1,4-disubstituted piperazines, suitable for the treatment of asthma and inflammation of the respiratory tract, the method of production thereof, pharmaceutical preparations based on them and the way they are received

 

(57) Abstract:

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases. The method of obtaining compounds of formula (I) by reacting the compounds of formula (II) with the compound of the formula (III) with a compound of formula (Ia), which are converted into the compounds of formula (I) by transformation-COOR groups in the-COOH group. Medicine to reduce the increased bronchial reactivity, containing as active ingredient an effective amount of the compounds of formula (I), and the method of its production. 4 C. and 6 C. p. F.-ly, 1 table.

The invention relates to 1,4-disubstituted the piperazines of formula (I):

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their enantiomeric and diastereomeric forms, their mixtures and their salts of pharmaceutically acceptable acids and bases, in which:

B is-CO -,- CH2OCO -, - CH2OCS-, -CH2NHCO-, -CH2NHCS-group;

D is a 5-6-membered heterocycle with 1-3 nitrogen atoms, possibly substituted by 1 or 2 amino, mono-C1-C6-alkylamino, mono-C3-C7alkenyl - or mono-C3-C7-alkynylamino, di-C1-C6-alkylamino, (C1-C6)alkyl(C3-C7)alkenylamine, piperidine-1-yl, morpholine-4-yl, pyrrolidin-1-yl groups;

Ra and Rb are hydrogen, C1-C3-alkyl or taken together with the carbon atom to which they are attached, they form a C3-C6-cycloalkyl group;

n is an integer from 1 to 4.

Examples of C1-C3or C1-C6-alkyl groups are methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, tert-bucilina, n-pencilina, n-exilda.

Examples of 5 - or 6-membered heterocyclic group with 1-3 nitrogen atoms, possibly substituted by 1-2 amino groups are [2,6-bis(diethylamino)-4-pyrimidinyl], [2,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl], [3,6-bis(diethylamino)pyridine-2-yl] , [3,6-bis(pyrrolidin-1-yl)pyridin-2-yl] , [3,6-bis(allylamino)pyridine-2-yl] , [3,6-bis(propargylamine)pyridine-2-yl] , [3,6-bis(N-ethyl-N-allylamino)pyridine-2-yl], [3-ethylaminomethyl-2-yl].

Examples of mono-C1-C6-alkylamino are methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, tert-butylamino.

Examples of mono-C3-C6alkenyl or monoalkyl are allylamino, propargylamine.

Examples of di-C1-C6-alkylamino are dimethylamino, diethylamino, methylethylamine, methylpropylamine, methylethylenediamine, Diisopropylamine, methyl-n-butylamino.

Examples (C1-C6)alkyl-(C3-C7)alkenylamine are methylethylamine, ethylethylene, propylethylene, isopropylacrylamide. Ra and Rb are preferably hydrogen, stands, ethyl or together with the carbon atom to which they are attached, are cyclopropenes, cyclopentyloxy or tsiklogeksilnogo group.

Particularly preferred compounds (I) are those in which B represents-CO - or-CH2OCO-group; D is a heterocycle selected from the group, astrein-2-yl] [3-ethylaminomethyl-2-yl], Ra, which is the same as Rb is hydrogen or methyl, and n is 1.

Acidic or basic groups can form salts with pharmaceutically acceptable bases and acids. Non-toxic salts thus obtained, as well as single enantiomers, diastereomers, diastereomeric mixtures and racemates of the compounds of formula (I) are included in the scope of the invention.

The compound (I) can form salts with inorganic and organic acids which are pharmaceutically acceptable, for example, hydrochloric, Hydrobromic, idiscovered, phosphoric, metaphosphoric, nitric, or sulfuric, acetic, oxalic, tartaric, citric, benzoic, glycolic, gluconic, glucuronate, succinic, maleic, fumaric, etc. acids. Carboxypropyl can form salts with bases of different nature on one condition, namely that the salts are pharmaceutically acceptable. The examples mentioned salts include salts with ammonium, sodium, potassium, calcium, magnesium, aluminum, iron, zinc, copper, or salts with pharmaceutically acceptable organic bases, for example, arginine, lysine, histidine, methylamine, ethylamine, chinatelecom described as ACE-inhibitors (Sankyo Co. , JP 82 91, 987; C. A., 97: 1982 18W, 1982). N-carbamoylating N-methylpiperazine known as filariidae funds (Indian J. Chem., Sect. b, 1987, 26B(8), 748-751).

Compounds of the invention exhibit pharmacological properties, in particular, increased bronchial reactivity.

Bronchial increased reactivity is the clinical symptoms of asthma and it is assumed that it is a direct consequence of pathological and hidden contractility and sensitivity of the mucous membrane of the bronchi.

Bronchial increased reactivity can cause an acute crisis of asthma after physical activity and/or after exposure to an external stimulus, for example, inhalation of smoke or dust, standing in the air, air pollutants, allergens and physiologically active substances.

The state increased bronchial reactivity can be simulated experimental model, which consists in the injection of PAF (600/l) Guinea pigs male, weighing 400-450 g, which hold when forced ventilation under urethane and bromide analgesia.

PAF, which is one of the most important mediators involved in the inflammatory process of the Airways, after the m agents.

The activity of compounds of the invention considered in pharmacological models installed by preventing increased reactivity caused by PAF, measured in the form of increasing insufflating pressure in the pulmonary artery (measured in accordance with a modified method of Konzett u Rossler, Haun. Schmied. Anh. bxper. Pathol. Pharmacol. 191,71, 1970).

Compounds of the invention that is administered 10 minutes prior to the introduction of PAF doses, which vary between 2 and 50 g/kg, showing a protective effect, which lasts for at least 4-6 hours and leads to a reduction of the increased reactivity caused by PAF. Such pharmacological effects associated with a dose.

From the foregoing it is clear that the compounds of the invention can be used in human therapy, the treatment of asthma and clogged Airways, in the treatment of inflammatory processes.

For targeted therapeutic applications, the compounds of the invention can be introduced in the form of pharmaceutical preparations which can be obtained with conventional fillers, conventional methods, for example as described in Remington's Pharmaccutical Sciences Handbook, Mack Pub. Co., N. 4. USA, 17 08 ed. 1985, adapted for nutrimedical on several factors, for example, the severity of the pathology and the patient's condition: it usually ranges from 1 to 50 mg of the compounds of formula (I) to a patient weighing 70 kg, administered once or several times a day.

The compounds of formula (I) are obtained by reacting the compounds of formula (II)

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in which

B and D are as defined above, with a compound of formula (III)

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in which

Ra, Rb and n have the above meaning, R is C1-C6-alkyl, benzyl, allyl group or any other group that can be removed easily;

E is a halogen (chlorine, bromine), N-imidazolyl, OH, O-hydroxysuccinimidyl, or taken together with the carbonyl group, it forms a mixed anhydride with a carboxylic or an acid (for example, triftormetilfullerenov) to obtain compounds of formula (Ia)

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The compounds of formula (Ia) can be converted into compounds of formula (I) by conventional reactions, for example:

a) when R is C1-C6-alkyl, by hydrolysis with mineral bases, such as hydroxides of sodium, potassium, lithium different concentrations and in different solvents (e.g. methanol, ethanol, dimethylformamide);

b) when R is ellipi various concentrations, skeletal Nickel catalyst pallidicornis(triphenylphosphine) etc. and in different solvents (e.g. methanol, ethanol, toluene, methylene chloride) or by methods of transmission of hydrogen, for example with ammonium formate, cyclohexene or hypophosphite sodium, in the presence of palladium on coal in solvents such as water, lower alcohols or their mixtures.

The reaction of the compound (II) with compound (III) is usually carried out in an inert solvent and in the presence of a suitable base. When the E-CO - is carboxypropyl (E=OH), the reaction is carried out in an inert solvent and in the presence of a condensing means, for example, carbodiimides, isonitriles etc.

Obtaining compounds of formula (II) is carried out on the basis of the acid of formula (IV)

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in which

R' is a suitable protecting group which can be removed by the reactions described below and with functional groups present in the molecule. Conventional protective groups of the formula R' can be: tert-butoxycarbonyl, methoxycarbonyl, 9-peroxycarbonates, 2,2,2-trichlorocyanuric, allyloxycarbonyl, benzyloxycarbonyl. The compounds of formula (IV) are commercially available or they can get the above-mentioned compounds are not commercially available, as their enantiomerically pure forms, they can be dissolved in a common manner, for example, by salt formation with optically active bases and separation of the diastereomeric salts.

The conversion of compounds of formula (IV) in the compounds of formula (V)

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in which R' has videopreteen values, you can perform normal reactions.

In particular:

a) synthesis of compounds of formula (Va)

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proceeding from compounds of formula (IV) can be performed by turning carboxypropyl in Succinimidyl, acid chloride, mixed anhydride, imidazole or other reactive derivative carboxypropyl and their condensation with amines of the formula (VI)

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b) synthesis of compounds of formula (Vb)

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in which

X=O or S, proceeding from compounds of formula (IV),

can be done by restoring carboxypropyl or the corresponding mixed anhydride or a derivative of an ether carboxylic acid to the primary alcohol (CH2OH), which can be converted to carbamate or THIOCARBAMATE by reaction with carbonyl diimidazol or thiocarbonyldiimidazole and subsequently with an amine of formula (VI). Restore carboxypropyl Proline or its mixed anhydride to alcohol can podhodjashee;

c) synthesis of compounds of formula (Vc)

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in which

X= O or S, can be accomplished by transformation of alcohols obtained as described in paragraph (b), the appropriate amine according to the reaction Mitsunobu's when used as a nucleophilic agent di-tert-butylmethacrylate and subsequent removal of the amino group of gaseous hydrochloric acid or triperoxonane acid. The obtained amines can be converted into the corresponding urea or thiourea by interacting respectively with the carbonyl - or thiocarbonyldiimidazole and subsequently with an amine of formula (VI).

The conversion of compounds of formula (V) into compounds of formula (II) can be accomplished in conventional ways to remove (removal) that are specific and selective for the use of the protective group and, in particular, in the case of BOC-derivative, using triperoxonane acid or trimethylsilylmethyl.

The compounds of formula (III) are obtained according to conventional methods described in the literature.

The invention is illustrated by the following examples and formulation. Concentration expressed as % ratio W/V. the Described connections should be considered as a racemic mixture is Lanovoy acid and its acylchlorides known in the literature or in any case, can be obtained in accordance with customary methods, which are widely described in the literature.

Example 1.

A solution containing 2.5 g of BOC - Proline in anhydrous THF (tetrahydrofuran) (10 ml) at a temperature of 0oC under the atmosphere of inert gas and with stirring to 2.9 g of N-hydroxysuccinimide dissolved in 10 ml of THF. The above solution is added dropwise to a solution of 2.1 ml of morpholinosydnonimine in 5 ml THF and stirring is continued at room temperature for 2 hours; the reaction mixture is acidified with 1 N hydrochloric acid until acidic pH (use litmus paper) and extracted with ethyl acetate (3x10 ml). The combined organic extracts are concentrated under vacuum until crystallization BOC - polynucleotide, which is separated by filtration to obtain 2.6 g melting point: 128-130oC.

1 g of BOC - polynucleotide dissolved in acetonitrile (7 ml) at room temperature and under inert gas atmosphere, then added with stirring 0.97 g of N-[4,6-bis/pyrrolidin-1-yl] 1,3,5-triazine-2-yl] piperazine dissolved in acetonitrile (5 ml). After 5 hours the reaction mixture is concentrated under vacuum to a small onyeiwu with ethyl acetate (3 x 10 ml), then the combined extracts are concentrated under vacuum to a small volume. Adding ethyl ether to obtain the precipitate of 1.5 g of (-)-N-pyrrolidin-1-tert-butoxycarbonyl-2-yl) carbonyl] - N' -[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] piperazine after recrystallization from diisopropyl ether, melting point: 148oC []D= -20,25o(c=2,01 in EtOH).

Example 2.

Through the interaction of a solution of BOC-Proline-N-hydroxysuccinimidyl in acetonitrile with a suitable N-substituted piperazine according to the procedure described in example 1 given the following N',N-disubstituted piperazines:

N'-[pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl]-N-[2,6 - bis/diethylamine/pyrimidine-4-yl/piperazine];

N'-[pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl]-N-[2,6 - bis/allylamino/pyrimidine-4-yl]piperazine;

(-)-N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N-[2,6 - bis(pyrrolidin-1-yl)pyrimidine-4-yl]piperazine, melting point: 168-170oC;

[]D= -20,7o(C = 2 in EtOH);

(+)-N'-[pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N-[2,6 - bis(pyrrolidin-1-yl)pyrimidine-4-yl]piperazine, [ []D]D= +20,2o(c = 2.03 in EtOH);

N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis/Pirro is N-[4,6-bis/ allylamino-1,3,5-triazine-2-yl]piperazine;

N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [4,6-bis/diethylamine/-1,3,5-triazine-2-yl]piperazine;

(-)-N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N - 3,6-bis/diethylamine/pyridine-2-yl]piperazine,

[]D= -19,3o(c = 2,07 in EtOH);

(+)-N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N - 3,6-bis/diethylamine/pyridine-2-yl]piperazine,

[]D= +19,8o(c = 2,01 in EtOH);

N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [3,6-bis(pyrrolidin-1-yl)pyridin-2-yl]piperazine;

N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[(pyrrolidin-1-tert-butoxycarbonyl] -2-yl/carbonyl]-N- [3,6-bis((N-ethyl-N-allylamino)pyridine-2-yl]piperazine;

N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [3-ethylaminomethyl-2-yl]piperazine.

Example 3.

With stirring and under an inert gas atmosphere to a solution of 1.4 g of (-)-N'-[(pyrrolidin-1-tert-butoxycarbonyl-2-yl)carbonyl]-N- [4,6-bis/pyrrolidin-1-yl)-1,3,5-triazine-2-yl] piperazine in 10 ml of methylene chloride add to 2.54 ml triperoxonane acid. After 3 hours at room temperature the reaction mixture was added to 1N NaOH until basic pH, then it is extracted with methylene chloride and repeat the t under reduced pressure. The crude product vykristallizovyvalas from ethyl ether to obtain 950 mg of (-)-N'-[(pyrrolidin-2-yl/carbonyl]-N-[4,6-bis/ pyrrolidin-1-yl/1,3,5-triazine-2-yl]piperazine, melting point: 143oC,

[]D= -65,75o(C = 0,23 in EtOH):

Example 4

By reacting N,N'-disubstituted piperazine as described in example 2, according to the procedure described in example 3 given the following N'-substituted N-[pyrrolidin-2-yl(carbonyl)piperazines:

N'-[(pyrrolidin-2-yl/carbonyl] -N-[2,6-bis(diethylamino) pyrimidine-4-yl] piperazine;

N'-[(pyrrolidin-2-yl/carbonyl] -N-[2,6-bis(allylamino)- pyrimidine-4-yl] piperazine;

(-)-N'-[(pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/ pyrimidinyl-4-yl] piperazine, melting point: 172 - 174oC []D= -56,6, (C = 1,88 in EtOH),

(+)-N-[(pyrrolidin-2-yl/carbonyl] -N-2,6-bis/pyrrolidin-1-yl/ pyrimidine-4-yl] piperazine, melting point: 148 - 151oC []D= +53,5o(C = 2,02 in EtOH);

N'-[(pyrrolidin-2-yl/carbonyl] -N-2,6-bis/pyrrolidin-1-yl/ pyrimidine-4-yl]piperazine, melting point: 137oC;

N'-[(pyrrolidin-2-yl/carbonyl] -N-4,6-bis/allylamino/-1,3,5 - triazine-2-yl]piperazine;

N'-[(pyrrolidin-2-yl/carbonyl] -N-4,6-bis(diethylamino)-1,3,5 - triazine-2-yl]piperazine;

(-)-N'-[(pyrrolidin-2-yl/carbonyl]-N-[3,6-bis(dieti the bis(diethylamino) pyridine-2-yl] piperazine; []D= +48,4o(C = 2,01 in EtOH);

N'-[(pyrrolidin-2-yl/carbonyl]-N-[3,6-bis(pyrrolidin-1-yl) pyridin-2-yl] piperazine;

N'-[(pyrrolidin-2-yl/carbonyl] -N-[3,6-bis(allylamino)-pyridine - 2-yl]piperazine;

N'-[(pyrrolidin-2-yl/carbonyl] -N-[3,6-bis(N-ethyl-N-allylamino/ pyridine-2-yl]piperazine;

N'-[(pyrrolidine-2-yl/carbonyl]-N-[3-ethylaminomethyl-2-yl] piperazine.

Example 5

0.8 g of (-)-N'-[(pyrrolidin-2-yl/carbonyl]-N-[4,6-bis-(pyrrolidin-1-yl)- 1,3,5-triazine-2-yl]piperazine dissolved in 20 ml of acetonitrile, add at 0oC and stirring to 0,22 g of potassium bicarbonate and a solution of 0.28 ml ethylmaleimide in 5 ml of acetonitrile. After 4 hours at room temperature and stirring, the reaction mixture was added to water (50 ml) and extracted again with ethyl acetate (320 ml). The combined organic extracts dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue (0,86 g) was purified by chromatography on silica gel using as eluent hexene (AcOEt at a ratio 1:1) to obtain 0.6 g of (-)-N'-[(1-ethoxypyrrolidine-2-yl/carbonyl]-N-[4,6-bis/ pyrrolidin-1-yl)-1,3,5-triazine-2-yl]piperazine, melting point: 115oC,

[]D= -23,95 (c = 0.2 in EtOH).

Example 6

In the C complex monoether acid chlorides malonic acid, perhaps 2,2-disubstituted receive the following piperazines:

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis/ diethylamine/pyrimidine-4-yl]piperazine;

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis/ allylamino/pyrimidine-4-yl]piperazine;

(-)-N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl/piperazine; melting point: 170 - 172oC []D= -26,5o(c = 2,19 in EtOH);

(+)-N'-[(1-ethoxypyrrolidine-2-yl/carbonyl]-N-[2,6-bis (pyrrolidin-1-yl/pyrimidine-4-yl] piperazine; melting point: 133 - 135oC; []D= +26,5o(C = 2,14 in EtOH).

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis (pyrrolidin-1-yl)pyrimidine-4-yl]piperazine, melting point: 127 - 129oC;

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[4,6-bis/ allylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[4,6-bis/ diethylamine/-1,3,5-triazine-2-yl]piperazine;

(-)-N'-[(1-ethoxypyrrolidine-2-yl)carbonyl]-N-[3,6-bis (diethylamino/pyridine-2-yl]piperazine. The melting point of the hydrochloride 80 - 85oC []D= -20,6 (free base, c = 2.09 EtOH), (+)-N'-[(1-ethoxypyrrolidine-2-yl) carbonyl]-N'-[3,6-bis(diethylamino)pyridine-2-yl] piperazine, []D= +2,01 (c = 2, a'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3,6-bis/ allylamino/pyridine-2-yl]piperazine;

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl]-N-[3,6-bis/N-ethyl - N-allylamino/pyridine-2-yl]piperazine;

N'-[(1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3-ethyl - aminopyridine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[2,6-bis/ diethylamine/pyrimidine-4-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[2,6-bis( allylamino)pyrimidine-4-yl]piperazine;

(-)-N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[2,6 - bis/pyrrolidin-1-yl/pyrimidine-1-yl/pyrimidine-4-yl] piperazine; melting point: 144 - 145oC; []D= -26,5 (c = 0,23 in EtOH);

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[4,6-bis( allylamino)-1,3,5-triazine-2-yl]piperazine;

N'-(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[4,6-bis (diethylamino)-1,3,5-triazine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[4,6-bis (pyrrolidin-1-yl)-1,3,5-triazine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[3,6-bis (diethylamino)pyridine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl] -N-[3,6- (pyrrolidin-1-yl)pyridin-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl/carbonyl]-N-[3,6-bis (allylamino)pyridine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl)carbony-bis (N-ethyl-N-allylamino)pyridine-2-yl]piperazine;

N'-[(1-benzyloxypyrrolidine-2-yl)carbonyl] -N-[3-N-ethyl - aminopyridine-2-yl]piperazine;

N'-[(1-//2', 2'-dimethyl(benzoyloxymethyl/pyrrolidin-2-yl/carbonyl]- N-[2,6-bis(diethylamino)pyrimidine-4-yl]piperazine;

N'-[1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[2,6-bis/allylamino/pyrimidine-4-yl]piperazine;

(-)-N'-[(1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, melting point: 104 - 106o, []D= -43,2o(c = 0,24 in EtOH);

N'-[/1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/1-//2',2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/carbonyl]-

N-[4,6-bis/diethylamine/-1,3,5-triazine-2-yl]piperazine;

N'-[(1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[3,6-bis/pyrrolidin/pyridine-2-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[3,6-bis/(allylamino)pyridine-2-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/benzoyloxymethyl/pyrrolidin-2-yl/ carbonyl]-N-[3-ethylaminomethyl-2-yl]piperazine.

Example 7

A solution of 0.5 g is La added under stirring and under an atmosphere of inert gas to 80 ml of sodium hydroxide (35% aqueous solution). Stirring is continued for 20 hours, then the reaction mixture is adjusted to neutral pH by adding sodium bicarbonate, filtered over brownmillerites and the solvent is evaporated under reduced pressure. The crude product (0.52 g) purified by chromatography on silica gel (using as elution solvent a mixture of methylene chloride and methanol at a ratio in a mixture of 9:1) to obtain 0,43 g (-)-N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl/]-N- [4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine, melting point: 208 - 211oC []D= -21,7o. (C = 0.3 in EtOH).

Example 8

1.5 g of (-)-N'-[/1-benzyloxypyrrolidine-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine dissolved in a mixture of 20 ml of methanol and 6 ml of toluene, then gently under nitrogen protection add 1.5 g of 10% palladium on coal. The resulting reaction mixture is subjected to catalytic hydrogenation under atmospheric pressure, using, for example, such an apparatus, which is described in Vogel''s Textbook of Practical Organic Chemistry, 5th ed., Longman Scientific & Technical (USA Gohn Wiley & Sons, Inc.). 1989, S. S. 89 - 92. After 10 minutes the reaction mixture was filtered through brownmillerite tube to remove catalyst and the solvent is evaporated under reduced of DIN-2-yl/carbonyl]-N-[2,6-bis- (pyrrolidin-1-yl)pyrimidine-4-yl] piperazine melting point: 205 - 207oC []D= -19,25o(c = 0.21 in EtOH).

Example 9

Following the procedure described in example 7 or example 8, on the basis of the corresponding esters described in example 6, you receive the following carboxylic acids:

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ diethylamine/pyrimidine-4-yl]piperazine, melting point: 193 - 195oC.

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ allylamino/pyrimidine-4-yl]piperazine;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[4,6-bis/ allylamino/-1,3,5-triazine-2-yl]piperazine, melting point of 200 - 201oC;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[4,6-bis/ diethylamine/1,3,5-triazine-2-yl]piperazine;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/ diethylamine/pyridine-2-yl]piperazine, melting point sodium salt: 188 - 191oC.

N'-[/1/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/ pyrrolidin-1-Il/pyridine-2-piperazine;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/ allylamino/pyridine-2-yl]piperazine, melting point of the potassium salt 179 - 180oC.

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/N-ethyl - N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/carbonyl] -N-[3 - ethylamino-2-yl/carbonyl] -N- [2,6-bis/diethylamine/pyrimidin-4-yl]piperazine, the melting point of 166 to 168oC.

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/allylamino/pyrimidine-4-yl]piperazine;

(-)-N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, melting point: 160 - 163oC []D= -28,4o(c = 0.2 in EtOH);

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine melting point of 170 172oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [4,6-bis/diethylamino)-1,3,5-triazine-2-yl]piperazine;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine, point palenia: 180 - 181oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/diethylamine/pyridine-2-yl] piperazine, melting point sodium salt: 189-192oC;

N'-/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] -N- [3,6-bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine,

N'[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[/1-2', 2'-dimethyl-1'-malonyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/N-ethyl-allylamino/pyridine-2-yl]piperazine, melting point of potassium salt: 195-200ooC.

Example 10

A solution of BOC-(L)-Proline in 60 ml of anhydrous THF (tetrahydrofuran), cooled to -10oC brine, add to the 6.1 ml of triethylamine and 1 g of 4oA molecular sieves, and then maintaining the temperature below -5oC there are added dropwise a solution of 4.16 ml ethylchloride in 5 ml of anhydrous THF. After 30 minutes under stirring, the reaction mixture was filtered to remove the precipitate of triethylammonium and the filtrate concentrated under reduced pressure to a volume of 30 ml. of the resulting solution was poured dropwise into a suspension of 7.5 g of sodium borohydride in 50 ml of anhydrous THF, cooled to -10oC brine. After 2 hours the reaction mixture was added to 200 ml of aqueous saturated solution of monopotassium phosphate sodium while maintaining a temperature of 0oC using a mixture of ice water, then extracted with ethyl acetate (3x50 ml). The combined organic extracts repeatedly washed with aqueous saturated sodium bicarbonate solution (3x30 ml), dried over sodium sulfate and the solvent is evaporated under reduced pressure. By crystallization of the residue from hexane gain of 6.1 g of BOC-(L)-prolinol, melting point: 59-60oC []D= 54,9o(C=0.2 in EtOH).

Example 11

The residue (7.5 g) purified by chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate at a ratio in a mixture of 7:3 (to obtain 5.5 g (-(-N'-[/1-/tert-butoxycarbonyl/pyrrolidin-2-yl/methyloxycarbonyl] - N-[/2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, melting point: 147oC []D= -32oC, (C=0.25 EtOH).

Example 12

of 17.4 ml triperoxonane acid poured dropwise into a solution of 10 g of (-)-N'[/1-tert-butoxycarbonyl/pyrrolidin-2-yl/methyloxycarbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine in 300 ml of methylene chloride. Almost after 18 hours the reaction mixture was added 1 N aqueous solution of sodium hydroxide and extracted with methylene chloride the spruce is evaporated under reduced pressure. By crystallization of the residue from a mixture of diisopropyl ether and ethyl acetate in a ratio of components in a mixture of 9:1 to obtain 65 g of (-)-N'-[/pyrrolidin-2-yl(methoxycarbonyl]- N-[2,6-bis(pyrrolidin-1-yl)pyrimidine-4-yl] piperazine, melting point: 137-138oC., []D= -8,7o(c=0,23 in EtOH).

Example 13

A solution of 3.4 g monobenzyl ether of 2,2-dimethylmaleic acid in 75 ml of anhydrous dimethylformamide, cooled to 0oC brine, successively under stirring and under an atmosphere of inert gas added to 3.77 g of 1-hydroxybenzotriazole, of 1.55 ml of N-methylmorpholine, 6 g of (-)-N'-[/pyrrolidin-2-yl/methyloxycarbonyl] - N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine and finally to 5.35 g of N'-/3-dimethylaminopropyl/-N-ethyl-carbodiimides dissolved in 25 ml of dimethylformamide. The mixture is left to warm to room temperature, and then stirring is continued for a further 18 hours. The solvent is evaporated under reduced pressure, then the reaction mixture was added to 200 ml of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3x100 ml). The combined organic extracts dried over sodium sulfate and the solvent is evaporated under reduced pressure. Obtain 10.2 g si is the firmness of the eluent a mixture of petroleum ether and ethyl acetate in a ratio of components in a mixture 1: 1) to obtain 6.5 g of (-)-N'-[/1-/3'-benzyloxy-2',2'-demethylase-1-yl/pyrrolidin-2-yl/ methyloxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine as a pale brown foam. 6,45 g (-)-N'-[/1-/3'-benzyloxy-2',2'-demethylase-1'-yl/pyrrolidin - 2-yl/methoxycarbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine dissolved in a mixture of 100 ml of methanol and 40 ml of toluene. The above solution is carefully added to 0.65 g of 10% palladium on coal and formed the reaction mixture is subjected to catalytic hydrogenation under atmospheric pressure, using, for example, such an apparatus, which is described in Vogel''s Textbook of Practical Organic Chemistry, 5th ed. Longman Scientific & Technical (USA Gohn Wiley & Sons, Inc.) 1989, S. 89-92. After 10 minutes the reaction mixture is filtered through brownmillerite tube to remove the catalyst, and the solvent is evaporated under reduced pressure. By crystallization of the crude product from isopropyl ether to obtain 5.5 g of (-)-N'-[/1-/2',2'-demethylase-1'-yl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, melting point: 159-160oC []D= -49,8o(C=0.21 in EtOH).

Example 14.

Following the procedures described in examples 11, 12 and 13, on the basis of the corresponding N-substituted piperazines and the corresponding monoalkyl or monobenzyl esters of malonic acids, possibly 2,2-disubstituted received N', N'-disubstituted piperazines:

N'-[/1-/1'-malonyl/Pyrrhus the LASS="ptx2">

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/methoxycarbonyl]-N-[2,6 - bis/allylamino/pyrimidine-4-yl]piperazine;

(-)-N'-[/1-(1'-malonyl/pyrrolidin-2-yl)methyloxycarbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, melting point: 169 - 170oC []D= -38,1o(c = 0,2, EtOH);

N'-[1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl]-N-[4,6 - bis/allylamino/-1,3,5-triazine-2-yl]piperazine, melting point: 177 - 181oC;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl]-N-[4,6 - bis/diethylamine/1,3,5-triazine-2-yl]piperazine;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl]-N-[3,6 - bis/diethylamine/pyridine-2-yl] piperazine, melting point sodium salt: 198 - 199oC;

N'-[/1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl] -N- [3,6-bis/pyrrolidin-1-Il/pyridine-2-yl] piperazine, melting point sodium salt: 203 - 205oC;

N'-[1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl]-N - 3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'[/1-/1'-malonyl/pyrrolidin-2-yl/methyloxycarbonyl] -N- [3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1 malonyl/pyrrolidin-2-yl/methyloxycarbonyl]-N-[3 - ethylaminomethyl-2-yl]piperazine, melting point sodium salt: 200 - 201oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - Il/is Il/methyloxycarbonyl]-N-[2,6-bis/allylamino/pyrimidine-4-yl/piperazine, melting point: 161 - 162oC.

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl] piperazine, melting point: 167 - 170oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[4,6-bis/diethylamine/-1,3,5-triazine-2 - yl]piperazine;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[4,6-bis/pyrrolidin-1-yl/1,3,5-triazine - 2-yl] piperazine, melting point: 172 - 173oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methoxycarbonyl]-N-[3,6-bis/pyrrolidin-1-Il/pyridine-2 - yl] piperazine, melting point of potassium salt: 206 - 209oC;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl] piperazine, melting point sodium salt: 210 - 213oC;

N-[/1-/2', 2'-dimethyl-1'-malonyl/pyrrolidin-2 - yl/methyloxycarbonyl]-N-[3-ethylaminomethyl-2-yl]piperazine, melting point of potassium salt: 220 - 225oC.

The toxicity of the received sedimenta inflammatory cells (neutrophils and Sosnoviy) after "Bronchoalveolar Lavage" (BL) is carried out after 72 h after exposure of Guinea pigs pretreated with ovalbumin, to higher aerosol dose of ovalbumin as described in Hustou, P. A. et al., Am. Rev. Pespir. Dis, 137,548(1988). EGF is characterized by an increase in NL the number of total inflammatory cells.

This test along with the test hyperresponsiveness can accurately predict clinical activity, because asthma is usually considered as an inflammatory disease.

The value of LD50to connect C and D is equal to 0.96 mg/kg and 0.6 mg/kg, respectively.

The data presented in the table are sufficient to establish the basic trend for all declared in the application of the compounds, because they relate to the changes of the declared values.

Example.

Tablets are prepared by mixing and pressing in the usual way following components:

the compound of example 13 mg - 3,00

corn starch mg - 140,00

lactose mg - 160,00

magnesium stearate mg - 10,00

talc mg - 60,00

colloidal silicon mg - 40,006

1. 1,4-Disubstituted piperazines of General formula I

< / BR>
in which B stands for a group-CO - or-CH2-OCO-;

D means heteroaryl selected from a range, including 1,3,5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two Deputy, and-(C1-C6)-alkylamino-, (C1- C6)-alkyl-(C3-C7)-alkenylamine and pyrrolidin-1-yl group;

Raand Rbmeans a hydrogen atom or a (C1-C3) -alkyl;

n is an integer from 1 to 4

their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases.

2. Connection on p. 1, in which D is chosen from the group comprising [2,6-bis(diethylamino)-4-pyrimidinyl], [2,6 - bis(allylamino)-4-pyrimidinyl] , [2,6-bis(amino)-4-pyrimidinyl], [2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl] , [4,6-bis(allylamino)- 1,3,5-triazine-2-yl], [4,6-bis(diethylamino)-1,3,5-triazine-2 - yl] , [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] , [3,6 - bis(diethylamino)pyridine-2-Il] , [3,6-bis(pyrrolidin-1-yl)pyridine - 2-Il], [3,6-bis(allylamino)pyridine-2-Il] , [3,6-bis(N-ethyl-N-allylamino)pyridine-2-yl], [3-ethyl-aminopyridin-2-Il].

3. Connection on p. 1, in which B is chosen from the group comprising-CO - or-CH2OCO-group; D is heteroaryl selected from [2,6-bis(pyrrolidin-1-yl)-4-pyrimidinyl] , [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] , [3,6 - bis(diethylamino)pyridine-2-yl] [3-ethylaminomethyl-2-Il] ; Rathat is the same as Rbis hydrogen or stands and the b obtain the 1,4-disubstituted piperazines on PP. 1 - 3 of General formula (I)

< / BR>
where B is-CO-, -CH2OCO - group;

D means hetaryl selected from a range, including 1,3,5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino; mono-(C3-C7)-alkynylamino-, di(C1-C6)-alkylamino-, (C1-C6)alkyl-(C3-C7)alkenylamine and pyrrolidin-1-yl group;

Raand Rbmeans a hydrogen atom or a (C1-C3)- alkyl;

n is an integer from 1 to 4

their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases, characterized in that the compound of formula (II)

< / BR>
in which B and D are as defined above,

interacts with the compound of the formula (III)

< / BR>
in which n, Raand Rbhave the above meanings;

R is a (C1-C6)-alkyl, benzyl, allyl group or any other group that can be easily removed,

E is a halogen (chlorine, bromine), an N-imidazole, HE, O-hydroxysuccinimidyl or taken together with the carbonyl group, it forms a mixed anhydride with a carboxylic or with the PTO turning-COOR groups in the-COOH group.

6. The method according to p. 5, characterized in that compounds of the formula (Ia)

< / BR>
in which B, D, Ran and Rbare as defined above;

R is a (C1-C6)-alkyl,

turn in the compounds of formula (I) by hydrolysis with mineral bases corresponding concentration in a suitable solvent.

7. The method according to p. 5, characterized in that compounds of the formula (Ia)

< / BR>
in which B, D, Ra, Rband n are as defined above;

R is an allyl or benzyl,

turn in the compounds of formula (I) by catalytic hydrogenation.

8. The method according to p. 7, characterized in that the hydrogenation is performed with the use of a catalyst selected from the group comprising palladium on coal various concentrations of skeletal Nickel catalyst, palladium tetrakis(triphenylphosphine), in a suitable solvent or by treatment with compounds hydrogen donors.

9. Medicine to reduce the increased bronchial reactivity, including an active ingredient and an acceptable carriers and diluents, wherein as the active ingredient it contains effektivnosti increased bronchial reactivity, including mixing the active ingredient with a pharmaceutically acceptable carrier, diluent, wherein the active ingredient is used as a compound of General formula I on p. 1 in an effective amount.

 

Same patents:

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new biologically active chemical compounds, derived pyrazine formula I listed in the description, which is obtained by the interaction of the previously obtained through collaboration pyrazinamide with Amida sodium in liquid ammonia Na-salt pyrazin-2-carboxamide and 6-methyl-5-uracil sulfochloride in liquid ammonia

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

The invention relates to new pyridinesulfonamide General formula I or their acceptable for agriculture salts, have a weed-killing activity, as well as to a method for their production and compositions for combating the growth of unwanted vegetation

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new methods of stereoselective obtain derivatives substituted piperidino

The invention relates to the compound N-pyridylsulfonyl-N'-pyrimidinylidene formula 1

< / BR>
where R1denotes methyl or methoxy and R2denotes hydrogen or methyl; compounds and salts of these compounds with amines, bases, alkali or alkaline earth metal or Quaternary ammonium bases have good herbicide and regulating plant growth properties during selective use before and after germination
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