of the body and so the I) are in the same General and preferred ranges.

As solid compositions can be applied conventional non-toxic solid substances, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, glucose, sucrose, magnesium carbonate and other Videopreteen active compound may be in the form of candles, and as the carrier is used, for example, polyalkylene glycols, such as propylene glycol. Liquid pharmaceutical drugs can, for example, be obtained by dissolving, dispersing, etc. videopreteen active compounds and, if necessary, pharmaceutical impurities in the environment excipient, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc. in order to obtain a solution or suspension. If it is desired to be applied pharmaceutical composition may additionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, agents having a buffer action in relation to the pH value, etc. as, for example, sodium acetate, monolaurate sorbitan, triethanolaminato sodium, triethanolamine oleate, etc. Existing methods for such preparative forms known the least applied composition or used the product contains a therapeutically effective amount of the active compound (or active compounds, respectively), i.e., in a quantity sufficient to relieve symptoms we treat the patient.

For oral administration of pharmaceutically acceptable nontoxic composition is formed by introducing any commonly used excipients, such as pharmaceutical types of mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium, carbonate, etc. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, drugs with a slow release of active principles, and so on, Such compositions can contain 10-95% of active early, preferably 1-70%

Parenteral application, as a rule, is carried out either subcutaneous or intravenous injection. Drugs for injection get in the form of conventional drugs, either in the form of liquid solutions or suspensions, solid forms suitable for dissolution or weighing in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, salt, dextrose, glycerol, ethanol, or etc., If desired, used in the pharmaceutical compositions can optionally contain minor amounts of nontoxic action in relation to the pH value, etc. as, for example, sodium acetate, monolaurate sorbitan, triethanolamine oleate, etc.

On the newly found method for parenteral use employ the technique of implantation system slow release of the current early to ensure a constant level of dosage (U.S. patent 3710795, which belongs to the prior art).

The following preparation methods and examples illustrate the invention. They cannot be understood in the sense of narrow or limit the scope of the invention.

Method of obtaining A. (Obtaining compounds of formula (A)

(a) In 76 g of 2-methoxyphenol dissolved in approximately 60 ml of water and 200 ml of dioxane containing 29 g of sodium hydroxide, slowly introducing a large excess of epichlorohydrin (80 g). The solution is stirred at the temperature of reflux distilled for 3 hours the Mixture is diluted with ether, washed with two portions of water and dried using anhydrous magnesium sulfate. Evaporation of the dried extract, followed by distillation of the residue receive the product 1-(2-methoxyphenoxy)-2,3-epoxypropane.

(b) Similarly, by (a), but using the stoichiometric equivalent of 2-METHYLPHENOL, 3-METHYLPHENOL, 4-METHYLPHENOL, 4-n-butylphenol, 2-methoxyphenol, 4-methoxy what orfanou, 4-methyl-5-chlorophenol, 3,4,5-trichlorophenol, 3,4,5-trimethoxyphenol, 3-methyl-4,5-dichlorophenol, 3-methyl-4-chloro-5-methoxyphenol, 2,3,4,5-tetrabromphenol, 3,6-dimethyl-4,5-dichlorophenol, 4-triptoreline, 4-methylthiophenol, 4-n-butylthiophenol, 4-methylsulfinylphenyl, 4-n-butylaniline, 4-methylsulfinylphenyl, 4-n-butylsulfonyl, 2-cyanophora, 2-acetylphenol, 4-n-butanolide, 4-(N,N-dimethylamino)phenol, 4-(N,N-di-n-butylamino)phenol, 1-naphthol, thiophenol, or 4-methylpentyl instead of 2-methoxyphenol receive the following epoxy compounds of the formula:

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-butoxyethoxy)-2,3-epoxidic - pan,

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

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

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

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

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

1-(4-methyl-5-chlorophenoxy)-2,3-epoxi - Roman,

1-(3,4-5-trichlorophenoxy)-2,3-epoxypropane,

1-(3,4,5-trimethoxyphenyl)-2,3-epoxi

1-(2,3,4,5-tetrabromphenol)-2,3-epoxypropane,

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

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

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

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

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

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

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

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

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

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

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

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

1-[4-(N,N-di-n-butylamino)phenoxy]-2,3-epoxypropane,

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

1-(phenylthio)-2,3-epoxypropane, or

1-(4-methylphenylthio)-2,3-epoxypropane.

These compounds have a purity sufficient for use in the sequences of reactions 1 and 2.

(C) Similarly, by (a) this method get, but with the use of a stoichiometric equivalent amount of S-epichlorohydrin instead of epichlorohydrin, get good output R-1-(2-methoxyphenoxy)-2,3-epoxypropane.

(g) Similarly, by () this method get, but using studiesstudies R-substituted, phenoxy-epoxy compounds of formula A.

(d) Similarly, by (a) this method get, but with the use of a stoichiometric equivalent amount of R-epichlorohydrin instead of epichlorohydrin, get a good yield of the corresponding (S)-1-(2-methoxyphenoxy)-2,3-epoxypropane.

(e) Similarly, by (d) of the method of receipt, but with the use of a stoichiometric equivalent amount of R-epichlorhydrine instead of epichlorohydrin, and the substituted phenol instead of 2-methoxyphenol, get a good yield of the corresponding (S)-1-substituted-phenoxy--2,3-epoxypropane.

(g) Similarly, by (a), (b), (C), (d), (e) or (f), but using a stoichiometric equivalent amount of the substituted or unsubstituted derived fenistil instead of 2-methoxyphenol receive the respective R-, S - or R,S-1-(substituted or unsubstituted, phenylthio)-2,3-epoxypropane.

Method of obtaining B. Obtain [(2,6-dimetilfenil)-aminocarbonylmethyl]chloride.

(Compound of formula (E).

(a) 96 g (793 mmole) of 2,6-dimethylaniline and 96 g (130 ml) of triethylamine (tea) dissolved in 1 l of methylene chloride. The mixture is cooled in ice, then slowly add the acid chloride Chloroacetic acid number 89,6 g (800 mmol). The mixture plumage is estevadeordal acid and concentrated in vacuo. Add hexane for precipitation of the product, [(2,6-dimetilfenil)aminocarbonylmethyl]-chloride, the crude product is filtered, washed and dried. Receive the output of 130 g of product with a purity sufficient for use in sequencing reactions 1 or 2.

(b) Proceeding as above, using a stoichiometric equivalent amount of aniline, 2-Chloroaniline, 3-Chloroaniline, 4-Chloroaniline, 2-bromoaniline, 3-bromoaniline, 4-bromoaniline, 2-foranyone, 2-foranyone, 4-foranyone, 2-methylaniline, 3-methylaniline, 4-methylaniline, 4-n-butylaniline, 2-methoxyaniline, 3-methoxyaniline, 4-methoxyaniline, 4-n-butoxyaniline, 2-triptorelin, 3-triptorelin, 4-triptorelin, 2,6-dichloraniline, 3,5-dimethoxyaniline, 3,4-methylenedioxyaniline, 2-chloro-5-methylaniline, 4-methylthioinosine, 4-methylsulfinylphenyl, 4-methylsulfinylphenyl, 4-methylsulfonylamino, 4-n-butylthiourea, 4-n-butylaniline, 4-n-butylsulfonyl, 3,4-diferencia, 4-chloro-3-triptorelin, 4-fluoro-3-triptorelin, 2,5-diethoxyaniline, 2,4,5-trichloroaniline, 3,4,5-trimethoxyaniline, 2,4,5,6-tetrachloroaniline, 2,3,4,6-tetramethylaniline, 2,3,4,5,6-pentachloroaniline, 3-chloro-2,4,6-trimethylaniline, 2-cyanoaniline, 4-(Aset the-2,6-dimethylaniline, or N-n-butyl-2,6-dimethylaniline

instead of 2,6-dimethylaniline get the following substituted chlorides of the formula E:

(phenylenecarbonyl)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-forfinal)aminocarbonylmethyl]chloride,

[(3-forfinal)aminocarbonylmethyl]chloride,

[(4-forfinal)aminocarbonylmethyl]chloride,

[(2-were)aminocarbonylmethyl]chloride,

[(3-were)aminocarbonylmethyl]chloride,

[(4-were)aminocarbonylmethyl]chloride,

[(4-n-butylphenyl)aminocarbonylmethyl]chloride,

[(2-methoxyphenyl)aminocarbonylmethyl]chloride,

[(3-methoxyphenyl)aminocarbonylmethyl]chloride,

[(4-methoxyphenyl)aminocarbonylmethyl]chloride,

[(4-n-butoxyphenyl)aminocarbonyl - til]chloride,

[(2-triptoreline)aminocarbonylmethyl]chloride,

[(3-triptoreline)aminocarbonylmethyl]chloride,

[(4-triptoreline)aminocarbonylmethyl]chloride,

[(2,6-dichlorophenyl)aminocarbonylmethyl]chloride,

[(3,5-dimethoxyphenyl the Nile)aminocarbonyl - methyl]chloride,

[(4-methylthiophenyl)aminocarbonyl - til]chloride,

[(4-methylsulfinylphenyl)aminocarbonylmethyl]chloride,

[(4-methylsulfinylphenyl)aminocarbonylmethyl]chloride,

[(4-n-butylthiophene)aminocarbonylmethyl]chloride,

[(4-n-butylsulfonyl)aminocarbonylmethyl]chloride,

[(4-n-butylsulfonyl)aminocarbonylmethyl]chloride,

[(3,4-differenl)aminocarbonylmethyl]chloride,

[(4-chloro-3-triptoreline)aminocarbonylmethyl]chloride,

[(4-fluoro-3-triptoreline)aminocarbonylmethyl]chloride,

[(2,5-dioxyphenyl)aminocarbonylmethyl]chloride,

[(2,4,5-trichlorophenyl)aminocarbonylmethyl]chloride,

[(3,4,5-trimethoxyphenyl)aminocarbonylmethyl]chloride,

[(2,4,5,6-tetrachlorophenol)aminocarbonylmethyl]chloride,

[(2,3,4,6-tetramethylene)aminocarbonylmethyl]chloride,

[(2,3,4,5,6-pentachlorophenyl)aminocarbonylmethyl]chloride,

[(3-chloro-2,4,6-trimetilfenil)aminocarbonylmethyl]chloride,

[(2-cyanophenyl)aminocarbonylmethyl]chloride,

[(4-acetamidophenyl)aminocarbonylmethyl]chloride,

[(4-N-methylacetamide)aminocarbonylmethyl]chloride,

[(4-N-n-butylacetamide)aminocarbonylmethyl]chloride,

[(N-methyl-N-(phenyl)aminocarbonylmethyl]chloride,

[(N-n-butyl-N-(phenyl)aminocarbonyl - methyl]harbormaster]chloride,

having a purity sufficient for use in sequencing reactions 1 or 2.

(C) Repeating the above method (a), using a stoichiometric equivalent amount of 2-chlorpropramide, 2-chloro-n-butanolate or 2-chloro-n-hexanophenone instead of chloroacetanilide get the following substituted chlorides of the formula E:

[(2,6-dimetilfenil)aminocarbonyl-1-ethyl]chloride,

[(2,6-dimetilfenil)aminocarbonyl-1-n-propyl]chloride, or

[(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]chloride,

(g) Repeating the above method (a), using a stoichiometric equivalent amount of aniline, N-methyl-2,6-dimethylaniline or N-n-butyl-2,6-dimethylaniline instead of 2,6-dimethylaniline and 2-chlorpropramide instead of chloroacetanilide, get the appropriate

(phenylenecarbonyl-1-ethyl)chloride,

[N-methyl-N-(2,6-dimetilfenil)aminocarbonyl-1-ethyl]chloride or

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-ethyl]chloride.

(d) Repeating the above method (a), using a stoichiometric equivalent amount of aniline, N-methyl-2,6-dimethylaniline or N-n-butyl-2,6-dimethylaniline instead of 2,6-dimethylaniline and 2-chloro-n-hexanophenone instead chloric is phenyl)aminocarbonyl-1-n-pentyl]chloride, or

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]chloride.

Method of obtaining Century, Obtaining 1-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine.

(Compound of formula G).

(a) 50 g (0.25 mole) obtained according to method B. the crude [(2,6-dimetilfenil)aminocarbonylmethyl] chloride and 86 g (1 mol) of piperazine dissolved in 500 ml of ethanol. The resulting mixture was heated under reflux for 2 h, then cooled and evaporated. The product distinguish by injecting aqueous ammonia to the residue and extraction of methylene chloride. Apply three portions of methylene chloride, which is collected, washed with water and evaporated to a semi-solid state. Due to the addition of ether, the product crystallized, after which it is filtered. The resulting crude mixture is boiled with the use of ether, after which it is evaporated to obtain a residue and triturated with hexane to obtain pure material - 1-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine. This material has a purity sufficient for use in sequencing reactions 1 or 2.

(b) Similarly, repeating the above method (a), using the stoichiometric equivalent

phenyleneoxymethylene,

[the l)aminocarbonylmethyl]chloride

[(3-chlorophenyl)aminocarbonylmethyl]chloride

[(2,6-dichlorophenyl)aminocarbonylmethyl]chloride

[(2,4,6-trimetilfenil)aminocarbonyl - methyl]chloride

[(3,5-acid)aminocarbonylmethyl]chloride

[(4-methylthiophenyl)aminocarbonyl - til]chloride

[(4-n-butylthiophene)aminocarbonylmethyl]chloride

[(4-methylsulfinylphenyl)aminocarbonylmethyl]chloride

[(4-n-butylsulfonyl)aminocarbonylmethyl]chloride

[(4-methylsulfinylphenyl)aminocarb - ylmethyl]chloride

[(4-n-butylsulfonyl)aminocarbonylmethyl]chloride

[(4-triptoreline)aminocarbonylmethyl]chloride

[(2-chloro-5-were)aminocarbonyl - methyl]chloride

[(3,5-differenl)aminocarbonylmethyl]chloride

[(4-chloro-3-triptoreline)aminocarbonylmethyl]chloride

[(4-fluoro-3-triptoreline)aminocarbonylmethyl]chloride

[(2,6-dioxyphenyl)aminocarbonyl - til]chloride

[(3-bromo-4-ethylphenyl)aminocarbonylmethyl]chloride

[(4-n-butylphenyl)aminocarbonylmethyl]chloride

[(4-isobutylphenyl)aminocarbonylmethyl]chloride

[(3,4,5-trimethoxyphenyl)aminocarbonylmethyl]chloride

[(2,3,4,5-tetrachlorophenyl)aminocarbonylmethyl]chloride

[(2,3,4,5,6-pentachlorophenyl)aminocarbonyl the chloride,

[(4-N-methylacetamide)aminocarbonylmethyl]chloride

[(4-N-n-butylacetamide)aminocarbonylmethyl]chloride

[N-methyl-N-(phenyl)aminocarbonyl-til]chloride

[N-n-butyl-N-(phenyl)aminocarbonylmethyl]chloride

[N-methyl-N-(2,6-dimetilfenil)amino - carbonylmethyl]chloride

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonylmethyl]chloride

[(2,6-dimetilfenil)aminocarbonyl-1-ethyl]chloride

[N-methyl-N-(2,6-dimetilfenil)amino - carbonyl-1-ethyl]chloride

[N-methyl-N-(2,6-dimetilfenil)amino - carbonyl-1-ethyl]chloride

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-ethyl]chloride

[(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]chloride

[N-methyl-N-(2,6-dimetilfenil)amino - carbonyl-1-n-pentyl]chloride, or

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]chloride

instead of [(2,6-dimetilfenil)aminocarbonylmethyl] chloride, get the following piperazines:

1-(phenylenecarbonyl)piperazine,

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

1-[(4-were)aminocarbonyl - til]piperazine,

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

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

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

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

1-[(4-n-butylthiophene)aminocarbonyl]piperazine,

1[(4-methylsulfinylphenyl)aminocarbonylmethyl]piperazine,

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

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

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

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

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

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

[(4-chloro-3-triptoreline)aminocarbonylmethyl]piperazine,

[(4-fluoro-3-triptoreline)aminocarbonylmethyl]piperazine,

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

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)aminocarb - boiler]piperazine,

[(2-cyanophenyl)aminocarbonylmethyl]piperazine,

[(4-acetamidophenyl)aminocarbonylmethyl]piperazine,

[(4-N-methylacetamide)aminocarbonylmethyl]piperazine,

[(4-N-n-butylacetamide) is aminocarbonylmethyl]piperazine,

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

1[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonylmethyl]piperazine,

[(2,6-dimetilfenil)aminocarbonyl-1-ethyl]piperazine,

[N-methyl-N-(2,6-dimetilfenil)aminocarbonyl-1-ethyl]piperazine,

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-ethyl]piperazine,

[(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]piperazine,

[N-methyl-N-(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]piperazine,

or

[N-n-butyl-N-(2,6-dimetilfenil)aminocarbonyl-1-n-pentyl]piperazine,

having a purity sufficient for use in the sequences of reactions 1 and 2.

A method of obtaining, Obtaining 1-[3-(2-methoxyphenoxy)-2-oksipropil]-piperazine.

(Compound of formula D).

(a) Proceeding analogously to section (a) of the method of obtaining B, but using 1-(2-methoxyphenoxy)-2,3-epoxypropane instead of the original chloride, maintaining the reaction mixture at room temperature for 2 days, receive a corresponding compound of formula D, namely:

1-[3-(2-methoxyphenoxy)-2-oksipropil]piperazine.

(b) Similarly, repeating the above method [section (a)] with the use of a stoichiometric equivalent amount

1-(2-methylphenoxy)-2,3 is phenoxy)-2,3-epoxypropane,

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

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

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

1-(2-n-butoxyethoxy)-2,3-epoxypropane,

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

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

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

1-(2,4-dichlorphenoxy)-2,3-epoxypropan - on,

1-(3,4,5-trichlorophenoxy)-2,3-epoxypropane,

1-(3,4,5-trimethoxyphenyl)-2,3-epoxypropane,

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

1-(2,3,4,5-tetrabromphenol)-2,3-epoxypropane,

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

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

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

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

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

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

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

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

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

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

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

1-(4-N,N-dimethylaminoethoxy)-2,3-epoxypropane,

1-(4-N,N-di-n-butylamines)-2,3-epoxypropane,

1-(1-naphthoxy)-2,3-amodimethicone)aminocarbonylmethyl]chloride, get the following piperazines:

1-[3-(2-methylphenoxy)-2-oksipropil]piperazine,

1-[3-(2-methoxyphenoxy)-2-oksipropil]piperazine,

1-[3-(2-chlorophenoxy)-2-oksipropil]PI - perazin,

1-[3-(2-bromophenoxy)-2-oksipropil]PI - perazin,

1-[3-(4-methylphenoxy)-2-oksipropil]piperazine,

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

1-[3-(2-isopropoxyphenoxy)-2-oksipropil]piperazine,

1-[3-(2-n-butoxyethoxy)-2-oksipropil]piperazine,

1-[3-(4-chlorophenoxy)-2-oksipropil]PI - perazin,

1-[3-(2,4-dimethylphenoxy)-2-oxypro - MPI]piperazine,

1-[3-(2,4-dichlorophenoxy)-2-oksipropil]piperazine,

1-[3-(3,4,5-trichlorophenoxy)-2-oksipropil]piperazine,

1-[3-(3,4,5-trimethoxyphenyl)-2-oksipropil]piperazine,

1-[3-(3-methyl-4-chloro-5-methoxyphenoxy)-2-oksipropil]piperazine,

1-[3-(2,3,4,5-tetrabromphenol)-2-oksipropil]piperazine,

1-[3-(2,6-dimethyl-3,4-diclofenac)-2-oksipropil]piperidin,

1-[3-(4-triptoreline)-2-oksipropil]piperidin,

1-[3-(4-methylthiophene)-2-oksipropil]piperazine,

1-[3-(4-methylsulfinylphenyl)-2-oksipropil]piperazine,

1-[3-[4-methylsulfonylbenzoyl)-2-oksipropil]piperazine,

1-[3-(4-n-butylthiophene)-2-oksipropil]piperazine,

1-[3-(4-n-butylsulfonyl)-2-oksipropil]piperazine,
1-[3-(4-n-butanoyloxy)-2-oksipropil]piperazine,

1-[3-(4-aminocarbonylmethyl)-2-oksipropil]piperazine,

1-[3-(4-N,N-dimethylaminoethoxy)-2-oksipropil]piperazine,

1-[3-(4-N,N-di-n-butylamines)-2-oksipropil]piperazine,

1-[3-(1-naphthoxy)-2-oksipropil]piperazine,

1-[3-(phenylthio)-2-oksipropil]Pipera - zine, or

1-[3-(4-methylphenylthio)-2-oksipropil] piperazine.

(C) Similarly, repeating the above method [section (a)] with the use of a stoichiometric equivalent amount of R-3-(2-methoxyphenoxy)-2,3-epoxide instead of 3-(2-methoxyphenoxy)-2,3-epoxide, get the appropriate R-1-[3-(2-methoxyphenoxy)-2-oksipropil]piperazine.

(g) Similarly, repeating the above method [section (a)] with the use of a stoichiometric equivalent amount of one of the R-substituted, phenoxy-2,3-epoxides obtained by the method of A [section (b)] instead of 1-(2-methoxy)-2,3-epoxypropane receive the corresponding R-[3-(substituted phenoxy)-2-oksipropil]piperazine.

(d) Similarly, repeating the above method [section (a)] with the use of a stoichiometric equivalent amount of S-1-(2-methoxyphenoxy)-2,3-epoxypropane instead of 1-(2-methoxyphenoxy)-2,3-epoxypropane receive the appropriate S-1-[3-(2-detoxifies stoichiometric equivalent amount of one of S-1-(substituted phenoxy)-2,3-epoxypropanol, obtained by the method of A [section (d)] instead of 1-(substituted phenoxy)-2,3-epoxypropane receive the appropriate S-1-(substituted phenoxy)-2-oksipropil]piperazine.

(g) Similarly, repeating the above method [section (a)] with the use of a stoichiometric equivalent amount of a mixture of one of the R-and S-unsubstituted aryl, phenoxy-2,3-epoxides obtained by the method A[sections (d) or (e)] instead of 1-(2-methoxyphenoxy)-2,3-epoxypropane, get the appropriate mixture of R - and S-unsubstituted or substituted aryl, phenoxy-2-oksipropil/piperazine.

Example 1. Obtaining 1-[3-(2-methoxyphenoxy)-2 - oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine (sequence of reactions 1)

(a) [(2,6-dimetilfenil)aminocarbonylmethyl]chloride according to method B [section (a)] (12.9 g, 65 mmol) and 1-[3-(2-methoxyphenoxy)-2-oksipropil] piperazine according to method G [section (a) (15 g, 65 mmol) are mixed in 100 ml of dimethylformamide. For the dissolution of the components of the resulting mixture was stirred at 65oC and then at 90oC during the night. The entire mixture was added to water and acidified with hydrochloric acid. The resulting homogeneous mixture is washed with ether, after which it podsalivayut ammonia and the and water, after which it is evaporated to obtain 28 g of oil. Last purify by chromatography using 500 g of silica gel with 5% methanol in methylene chloride. 20 g of the obtained yellow oil was dissolved in methanol and vykristallizovyvalas the addition of hydrochloric acid. The complete precipitation by adding ether. The result is 16 g of oily product-1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6 - dimetilfenil)aminocarbonylmethyl]piperazine.

Due to the fact that 1-[3-(2-methoxyphenoxy)-2-oksipropil]piperazine, in accordance with the method of obtaining G has undefined stereochemical at the carbon atom in position 2 circuit, this connection and substituted compounds in the following subsections (b), (C) and (d) are obtained as mixtures of R-and S-isomers, respectively.

(b) Similarly, section (a), but using a stoichiometric equivalent amount of one of the substituted chloride compounds obtained in accordance with method B, instead of 1-[(2,6-dimetilfenil)aminocarbonylmethyl] chloride receive the corresponding 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(substituted phenyl)aminocarbonylmethyl]piperazine.

An example of such compounds is: 1(1) 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(4-ativan the use of a stoichiometric equivalent amount of one of the substituted chloride compounds, described in accordance with the method of obtaining B instead of 1-[(2,6-dimetilfenil)aminocarbonylmethyl]chloride and a stoichiometric equivalent amount of one of the substituted piperazinone compounds described in connection with method of obtaining G [section (b) instead of 1-[3-(2-methoxyphenoxy)-2-oksipropil]piperazine get the appropriate 1-[3-(substituted phenoxy)-2-oksipropil]-4- [(substituted phenyl)aminocarbonylmethyl]piperazine.

An example of such compounds is: 1(2) 1-[3-(2-methylphenoxy)-2-oksipropil] -4-[(3 - triptoreline)aminocarbonylmethyl] piperazine, melting point 162oC.

Example 2. Obtaining 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine (sequence of reactions 2)

(a) 1-(2-methoxyphenoxy)-2,3-epoxypropane (2.0 g) in accordance with the method of obtaining and 4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine (2.5 g) was dissolved in 20 ml of methanol and 40 ml of toluene. The resulting solution dephlegmator for 5 h, evaporated and chromatographic on silica gel using 5% methanol/methylene chloride as eluent. Then add an excess of hydrochloric acid in methanol, resulting in a gain dihydrochloride salt, which widely is another method of 1-(2-methoxyphenoxy)-2,3-epoxypropane (of 3.78 g) in accordance with the method of obtaining and 4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine (4.94 g) was dissolved in 25 ml of isopropanol, then the resulting solution was heated under reflux for 3 hours, the Hot solution is filtered and acidified with methanolic solution of hydrogen chloride. The resulting mixture is heated on the steam bath and induce crystallization by scratching on the inner surface of the flask. After cooling, is filtered off dichloride salt, 7,3 g, melting point 224-225oC.

Analysis for C24H35N3O4Cl2(0.5 H2O):

calculated C 56,58; H7,12; N 8,25;

found, C 56,38; H 7,27; N 8,11;

1H NMR (DMSO-d6d are 2.19 (s, 6H); 3,30-3,55 (m, 2H, CH2N); of 3.78 (s, 3H, OCH3; 3,60-of 3.85 (m, 8H, piperazine CH2); 3,90-4,08 (m, 2H, OCH2); of 4.35 (s, 2H, NCH2CO) of 4.45 (m, 1H, CHOH); 6,85-was 7.08(m, 3H); 7,10 (s,4H): 10,32 (s, 1H, NH).

Due to the fact that 1-(2-methoxyphenoxy)-2,3-epoxypropane in accordance with the method of obtaining And [section (a)] is undefined stereochemical at the carbon atom in position 2 of the ring, this compound and the substituted compounds of the following sections (b), (C), and (g) are obtained as mixtures of R - and S - configuration.

(b) Similarly, section (a), but using a stoichiometric equivalent amount of one of the substituted phenylpiperazine compounds described in connection with method B, instead of ropyl]-4-[(substituted phenyl)aminocarbonylmethyl]piperazine.

Examples of such compounds listed in example 1 [section (b)]

(C) Similarly, section (a), but using a stoichiometric equivalent amount of one of the substituted, phenoxy epoxy compounds described in connection with method of obtaining And [section (b)] instead of the epoxide get the appropriate 1-[3-(substituted phenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine.

Examples of such compounds are named in example 1.

(g) Similarly, section (a), but using a stoichiometric equivalent amount of one of the substituted phenylpiperazine compounds described in connection with a method of receiving, instead of 1-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and stoichiometric equivalent amount of one of the substituted phenoxyethoxy in accordance with the method of obtaining And, instead of 1-(2-methoxyphenoxy)-2,3-epoxypropane get the appropriate 1-[3-(substituted phenoxy)-2-oksipropil]-4-[(substituted phenyl)aminocarbonylmethyl]piperazine.

Examples of such compounds are described in example 1 [section (C)] and there is also

2(1) 1-[3-(phenoxy)-2-oksipropil]-4- (phenylenecarbonyl)piperazine, melting point 182oC.

Example 2A.

(a) Obtaining S-1-(2-methoxyphenoxy)-2,3-epoxypropane

(R)-2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich) (10 g) is transformed into toilet using p-toluensulfonate in pyridine in the usual reception. Toilet extracted to a solution of 2-methoxyphenol (15 years) and tert-butanolate potassium (13,4 g) MMF (100 ml) and the resulting mixture stirred for 3 h at 70oC. the Cooled mixture is diluted with water and the product emit extraction with ether. The obtained product is dissolved in 50 ml water, 50 ml of acetone and 5 ml of hydrochloric acid, after which the resulting mixture was heated under reflux for 30 minutes, the Mixture is evaporated under reduced pressure to obtain solid, which was washed with ether and filtered to obtain 12 g of diol 9,07oCH3OH), the melting point of 96-97oC.

The solution of this diol (11.3 g) in 80 ml of pyridine is cooled to -5oC, and then added dropwise to methanesulfonanilide (4.6 ml). The resulting mixture was added to water and extracted with ether. The ether is washed with 5% solution of hydrogen chloride, water and brine. Then evaporated to obtain a residue, which was dissolved in 50 ml of THF. Then minor portions add tert-butanolate potassium until the completion of reaction (by Dhatariya (50% ether-hexane) to obtain the S-epoxide, 4,9 12,2 goCH3OH).

(b) S-1-[3-(2-methoxyphenoxy)-2-oksipropil] -4- [(2,6-dimethyl-phenyl)aminocarbonylmethyl] piperazine is obtained from S - epoxide by the same technique that was used for the racemic compound in example 2(a), the melting temperature (as dihydrochloride) 226-230oC []D=10,3o(CH3OH).

Analysis for C24H35N3O4Cl2:

calculated C 57,60; H 7,05; N 8,39;

found, C 57,68; H 7,05; N by 8.22.

(AI) Obtaining R-1-[3-(methoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine

(a) Obtaining R-1-(2-methoxyphenoxy)-2,3-epoxypropane

R-1-(2-methoxyphenoxy)-2,3-epoxypropan receive in accordance with the technique described Caroon et al. J. Med. Chem. 24, 1320 (1981).

(b) R-1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(2,6-dimethyl-final)aminocarbonylmethyl] piperazine is obtained from the R-epoxide the same method that was used to obtain the racemic compound in example 2(a), the melting temperature (as dihydrochloride) 220-222oC +9,84 (CH3OH).

Example 2B. Obtaining 1-[3-(4-dimethylaminoethoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine

(a) 1-(4-nitrophenoxy)-2,3-epoxypropan obtained from 4-NITROPHENOL, p-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine is obtained from 1-(4 - nitrophenoxy)-2,3-epoxypropane and 4 -[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine technique used in example 2(a).

(b) Is 4-nitro-restore connection to the corresponding 4-amino compound by hydrogenation in the presence of PtO2in methanol as reaction medium. The reaction is complete after one hour, then add an excess of formaldehyde to the environment, which is heated in an atmosphere of hydrogen for 2 h at 40oC. and Then evaporated the solvent, after which the resulting residue is purified column chromatography (silica gel) using MeOH/CH2Cl2(1/9) as eluent, and receive the above-mentioned connection. Trichloride salt of this compound receive in accordance with example 2(a), melting point 192oC connection 2(2).

(g) Similarly, the target product can be obtained by using 4-dimethylaminophenol as source material.

Example 3. Obtaining salts of compounds of formula I.

(a) the Solution to 0.70 g of 1-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine and 0.71 g of 1-phenoxy-2,3-epoxypropane in 20 ml toluene and 20 ml of methanol is collected and heated at the temperature of reflux distilled for 12 hours In the evaporation and chromatography of the were)aminocarbonylmethyl] piperazine which is then dissolved in methanol containing excess hydrogen chloride, and precipitated with ether to obtain dihydrochloride salt, the melting point of 193-195oC.

(b) Similarly, section (a), but using the corresponding 1-(Deputy allumination)piperazine according to method B instead of 1-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine get a connection example in the form of dihydrochloride salts.

Example 4.

(a) Similarly, using one of the methods of examples 1, 2 or 3 receives the connection of the formula I and in example 3 or 5, the following compounds in the form of cleaners containing hydrochloride or dihydrochloride salts. If desirable, the following compounds of example 4 and salts are converted into the free base using reception of examples 6 and 9, respectively, or in other salt according to example 7.

1-[3-(2-cianfrocca)-2-oksipropil]-4-[(2,6 - dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, di-HCl, melting point 213-215oC,

4(1) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, R-di-HCl, melting point 220-222oC,

4(2) 1-[3-(4-chlorophenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)A2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, RS-di-HCl, melting point 195oC,

4(4) 1-[3-(3,4,5-trimethoxyphenyl)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 210oC,

4(5) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-(3,4-dichlorophenyl)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 192oC,

4(6) 1-[3-(2-acetylphenol)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride salt, R,S-di-HCl, melting point 195oC,

4(7) 1-[3-(4-aminocarbonylmethyl)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride salt, R,S-di-HCl, melting point 148-150oC,

4(8) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(4-methoxyphenyl)aminocarbonylmethyl)piperazine and dihydrochloride, R, S-di-HCl melting point 162oC,

4(9) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(3-forefeel)aminocarbonyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 169oC,

4(10) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[4(4-bromophenyl)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 170oC,

4(11) 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(2,6-acid)aminocarbonylmethyl] p is] -4-[(3,4-acid)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 132oC,

4(13) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(4-n-butylphenyl)aminocarbonylmethyl] piperazine and dihydrochloride salt, RS-di-HCl, melting point 180oC,

4(14) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2-methoxyphenyl)aminocarbonylmethyl] piperazine and dihydrochloride, RS-di-HCl, melting point 196oC,

4(15) 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(2,4-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 202oC,

4(16) 1-[3-(2-isopropoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 180oC,

4(17) 1-[3-(2-n-butoxyethoxy)-2-oksipropil] -4-[(2,6-acid)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, temperature melting 160oC,

4(18) 1-[3-(1-naphthoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 154-156oC,

4(19) 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(3-triptoreline)aminocarbonylmethyl] piperazine and dihydrochloride, R,S-di-HCl, melting point 158oC,

4(20) 1-[3-(phenoxy)-2-oksipropil]-4-[N-methyl-N -(phenyl)aminocarbonyl-1-ethyl]piperazine and digital]piperazine and dihydrochloride, di-HCl, melting point 148oC,

4(22) 1-[3-(4-chlorophenoxy)-2-oksipropil]-4-[N-methyl-N-(phenyl)aminocarbonyl-1-ethyl] piperazine and dihydrochloride, di-HCl, melting point 210oC,

4(23) 1-[3-(phenoxy)-2-oksipropil]-4-[(4-bromophenyl)aminocarbonylmethyl] piperazine, melting point 196oC,

4(24) 1-[3-(2,6-dimethoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine, melting point 190oC,

4(25) 1-[3-(4-cianfrocca)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine, melting point 180oC,

4(26) 1-[3-(phenoxy)-2-oksipropil]-4-[(3-triptoreline)aminocarbonylmethyl]piperazine, melting point 168oC,

4(27) 1-[3-(3-triptoreline)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine, melting point 175oC,

4(28) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(3-methylthiophenyl)aminocarbonylmethyl]piperazine, melting point 166oC,

4(29) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(4-cyanophenyl)aminocarbonylmethyl]piperazine, melting point 177oC,

4(30) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(3-trifluoromethyl-4-chlorophenyl)aminocarbonylmethyl]piperazine, melting point 189oC,

4 (the 164oC,

4(32) 1-[3-(4-propylenoxide)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine, melting point 148oC,

4(33) 1-[3-(2-methylphenoxy)-2-oksipropil]-4-[(4-bromophenyl)aminocarbonylmethyl]piperazine, melting point 204oC,

4(34) 1-[3-(3-iodinase)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl]piperazine, melting point 190oC,

4(35) 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(3-trifluoromethyl-4-forfinal)aminocarbonylmethyl]piperazine, melting point 180oC.

Example 5. The transformation of the free base in salt.

8.0 g of 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine dissolved in methanol and acidified with methanolic solution of hydrochloric acid. The precipitate was washed with ether to obtain 7.0 g dihydrochloride salt of 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine, which has a melting point 224-225oC.

In a similar manner, all compounds of formula I in the form of the base obtained in accordance with examples 1,2,3 or 4, can be converted into the corresponding pharmacologically acceptable salts with acids by treatment with an appropriate acid, oxalic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, almond, methansulfonate, econsultancy, p-toluensulfonate and other similar acids.

Example 6. Turning salt into the free base.

1.0 g of 1-[3-(2-methoxyphenoxy)-2-oksipropil]-4-[(2,6-dimetilfenil)aminocarbonylmethyl] 2HCl suspended in 50 ml of ether is stirred with excess dilute aqueous potassium carbonate solution until the salt is completely dissolved. Then separate the organic layer, washed twice with water, dried with magnesium sulfate and evaporated to obtain 1-[3-(methoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonylmethyl] piperazine in the form of free base.

Similarly salts with acids obtained in accordance with example 5 is converted into the corresponding free base.

Example 7. Direct interchange salts with acids.

Acetate 1-[3-(2-methoxyphenoxy)-2-oksipropil] -4-[(2,6-dimetilfenil)aminocarbonyl] piperazine (1.0 g) is dissolved in 50 ml of 50% aqueous sulfuric acid, after which the resulting solution is evaporated to dryness. Then the product is weighed in ethanol and filtered, dried who is phenyl)aminocarbonylmethyl]piperazine

where R1hydrogen, lower alkyl or lower alkoxy;

R2hydrogen, lower alkoxy, halogen, trifluoromethyl or alkylthio;

R3hydrogen, lower alkyl, lower alkoxy, halogen or cyano;

R4hydrogen or lower alkoxy;

R5hydrogen or lower alkyl;

R6hydrogen, lower alkyl, lower acyl, lower alkoxy;

R7hydrogen, lower alkoxy, trifluoromethyl, halogen, or together with R6form the group-CH=CH-CH=CH-;

R8hydrogen, lower alkyl, lower alkoxy, halogen, aminocarbonylmethyl, cyano or di(lower)alkylamino;

R9and R10each nazwisko hydrogen or lower alkoxy;

R11and R12each independently hydrogen or lower alkyl;

W is oxygen,

and their pharmaceutically acceptable esters and acid additive salt.

 

Same patents:

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

-phenylpiperazine)ethyl] benzamide, possessing neuroleptic activity, and 3 - methyl-n-[2-(4-phenylpiperazine)ethyl]benzamide as a starting compound for the synthesis of" target="_blank">

The invention relates to new chemical compounds of the hydrochloride of 3-methyl-N-[2-(4-phenylpiperazine)ethyl]benzo - foreign formula I

< / BR>
(I) possessing neuroleptic activity, and 3-methyl-N-[2-(4-phenylpiperazine)ethyl] benzamide as starting compounds in the synthesis of hydrochloride of 3-methyl-N-[2-(4-phenylpiperazine)ethyl]benzo - Mead

The invention relates to new Daminova compounds and their acid additive salts and cerebral protective medicines containing these compounds or their salts, more particularly to Daminova compounds and their acid additive salts, which are characterized by excellent cerebral protective effect and are used as medicines in the treatment of disorders of cerebral function or to prevent the development of such disorders, and cerebral protective medicines containing diamino compounds or their acid additive salt

The invention relates to the production of new derivatives of N-acryloylmorpholine, which has antagonistic activity to РАF and useful for the treatment of various diseases and disorders in mammals (e.g. humans) associated with imbalance in the system РАF

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate

The invention relates to medicine, namely to psychiatry and neurology

The invention relates to new biologically active compounds 2-piperazinone, namely 3-(21-naphthylmethyl)-piperazine-2-ONU (I) and 1-N-ventilationperfusion-2-ONU (II) formula:

< / BR>
I R 2-naphthyl; RI=H;

II R C6H5; RIC6H5

-phenylpiperazine)ethyl] benzamide, possessing neuroleptic activity, and 3 - methyl-n-[2-(4-phenylpiperazine)ethyl]benzamide as a starting compound for the synthesis of" target="_blank">

The invention relates to new chemical compounds of the hydrochloride of 3-methyl-N-[2-(4-phenylpiperazine)ethyl]benzo - foreign formula I

< / BR>
(I) possessing neuroleptic activity, and 3-methyl-N-[2-(4-phenylpiperazine)ethyl] benzamide as starting compounds in the synthesis of hydrochloride of 3-methyl-N-[2-(4-phenylpiperazine)ethyl]benzo - Mead

The invention relates to new Daminova compounds and their acid additive salts and cerebral protective medicines containing these compounds or their salts, more particularly to Daminova compounds and their acid additive salts, which are characterized by excellent cerebral protective effect and are used as medicines in the treatment of disorders of cerebral function or to prevent the development of such disorders, and cerebral protective medicines containing diamino compounds or their acid additive salt

The invention relates to new nitrogen-containing heterocyclic compounds, in particular to derive hinzelin or benzodiazepina.beloe acid formula

(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

Up!