L-(-)-2-(aminocarbonyl)-n-(4-amino-2,6-dichlorophenyl-4[5,5 - bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate, method thereof, and means for storing heart donor

 

(57) Abstract:

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production. The method consists in the cyclization of (-)-(S, S)-N1-N2bis-(1-ventilated)-1,2-academia with 2,3-dibromopropionamide, the intermediate connection gidrogenit, reductive N-alkylate and restore. The tool is intended for storage heart transplantation in 24 hours in cold cardioplegic solution, 3 C. p. f-crystals.

The problem of relapse during recovery, circulation, i.e., the recovery of passing the blood through tissues and organs, previously deprived of their blood supply (for example, thrombosis, heart after open-heart surgery or heart transplantation) is the problem of further degeneration of this tissue or organ by leukocytes and their cytotoxic products.

The novelty of this invention is that the way to prevent or limit the risk of re-perfusion is carried out by applying special the emission at a significantly extended shelf life.

Compounds such as those described, are used in this invention; compounds known from U.S. patent N 4766125, was used as a means to protect the heart during myocardial damage caused by ischemia, anoxia or hypoxia.

Such compounds have also been described in U.S. patent N 4880808 as therapeutic agents, improves sleep and resisting sleep disorders.

The compounds of the present invention are (l)-(-)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,5-bis(4-forfinal)-pentyl] -1-piperazineethanol its pharmaceutically acceptable acid salt additive, its hydrated forms, in particular, mono and palpitate.

Acid additive salts can be obtained by processing the basic form of a suitable acid. These acids can be inorganic acids such as: kaleidotrope acid; hydrochloric or Hydrobromic acid; sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, for example acetic, propionic, glycolic, 2-propanoate, 2-oxopropionate, oxalic acid, perpendiculat, butanedioate, (Z)-2-butandikislota, (E)-2-butandikislota, 2-hydroxybutyrate, 2,3-dihydroxybutanedioate, 4-methylbenzenesulfonate, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-oxybenzone acid and so on, the Term "acid additive salt" includes a solvate, which claimed compounds and their acid additive salts are able to form. Examples of the solvate is a hydrate, alcoholate, etc., Mentioned compounds of greatest interest, brand new and have a unique combination of pharmacological selectivity and favorable characteristics that are not shared with the previously known compounds N-arylpiperazines. In addition, being highly potent, selective transport nucleoside inhibitors do not have the Ca2+antagonistic properties. They have a very low acute and chronic toxicity. Moreover, these compounds do not in any way bind plasma proteins, and therefore, they have a great bioprospect. This greatly simplifies their use in therapy, as they are easily absorbed, they can be used orally. In combination with the above properties, this method of assignment of these compounds makes them particularly suitable for prolonged use, for example, as a preventive credentia pure enantiomeric compounds is the fact that the number of prescribed medications can be reduced, due to the absence of unwanted inactive enantiomers. This is an advantage, because it reduces the likelihood of overdose and adverse side effects, such as inhibition of cardiac activity, caused by an overdose.

New connection (l)-(-)-2-(aminocarbonyl)-N-(4-amino-2,6 - dichlorophenyl)-4-/5,5-bis(4-forfinal)pencil/-1-piperazineethanol, of the formula (I)

< / BR>
can be obtained by starting from (-)-(S,S)-N', N'-bis(1-phenyl-ethyl)-1,2-academia.

< / BR>
which is subjected to cyclization to piperazine derivatives by double N-alkylation of 2,3-dibromopropionamide in an inert solvent in the presence of a base. Suitable solvents are aromatic hydrocarbons, such as benzene, methylbenzol and similar compounds; halogenated hydrocarbons, for example, tetrachlormethane, chlorobenzol, etc. Suitable bases may be carbonates of alkali and alkaline earth metals such as potassium carbonate and sodium. The cyclization is carried out by the reverse flow temperature (flegma) reactive mixture.

Intermediate compound 1 is converted into an intermediate compound 2 by restoring the complex ester is idarraga catalyst, such as charcoal with palladium or platinum plated, etc.

< / BR>
Intermediate compound 2 is restored N-alkylation by reaction with 5,5-bis(4-forfinal)metaldehyde in the atmosphere of hydrogen alkanol, for example, methanol, ethanol; in the presence of a hydrogenating catalyst, such as charcoal with palladium or platinum plated. To prevent interaction of the resulting reaction products in the mixture it is necessary to add a catalyst poison, such as thiophene. To increase the rate of reaction, the reaction mixture was slightly heated to a temperature of 40-60oC.

< / BR>
On the other hand, the intermediate compound 3 can be prepared N-alkylation of intermediate compound 2 5,5-bis(4-forfinal)pentane-1-halide or a sulfonate having the formula:

< / BR>
where

W halo, for example, chlorine or bromine; or sulfonyloxy is, for example, methanesulfonate, 4-methylbenzenesulfonate, etc. Specified alkylation can be carried out in an inert solvent, for example, in alkanol methanol, butanol, cyclohexanol: dipolar besprochen solvent, e.g. N, N-dimethylformamide, dimethyl sulfoxide; in the presence of a base hydroxides saloon the P> Thus obtained intermediate compound 3 N-alkylated with a reagent of the formula

< / BR>
where

W represents a reactive group, such as chlorine, bromine, etc. in an inert solvent in the presence of base

< / BR>
N-alkylation is carried out under stirring and heating of the reacting substances to a temperature of 70-100oC. Suitable solvents are methanol, ethanol, butanol, dipolar besplatnye solvents (N,N-dimethylformamide, dimethyl sulfoxide, or mixtures of these solvents. Suitable bases are hydroxides of alkali and alkaline earth metals, hydrogen carbonates, organic amines (N,N-diethylethanamine, pyridine, morpholine). To accelerate the reaction it is possible to add the alkali metal iodide, such as potassium iodide.

Intermediate compound 4 eventually turns into a new connection (l)-(-)-(1) in the recovery from nitro to amino.

< / BR>
This reduction can be performed in an inert solvent by known techniques of recovery. For example, the intermediate compound 4 was stirred in an atmosphere of hydrogen alkanol (methanol, ethanol) in the presence of a hydrogenating catalyst such as DCE recovery can be carried out by treatment of intermediate compounds 4 in such reagents as sodium sulfite, sodium sulfide, sodium sulfide, chloride titanium (III).

Another feature of the present invention is a method of storing heart intended for transplantation, in cardioplegic solution in the cold. The method includes the introduction to this cardioplegic solution in such an amount of compounds of formula I, which can prolong the storage of the heart.

Of particular interest is the fact that applying for storing heart intended for transplantation, cardioplegic solution containing the compound of the formula I, can greatly extend its shelf life. While the heart can be successfully stored for 4 hours, using conventional cardiac solution not containing the compounds of formula I in the cold; the novelty of the invention is the fact that during storage of the heart in a cold cardioplegic solution containing the compounds of formula I, can be extended shelf life of at least 24 hours. Thus, the present invention provides a method for storing heart intended for transplantation in a cold cardioplegic solution, mentioned above, where the donor heart is protected by a certain number of connections, keystone from 0.1 M to 10 m M, in particular from 0.5 to 5 m M, more specifically from 0.8 m M to 2 m M

Example 1. Preparation of (-)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5 - bis(4-forefeel)-pentyl]-1-piperazineethanol

A mixture consisting of 108,4 parts of (-)-(S,S)-N1-N2bis(1-phenyl-ethyl)-1,2-academia; 93.8 parts of 2,3-dibromopropionamide; 334,5 parts of potassium carbonate and 2958 parts of methylbenzol subjected to a process of reflux distilled within 24 hours using a water separator. The reagent mixture was filtered hot, and the residue is divided between water and dichloromethane. The organic layer was separarely and combined with the filtrate. All this was dried, filtered and evaporated. The residue was purified in column chromatography (Lichroprep PP18; H2O (0.5% OF CH3COONH4)/CH3CN55: 45/. The solvent for elution of the desired fraction was evaporated, the yield of the final product was 20.8 parts (15,4%) I(S), 2A,4 (S)-1,4-bis(1-phenylethyl)-2-piperazinecarboxamide (intermediate compound 1). IV

A mixture of 20.8 parts of intermediate 1 and 198 parts of methanol, was hydrogenosomal at normal pressure and at room temperature with two parts of 10% palladium catalyst on charcoal. After counting the number of absorbed hydrogen the catalyst from the Yes (intermediate compound 2). V

A mixture of 3.9 parts of the intermediate product (2); 8.3 parts of 5,5-bis(4-forfinal)-metaldehyde, (VI), two parts of thiophene in methanol (4% ) and 198 parts of methanol, was hydrogenatable at normal pressure and a temperature of 50oC with 2 parts of 10% palladium catalyst on charcoal. After counting the number of absorbed hydrogen, the catalyst was filtered and the filtrate evaporated. The residue was converted into atendimento Sol in ethanol. Sol was subjected to re-crystallization from a mixture of ethanol and methanol. The product was filtered, dried, the yield of the final product was 8.82 parts 61,6% ) (+)-4-[5,5-bis(4-forfinal)pentyl] 2-piperazinecarboxamide of atendimento (1:1); []2D010,02o(concentration of 0.5% DMF) (intermediate compound 3). VII

8,82 of the intermediate compound 3 was absorbed water and was transformed into the free base with NH4OH. The base was extracted with dichloromethane (3x), the combined extracts were dried, filtered and evaporated. To the residue was added 6.5 parts of 1-chloro-N-(2,6-sodium dichloro-4-nitrophenyl)ndimethylacetamide, 3.75 parts of N,N-diethylethanamine and 113 parts of N,N-dimethylformamide. All this was stirred for 2 days at a temperature of 70oC, and p is abusively, was filtered and evaporated. The residue was purified column chromatography (silica gel, CH2Cl2/CH2Cl21-10% CH3OH) 70:30). The solvent for elution of the required fractions were evaporated, and the residue was converted into cleaners containing hydrochloride salt in 2-propanol. The product was filtered and dried under vacuum at a temperature of 50oC, the yield of the final product was 3.78 parts(30,5%) (-)-2-(aminocarbonyl)-4-[5,5-bis- (4-forefeel)pentyl]-N-(2,6-sodium dichloro-4-nitrophenyl)-1-piperazine of ndimethylacetamide monohydrochloride; []2D0-18,47o(concentration of 0.5% in CH3OH) (intermediate compound 4). IX

A mixture of 3.6 parts of intermediate compound 4, one part of a solution of thiophene in methanol (4%), 119 parts of methanol, was hydrogenatable at normal pressure and room temperature with two parts of 10% palladium catalyst on charcoal. After counting the number of absorbed hydrogen, the catalyst was filtered and the filtrate evaporated. The residue was purified column chromatography (Lichroprep R-18; H2O (0.5% OF CH3COONH4)/CH3OH/CH3CN 40: 20: 40). The desired fraction was concentrated, the product was subjected to crystallization from the resulting aqueous solution. It was filtered off, dried enacarbil) -N-(4-amino-2,6-dichlorophenyl)-4-[5,5 bis(4-forfinal)-pentyl] 1-piperazineethanol hemihydrate; the melting point 123,4oC; []2D0-29,63o(concentration of 0.5% in CH3OH) (compound 1-b).

Example 2. Biological example.

Heart dogs stopped or hypersaline the NIH cardioplegia (group I, paragraph 6), or similar cardioplegia after adding 2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4[5,5 - bis(4-forefeel)pentyl] -1-piperazineethanol (group II, item 6). The heart was kept in the cold for 24 hours at a temperature of 0-5oC (ice water) in the cardioplegic solution, and then transplanted in the homologous region. The dog recipient was administered 0.1 mg/kg body weight of 2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5 - bis(4-forefeel)pentyl] -1-piperazineethanol before transplantation. Performed a biopsy showed on the content in the myocardial high-energy phosphates (HEP). In group I, ATP was 50% and CrP 18% of the control content after 24 hours of storage. During the 60-minute recovery of blood flow in pulmonary heart channel (CPB) content HEP decreased (p<0.05) and after transplantation, all animals developed "changed heart". After 24 hours storage in group II, ATF 82% and CrP=28% of the control (p<0,05 vs. group I). After transplantation the content HEP-oscarson, you can achieve an optimal preservation of the myocardium with a combination of cardioplegia and inhibiting the transport of nucleosides.

Example 3. Examples of the composition.

1. Solutions for injection:

the active ingredientx1 g

of 0.1 N hydrochloric acid 0,04 l

2-hydroxypropyl- -cyclodextrin 50 g

sodium chloride 5.5 g

1 sodium hydroxide pH of 3.7-3.9

water 1 liter

x2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,5-bis(forefeel)-pentyl]-1-piperazineethanol.

The method of preparation.

50 g of HP - b-cyclodextrin was dissolved in 0.5 l of water. Continuously added 0,04 l of 0.1 N hydrochloric acid and 1 g of the active ingredient. All mixed to obtain a light solution. After dilution with water to 0.9 l, was dissolved 5.5 parts of sodium chloride under stirring. Acidity regulated odnomomentnym sodium hydroxide to pH of 3.7-3.9. The solution was diluted with water to 1 l, the output of solution for injection contains 1 mg/ml of active ingredient.

2. Solutions for oral administration.

the active ingredientx1 g

2-hydroxypropyl - b-cyclodextrin 50 g

0,1 hydrochloric acid 0,04 l

sorbitol 70% 0,1 l

propilenglikolstearat mouth 1 g

IN the sodium hydroxide pH=4,0

purified water 1 l

x2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,5-bis(4-forefeel)pentyl]-1-piperazineethanol.

The method of preparation.

50 g of HP - b-cyclodextrin was dissolved in 0.6 l of water. Added continuously 0,04 l of 0.1 N hydrochloric acid and 1 g of the active ingredient. All mixed to obtain a transparent solution. Was dissolved by stirring 2 g of Na2(EDTA), and then added 0.1 l of 70% sorbitol. To the homogeneous solution was continuously added to a solution consisting of 3 g of benzoic acid in 0.1 liter of propylene glycol and 1 g of the fragrance liquid for rinsing the mouth. Acidity regulation IN sodium hydroxide to a pH of 3.7-3.9. The solution was diluted with water to 1 l, the yield of the final product solution for oral administration contain 1 mg/ml of active ingredient.

1. (L)-(-)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4- [5,5-bis(4-forfinal)pentyl] -1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate of formula I:

< / BR>
2. A method of obtaining a (L)-(-)-2-(aminocarbonyl)-N- (4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-forfinal)pentyl] -1 - piperazineethanol, characterized in that conduct the cyclization of (-)-(S,S)- N1N2bis(1-phenylethyl)th intermediate compound II

< / BR>
subjected to hydrogenation in a hydrogen atmosphere in the environment of the lower alcohol in the presence of a hydrogenation catalyst to obtain (+)-2 - aminocarbonyl Zina formula III

< / BR>
which reductive N-alkylate 5,5-bis(4-forfinal)metaldehyde in the atmosphere of hydrogen, the lower alcohol in the presence of a hydrogenation catalyst obtained piperazine derivative of formula IV

< / BR>
N-alkylate compound of formula V

< / BR>
where W means tsepliaeva group in the medium of reaction inert solvent, in the presence of base, followed by reduction of the obtained intermediate compound of formula VI

< / BR>
in the presence of a reducing agent in a reaction-inert solvent.

3. Means for storing heart donor containing an active ingredient and a neutral carrier, characterized in that as the active ingredient it contains an effective amount of the compounds on p. 1.

 

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