Cyclohexylacetate, the way they are received and drug

 

(57) Abstract:

The invention relates to new esters of nitric acid derivative of cyclohexanol with a total fomulas I

where a is a trait denoting the valency,or1- C6-Allenova chain; In-group-NR1- CO-Z -,- NR1-SO2-Z or-CO-NR2Z, R1is hydrogen or C1- C6-ankylostoma; R2is hydrogen, hydroxy, hydroxy-C1- C6-alkyl, C1- C6-alkyl, C2- C6alkenyl-; Z is hydrogen, C1- C6alkyl, C2- C6alkenyl or2- C6-quinil group, which may be single - or multi-substituted with hydroxy, C1- C6-alkylcarboxylic-FROM1- C6-alkoxy-, halogen-, cyano-, carboxy-, C1- C6-alkoxycarbonyl-, -CO-NR3R4or1- C6-alkylcarboxylic or Z means pyridine, N-oxypyridine-or pyrolidine ring, or Z together with R2and nitrogen atom, which is associated with the Z and R2, forms a heterocyclic ring which can additionally contain an oxygen atom, R3and R4- C1- C6is alkyl, hydrogen, as well as their optically active forms. The invention concerns tangeretin for new nitric acid ester derivative of cyclohexanol with the General formula I

< / BR>
where

A-valence or C1-C6- Allenova chain;

B - group-NR1-CO-Z -,- NR1-SO2-Z or-CO-NR2-Z;

R1is hydrogen or C1-C6is an alkyl group;

R2is hydrogen, hydroxy-C1-C6-alkyl, C1-C6-alkyl, C2-C6alkenyl-;

Z is hydrogen, C1-C6-alkyl, C2-C6alkenyl or C2-C6alkenyl group which may be single - or multi-substituted with hydroxy, C1-C6- alkoxy-, halogen-, cyano-, carboxy-, C1-C6-alkoxycarbonyl-, -CO-NR3R4or C1-C6= alkylcarboxylic group, pyridinyl, N-oxypyridine, or pyrolidine ring, or Z together with R2and the nitrogen atom to which they are attached, form a six-membered heterocyclic ring which can additionally contain an oxygen atom, R3and R4- C1-C6= alkyl, hydrogen, as well as their optically active forms, and pharmaceutical preparations containing these compounds.

A similar connection nitrosopumilus known from earlier European applications [1, 2].

In [1] is described inter alia nitrocyclohexanone, with whom the group A-B are connected with pyrrolidinium or piperidinium ring. In EP-A-0.359.335 also described the preparations containing the derivatives of nitrate esters as active substances for the treatment of diseases of the heart and the circulatory system. In these examples 35-40 presents cyclohexanediamine substituted in 2-, 3 - and 4-positions cyclohexane ring, as respectively cyclohexanone with nitroxyl in the 2nd position.

Nitro compounds to treat diseases of the heart described in the patent [3].

Present invention in connection with formula (I) possess valuable pharmaceutical properties. It reduces the oxygen demand or heart, stimulate blood flow and reduce blood pressure. Suddenly able to establish that the claimed compounds have nitratomethyl the action of particularly long duration. Therefore, they can be used for the prevention and/or treatment of diseases of the heart and the circulatory system, for example, Angina pectoris.

Group A-B can be 2-, 3 - and 4-positions tsiklogeksilnogo ring, and 3 - and 4-th position can be considered more preferable. Group A-B may be in CIS-and TRANS-positions, and the TRANS-position is more preferable.

- carbonyloxy= groups, can be straight or branched and can contain 1-6 or 2-6 C-atoms, preferably 1-4 or 2-4 C-atoms. Linear alkyl radicals can represent a methyl-, ethyl-, n-propyl, n-butyl and n-interracial. Branched alkyl radicals can be, for example, a group-CH(CH3)-, -C(CH3)2-, -CH(CH3)-CH2- or-CH2-CH(CH3)-CH2.

Alkeneamine radicals are primarily linear radicals, such as vinyl, 1-propenyl-, or 2-propeciahttp. Quinil-radicals can be straight or branched, for example, propargyl - or 2-methyl-3-butenyl.

Present invention compounds of General formula I can be obtained by a known method, namely the compound of General formula II

< / BR>
where

A-B have the above meaning, are subjected to the reaction with the formation of the nitrate=ethers,

the compound of General formula III

< / BR>
interact with the compound of General formula IV

W-CO-Z (IVa) or W-SO2-Z (IVb)

where

R1and Z have the above meaning,

W represents a reactive group, or

the compound of General formula V

< / BR>
is reacted with a compound of General formula VI

R2-NH-Z (I) subsequently converted into other compounds of formula (I). Some compounds of General formula (I) are new compounds. They can be obtained using known methods, and

the compound of General formula VII

< / BR>
where

R1and A have the above meaning, interacting with the compound of General formula IV, or

the compound of General formula VIII

< / BR>
where

A and W have the above meaning and Y represents a protective group, is reacted with a compound of General formula VI, followed by removal of the protective group y

Reaction formation nitrate=ether to obtain the compounds of General formula I can be when interacting compounds of General formula II to form the esters of nitric acid reagent, such as fuming nitric acid, a mixture of fuming nitric acid and acetanhydride, a mixture of fuming nitric acid and concentrated sulfuric acid or patikis nitrogen at low temperatures in the presence or absence of an inert solvent.

The range of the reaction temperature ranges from room temperature to -60oC, preferably from -30 to 0oC. the Molar ratio of the reaction components from 1 to 10.

As reacciones group. Therefore, the activated carboxylic acid IV and V are in the form of esters, Laktionov, halides or anhydrides of carboxylic acids. However, the activation of carboxylic acids can also be performed using such reagents as N, N-carbonyldiimidazole, N,N-DICYCLOHEXYL-carbodiimide or esters of Harborview acid. The molar ratio for the reaction components are selected in the range of 1:100.

As a protective group V can be used conventional hydroxy-group, for example, actinograph.

Join in the General formula VII, where A is the valence, R1is hydrogen or acetyl, described in Ber, 72, 995, 1939. Such compounds can be obtained in a similar way. When A in the formula denoting the valency and R1-chloroacetyl - or chloropropionyl group, these compounds are described as intermediate products in [1]. Similarly can be obtained from other compounds with formula VII.

Compounds with the General formula VIII, where A is a valency, V - actinograph and W-hydroxyl group can be obtained according to the method described in J. Chem.Soc. 1950, 1979. Other compounds with formula VIII can be obtained by applying a similar method.

Compounds III and V are known from EP-A-192 829 and described there to the I into other compounds of formula I are becoming possible due to the fact, what carboxyl group due to the interaction with alcohols into corresponding derivatives of esters or by reaction with amines into the corresponding amides. Used carboxylic acid can be converted to active derivatives of carboxylic acids, such as anhydrides or halides, using known methods. In the case of Z-substituted on alkylcarboxylic group moiety, such compounds due to hydrolysis of the ester is converted to the corresponding replacement derivatives. When Z - N-oxopyridine ring preferably be obtained from the corresponding pyridine derivatives of formula I, by additional oxidation using capable of oxygen transfer reagents, such as, for example, hydrogen peroxide.

We present compounds with the General formula I represents a cyclohexane derivative, substituents in which ONO2and A - B can be in the 1,2-, 1,3-or 1,4-x positions. The structure can have CIS - and TRANS-configuration. In the case of clauses 1.2 and 1.3, we present the invention, the compounds have two chiral C-atom. Therefore, the subject invention are also all of the racemates, mixtures of diastereomers and optical active Faure is practical relation to salts of compounds of formula I is produced by interaction with the hydroxides or carbonates of alkaline or alkaline-earth metals or with organic bases, such as triethylamine.

Substances with the General formula I and their salts can be used in liquid or solid form interline or parenterale. As a medium for injection water is used, which is preferable, which contains the usual additives, such as stabilizing properties, stimulants dissolution or buffers. Adding such tools, such as tartrate or citrate buffer, ethanol, complexing agents (for example, ethylene - diaminetetraacetic acid or its nontoxic salt), high-molecular polymers (such as liquid polyethylene oxide), aimed at regulating the viscosity. Solid carriers are, for example, Kromah, lactose, mannitol, methylcellulose, talc, highly dispersed chiselheavy acid, high molecular weight fatty acids (e.g. stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable oils, and solid high molecular weight polymers (e.g. polyethylene glycol). Intended for oral administration the compositions may, if desired, contain flavoring and sweetening agents.

Drugs, containing compounds with formula I, are designed to Oder the research Institute of the connection number 1 - 50 mg, preferably 5 to 30 mg on the form of application.

Along with the following examples in this quality can be used, for example, the following connections:

monoamide N-methyl-N-(TRANS-4-nitrobenzyloxy)succinic acid;

diamid N-methyl-N-(TRANS-4-nitrobenzyloxy)succinic acid;

diamid N-methyl-N-(TRANS-4-nitrobenzyloxy) N N'- dimethylethanol acid;

CIS-N-formyl-3-nitrocyclohexanone;

monoamide N-(CIS-3-nitrobenzyloxy)succinic acid;

diamid N-(CIS-3-nitrobenzyloxy)succinic acid;

diamid N-(CIS-3-nitrobenzyloxy) N N'-dimethylethanol acid;

TRANS-N-forms-2-nitrocyclohexanone;

TRANS-N-acetic-2-nitrocyclohexanone;

monoamide N-(TRANS-2-nitrocyclohexanone)succinic acid;

diamid N-(TRANS-2-nitrocyclohexanone)succinic acid;

diamid N-(TRANS-2-nitrocyclohexanone)N N'-dimethylethanol acid;

amide 2-cyan-2-methyl-N-(TRANS-4-nitrocyclohexanone) propionic acid;

CIS-N-formyl-4-nitrocyclohexanone;

N-(tetrazol-5-yl)-amide, TRANS-4-nitrocyclohexanone acid;

amide 2-methylmercapto-N-(TRANS-4-nitrobenzyloxy)acetic KIS the Mino-3-methylmercapto-N-(TRANS-4-nitrobenzyloxy) propionic acid;

amide 2-methylamino-3-acetylmuramic-N-(TRANS-4 - nitrobenzyloxy) propionic acid;

amide 2-acetylamino-3-mercapto-N-(TRANS-4-nitrobenzyloxy) propionic acid;

amide 2-acetylamino-3-acetylmuramic-N-(TRANS-4 - nitrobenzyloxy) propionic acid;

amide of 2-amino-3-mercapto-N-(TRANS-4-nitrobenzyloxy) butyric acid;

amide of 2-amino-4-methylmercapto-N-(TRANS-4-nitrobenzyloxy) butyric acid;

amide 2-acetylamino-4-methylmercapto-N-(TRANS-4 - nitrobenzyloxy) butyric acid;

amide N-[2-//3-propionic acid ethyl ester/]-TRANS-4 - nitrocyclohexanone acid;

ethyl ester-amide N-[2-(3-acetylmuramic)propionic acid] TRANS-4-nitrocyclohexanone acid;

ethyl ester-amide N-[2-(4-methylmercapto)butyric acid] TRANS-4-nitrocyclohexanone acid;

N-(2-mercaptoethyl)-amide, TRANS-4-nitrocyclohexanone acid;

amide 2-mercapto-N-(TRANS-4-nitrocellulose)acetic acid.

Example 1. to 28.3 ml (0.3 mol) of acetic anhydride was mixed with 375 ml of acetonitrile, cooled in an ice bath to 0 - 5oC and added dropwise of 12.6 ml (0.3 mol) of 100% nitric acid. After 30 min when the pens 15.7 g (0.1 mol). The reaction mixture was continued to stir for 3 h at 0 to 5oC, then carefully poured into a solution of 150 g (1.8 mol) of acid sodium carbonate in 500 ml of ice water. After extraction using ether acetic acid, drying the organic phase and distillation under vacuum remained 17.8 g of crude product. After recrystallization from acetic ester was obtained 10.3 g is specified in the header connection with. so pl. 146 - 148oC, i.e. 50 % of theory.

By a similar method were obtained the following compounds:

1/1 TRANS-N-n-hexanoyl-4-cyclohexylamin of TRANS-N-n-hexanoyl-4-hydroxycyclohexanone with so pl. 100 - 101oC (ether), yield 58%.

1/2 Amide, TRANS-4-nitrocyclohexanone acid from Amide, TRANS-4-gidroksistearinovoj acid so pl. 160 - 159oC (ether acetic acid), yield 62%.

1/3 Dimethylamide TRANS-4-nitrocyclohexanone acid from dimethylamide TRANS-4-hydroxycyclohexanecarboxylate acid so pl. 108 - 110oC (ether acetic acid), yield 40%.

1/4. Morpholin TRANS-4-nitrocyclohexanone acid from morpholide TRANS-4-nitrocyclohexanone acid so pl. 89 - 90oC (ether), yield 40 %.

1/6. Amide 2-chloro-N-/TRANS-4-nitrocyclohexane/acetic acid from amide 2-chloro-N-/TRANS-4-hydroxycyclohexyl/acetic acid, with so pl. 102 - 104oC (ether). The output is 34%.

1/7. Amide 2-bromo-2-bromo-2-methyl-N-(TRANS-4-nitrocyclohexane /propionic acid of amide 2-bromo-2-bromo-2-methyl-N-(TRANS-4 - hydroxycyclohexyl /propionic acid with so pl. 92 - 94oC (ether/isohexane). Yield 60 %.

1/8. Amide N-/TRANS-4-nitrocellulose/acrylic acid from the amide N-/TRANS-4-hydroxycyclohexyl/acrylic acid so pl. 160 - 162oC (ether acetic acid). Yield 63 %.

1/9. Amide 2-cyan-N-/TRANS-4-nitrocellulose/acetic acid from amide 2-cyan-N-/TRANS-4-hydroxycyclohexyl/acetic acid, with so pl. 149 - 150oC (ether). Yield 53 % of theory.

Example 2. TRANS-N-acetyl-4-nitrocyclohexanone. A solution of 2.3 g (0.015 mol) of TRANS-4-nitrocyclohexanone in 25 ml of ether acetic acid was dissolved in 10 ml (0.13 mol) of acetic anhydride and during the night was stirred at room temperature. Then was cooled to 5oC, was added 100 ml of ethanol and, after keeping overnight at room temperature and distilled under vacuum. After trituration with ether was aspirated Chris the ptx2">

In a similar way received the following connections.

2/1 TRANS-N-acetyl-4-nitrocyclohexanone of TRANS-4-nitrocyclohexanone with so pl. 91 - 963oC (ether). A 30% yield.

2/2. CIS-N-acetyl-3-nitrocyclohexanone of CIS-3-nitrocyclohexanone with so pl. 112 - 113oC (ether). Yield 41 %.

2/3. TRANS-N-methyl-N-acetyl-4-nitrocyclohexanone of TRANS-N-methyl-4-nitrocyclohexanone with so pl. 37 - 39oC (ether/isohexane). Yield 77 % of theory.

2/4. TRANS-N-ethyl-N-acetyl-4-nitrocyclohexanone of TRANS-N-ethyl-4-nitrocyclohexanone with so pl. 68 - 69oC (ether). Exit 35 % of theory.

Example 3. TRANS-N-formyl-4-nitrocyclohexanone. A mixture of 6.8 ml (0,072 mol) of acetic anhydride and 2.8 ml (0,072 mol) of formic acid was heated for 2 h at 60oC, followed by cooling at 5oC was diluted to 1.9 g (0.012 mol) of TRANS-4-nitrocyclohexanone. Then during the night was stirred at room temperature, diluted with 100 ml ether, acetic acid was added 100 ml of water. After neutralization with a saturated solution of acid sodium carbonate organic phase was dried with sodium sulfate and kept under vacuum. After trituration with EFT.E. 66 % of theory.

In a similar way received the following connections.

3/1. TRANS-N-formyl-4-nitrocyclohexanone of TRANS-4-nitrocyclohexanone with so pl.: oil. Yield 70 %.

3/2. TRANS-N-methyl-N-formyl-4-nitrocyclohexanone of TRANS-N-methyl-4-nitrocyclohexanone with so pl. 52 - 54oC (ether/isohexane). Yield 60 % of theory.

Example 4. Monoamide N-(TRANS-4-nitrobenzyloxy)succinic acid. To a solution of 4.8 g (0.03 mol) of TRANS-4-nitrocyclohexanone in 25 ml of acetonitrile was added at 10oC 3 g (0.33 mol) of succinic acid anhydride and stirred at room temperature for 48 hours After the extraction remained 3.6 g specified in the connection header with so pl. 136 - 138oC, i.e. 46 % of theory.

In a similar way received the following connections.

4/1. Monoamide N-(TRANS-4-nitrobenzyloxy)of maleic acid from TRANS-N-nitrocyclohexanone of maleic anhydride with so pl. 178 - 179oC (acetonitrile). Yield 47 %.

4/2. Monoamide N-(TRANS-4-methyl)succinic acid from TRANS-4-nitrocyclohexanone and succinic acid anhydride with so pl. 79 - 81oC (ether). Yield 80 %.

Example 5. Diamid N-(TRANS-4-ary acid (example 4) in 100 ml of absolute methylene chloride was mixed with 3.1 g (0.015 mol) petaluridae phosphorus by cooling to 5 10oC. After two hours stirring at room temperature distilled under vacuum at a maximum temperature of 20oC, triturated with absolute ether and was sucked out. The acid chloride was immediately added to 50 ml of 10% aqueous ammonia at 5 to 10oC and was stirred over night at room temperature. After sucking remained 1.2 g specified in the connection header with so pl. 167 - 169oC, i.e. 30 % of theory.

In a similar way received the following connections.

5/1. Diamid N-/TRANS-4-nitrocyclohexane/maleic acid from monoamide T-(TRANS-4-nitrobenzyloxy)maleic acid (example 4/1) and ammonia with so pl. 151 - 1522 (ether acetic acid). Yield 31 %.

5/2. Diamid N-/TRANS-4-nitrocyclohexane/N N-dimethylethanol acid from monoamide N-(TRANS-4-nitrobenzyloxy)succinic acid (example 4) and dimethylamine with so pl. 120 - 1222 (ether). Yield 42 %.

5/3. Diamid N-(TRANS-4-nitrocyclohexanone)of succinic acid from monoamide N-(TRANS-4-nitrocyclohexanone)of succinic acid and ammonia, and so pl. 156 - 157oC (ether acetic acid). Yield 63 %.

5/4. Diamid N-/TRANS-4-nitrocyclohexanone/-N N'- dimethylethanol acid from monoamide N-(TRANS-4-nitroxyls-N-propionyl-4 nitrocyclohexane. To a solution of 3.2 g (0.02 mol) of TRANS-4-nitrocyclohexanone in 80 ml of absolute methylene chloride was added at 5 to 10oC 3 ml (0.02 mol)of triethylamine and then 2 g (0.02 mol) of Propionaldehyde in 20 ml of absolute methylene chloride. Was stirred overnight at room temperature, three times was dissolved in 25 ml of water, the organic phase is dried using sodium sulphate and distilled under vacuum. The residue is triturated with ether and was sucked out. Remained 2.8 g specified in the connection header with so square 138 - 140oC, i.e. 65 %: from theory.

In a similar way received the following connections.

6/1 Amide-2-methoxy-N-(TRANS-4-nitrocyclohexane/acetic acid from TRANS-4-nitrocyclohexanone and acid chloride methoxybutanol acid so pl. 98 - 99oC (ether). Yield 40%.

6/1 Amide 2-acetoxy-N-/TRANS-4-nitrocyclohexane/acetic acid from TRANS-4-nitrocyclohexanone and chlorhidrate acetoxidans acid so pl. 98 - 99oC (ether). Output 90%.

6/3 Amide 2-acetoxy-N-/TRANS-4-nitrocyclohexane/propionic acid from the acid chloride of TRANS-4-nitrocyclohexanone and the acid chloride of 2-acetoxy-propionic acid with

so pl. 104 - 105oC (ether acetic acid/ether). Yield 80%.

6/5 N-/TRANS-4-nitrocyclohexane/nicotinic acid from TRANS-4-nitrocyclohexanone and nicotinic acid azide with so pl. 171 - 173oC (ether acetic acid). Yield 46%.

6/6 Amide N-/TRANS-4-nitrocyclohexane/isonicotinic acid from TRANS-4-nitrocyclohexanone azide and isonicotinic acid so pl. 170 - 172oC (2-propanol). Yield 40%.

6/7 Amide 2-acetoxy-N-/TRANS-4-nitrocyclohexanone/acetic acid from TRANS-4-nitrobenzyloxy-methylamine and chlorhidrate acetoacetic acid so pl. 65 - 66oC (ether). Yield 60%.

6/8 Amide N-TRANS-4-nitrobenzyloxy-2,2-dimethylpropionic acid from TRANS-4-nitrocyclohexanone and acid chloride of 2,2-dimethylpropionic acid so pl. 148 - 151oC., Yield 25% of theory.

6/9 Amide N-TRANS-4-nitrobenzyloxy-methansulfonate of TRANS-4-nitrocyclohexanone and the acid chloride of methansulfonate with so pl. 154 - 155oC. Yield 84% of theory.

6/10 Amide 2,2-bis-/acetoxymethyl/-N-TRANS-4-nitrobenzyloxy - propionic acid from TRANS-4-nitrocyclohexanone and acid chloride of 2,2-bis-(-acetoxymethyl)propionic acid with so pl. 95 - 97oC (ether acetic acid). Exit 40% olovaha ether Harborview acid so pl. 93 - 94oC (ether/isohexane). Yield 56% of theory.

6/12 Amide 2-acetylmuramic-N-(TRANS-4-nitrobenzyloxy)-acetic acid from TRANS-4-nitrocyclohexanone and the acid chloride of 2-acetylmercaptosuccinic acid so pl. 127 - 129oC (ether). Yield 67% of theory.

Example 7. N-/2-methyl-3-butyl-2-yl/amide 4-nitrocyclohexanone acid. 6.2 g /0,075 mol 2-methyl-3-butyl-2-ylamine was dissolved in 100 ml of absolute ether acetic acid and cooled to 5 - 10oC was added dropwise with 5.2 g (0,025 mol) of acid chloride of TRANS-4-nitrocyclohexanone acid in 25 ml of absolute ether acetic acid. After three hours stirring at room temperature was dissolved in 100 ml of water, the ethyl acetate phase was dried using sodium sulphate and distilled under vacuum. The residue was diluted with ether and was sucked out. Received 2.6 g specified in the connection header with so square 138 - 139oC, i.e. 40% of theory.

In a similar way received the following connections.

7/1 N-(2-hydroxyethyl)amide, TRANS-4-nitrocyclohexanone acid from the acid chloride of TRANS-4(-nitrocyclohexane)carboxylic acid 2-hydroxyethylamine with so pl. 132 - 133oC (ether). The output 25%.

7/2 N-(3-hydroxyanthranilic acid and 3-hydroxypropylamino

so pl. 78 - 79oC. Yield 45%.

7/3 N-/N,N-dimethyl-acetamido/amide, TRANS-4-nitrocyclohexanone acid from the acid chloride of TRANS-4-nitrocyclohexanone acid and N, N-dimethyl-amide acetic acid, with

so pl. 142 - 144oC (ethanol). A yield of 20%.

7/4 N/2,2-dimethylacetamide/amide, TRANS-4-nitrocyclohexanone acid

of the acid chloride of TRANS-4-nitrocyclohexanone acid and amide 2-amino-2-methylpropionic acid

so pl. 180 - 181oC (water). Yield 53%.

7/5 N/methyl/hydroxylamin TRANS-4-nitrocyclohexanone acid from the acid chloride of TRANS-4-nitrocyclohexanone acid and N-methyl-hydroxylamine

so pl. 125 - 126oC (ether). Yield 53%.

7/6 N-2-/2-methyl-3-ethyl/amide, TRANS-4-nitrocyclohexanone acid

of the acid chloride of TRANS-4-nitrocyclohexanone acid and 2-amino-2-methyl-propanol with so pl. 150 - 151oC (ether). Yield 65% of theory.

7/7 N-bis-(2-hydroxy-ethyl) - amide, TRANS-4-nitrocyclohexanone acid

of the acid chloride of TRANS-4-nitrocyclohexanone acid and bis-(2-hydroxyethyl)amine with

so pl. 78oC (ethyl acetate/ether). Yield 80% of theory.

oC a solution of 3.1 g (0.015 mol) of acid chloride of TRANS-4-nitrocyclohexanone acid in 10 ml of dioxane. With the simultaneous addition of 2N sodium hydroxide (7.5 ml) maintained the pH at 12. The mixture was stirred for 2 h at room temperature, brought the pH to 1 and was extracted with ethyl acetate. The organic phase was dried with sodium sulfate and distilled under vacuum. After dilution with ether and suction was obtained 1.4 g specified in the connection header with so pl. 143 - 144oC (ether), i.e. 38% of theory.

In a similar way received the following connections.

8/1 N-propionic acid amide, TRANS-4-nitrocyclohexanone acid from the acid chloride of TRANS-4-nitrocyclohexanone acid and 2-amino-propionic acid with

so pl. 113 - 114oC (ether). The output 25%.

8/2 N-acetamido/amide, TRANS-4-nitrocyclohexanone acid from the acid chloride of TRANS-4-nitrocyclohexanone acid and amide aminouksusnoy acid

so pl. 170oC (ethyl acetate). Exit 35% of theory.

Example 9. Amide-2-hydroxy-N-/TRANS-4-nitrocyclohexane/acetic acid 6,1 g (is 0.023 mol) amide 2-acetoxy-N-(TRANS-4-nitroxinil at room temperature. After distillation under vacuum was dissolved with ethyl acetate and shaken with water. The ethyl acetate phase was dried with sodium sulfate and distilled under vacuum. After dissolved with ether and suction. Received 1.8 g specified in the connection header with the so-square 81 - 83oC, i.e. 36% of theory.

In a similar way received the following connections.

9/1 Amide 2-hydroxy-N-(TRANS-4-nitrobenzyloxy)propionic acid of the amide 2-acetoxy-N-(TRANS-4-nitrobenzyloxy)propionic acid (example 6/3) so pl. 117 - 118oC (ether). Yield 23%.

9/2 Amide 2-hydroxy-N-(TRANS-4-nitrobenzyloxy)-2,2 - dimethylpropionic acid

of amide 2-acetoxy-N-(TRANS-4-nitrobenzyloxy)-2,2 - dimethyl-propionic acid (example 6/4) so pl. 100 - 101oC (ether). Yield 28%.

9/3 Amide 2-hydroxy-N-/TRANS-4-nitrocyclohexanone/- acetic acid of the amide 2-acetoxy-N-(TRANS-4-nitrocyclohexanone)acetic acid (example 6/7) so pl. 111 - 112oC (ether). Yield 24%.

9/4 Amide 2,2-bis-(hydroxymethyl)-N-TRANS-4-nitrocyclohexanone acid from amide 2,2-bis-(acetoxymethyl)-N-TRANS-4-nitrocyclohexanone acid

so pl. 110 - 112oC (ethyl acetate). Yield 20% of theory.

Philamina was mixed with 5.7 ml of 4-butyrolactone and was stirred for 3 days at room temperature. To remove excess lactone was filtered through Kiselyev acid using ethyl acetate. After connecting the pure fractions were distilled under vacuum, triturated with ether and was sucked out. Remained 2.1 g specified in the connection header with so pl. 58 - 60% of theory.

Example 11. Amide N-(TRANS-4-nitrobenzyloxy-)-(S)-pyroglutamic acid.

2.1 g (to 0.016 mol) of (S)-pyroglutamic acid (2-pyrrolidon-5-carboxylic acid) was dissolved in 50 ml of absolute tetrahydrofuran and 2.5 ml (0.018 mol) of triethylamine. After cooling to 5oC was added dropwise 2 ml (0,016 mol) of pualeilani in 10 ml of absolute tetrahydrofuran. After 15 minutes of stirring at 5oC was added dropwise a solution of 3.9 g of TRANS-4-nitrocyclohexanone in 40 ml of absolute tetrahydrofuran and 2.8 ml (0.02 mol) of triethylamine. Then continued stirring for 2 days at room temperature, was pumped out and removed under vacuum of the solvent. The residue was dissolved in ethyl acetate and shaken with acidic sodium carbonate. After drying the ethyl acetate phase using sodium sulfate, kept under vacuum, triturated with ether and was sucked out. Received 1.5 g specified in the connection header with so pl. 166oC, mol) amide N-TRANS-4-nitrocyclohexanone acid (example 6/5) was dissolved in 4 ml of acetic acid, was added dropwise 4 ml of 30% hydrogen peroxide and stirring for 2 days at 40oC. After concentration and trituration with ether was aspirated crystals. Received 0.9 g specified in the connection header with so pl. 170 - 171oC, i.e. 53% of theory.

In a similar way received the following connections.

12/1 Amide-N-oxide N-/TRANS-4-nitrocyclohexane/isonicotinic acid from the amide N-(TRANS-4-nitrobenzyloxy)isonicotinic acid (example 6/6) so pl. 180oC (ethyl acetate). Yield 82%.

Example 13. TRANS-4-hydroxycyclohexyl /VII/

a) CIS-TRANS-4-hydroxycyclohexanecarboxylate acid

184 g (1.07 mol) of ethyl ester of CIS-TRANS-4-hydroxycyclohexanecarboxylate acid /see SACS, 70, /1948/, 1998/ heated in 1.8 l of water to 119.8 g (2,14 by moles) of potassium hydroxide for 3 h before phlegmy. After acidification with concentrated hydrochloric acid and was extracted with methylene chloride received 146 g of acid so pl. 111 - 1152, i.e. 94% of theory.

b) TRANS-4-0-acetylcyclohexanone acid

145 g (1.01 mol) of CIS-TRANS-4-hydroxycyclohexanecarboxylate acid suspended in 1 l of acetic acid was added dropwise to 123.5 g (1,21 mol) acetylchloride and was heated for 5 h to Flerova ether and after crystallization was sucked out. Received 112 g of crude product. After recrystallization in 740 ml of water received 84 g, i.e. 44% of theory of pure trance connection with so pl. 140 - 141oC.

C) Methyl ester of TRANS-4-O-acetylcyclohexanone acid.

84 g /0.45 mol of TRANS-4-O-acetylcyclohexanone acid was dissolved in 1 l of methanol, was added 8.6 g (of 0.045 moles) of para-toluenesulfonic acid and heated for 20 h before phlegmy. After distillation of the methanol, the residue was dissolved in water and neutralized the acid with sodium carbonate. The aqueous solution was saturated with sodium chloride and was extracted several times with ethyl acetate. Extracts of esters of acetic acid was dried with sodium sulfate, filtered, and distilled. Received 72,7 g of the ester, i.e. 80% of theory) of product as a colorless oil.

g) Amide, TRANS-4-hydroxycyclohexanecarboxylate acid

36 g /0.18 mol/ methyl ester of TRANS-4-O-acetylcyclohexanone acid were heated in 500 ml of methanol and 500 ml of liquid ammonia for 24 h at 100oC 2-liter autoclave. After evaporation of the ammonia and distillation of the methanol, the residue triturated with ether and was sucked out. Got to 21.6 g of amide with tons of dps, 208 - 210oC, i.e. 83% of theory.

l) TRANS-4-hydroxycyclohexanone.

To suspend the e/ TRANS amide-hydroxycyclohexanecarboxylate acid within 24 h was heated to phlegmy. After decomposition using 45 ml of saturated common salt solution was aspirated and the filtrate was distilled. The residue was pereirae with ether and sucked out the crystals. Received 11 g amine, i.e. 57% of theory so pl. 137 - 139oC.

Example 14. Pharmacological studies.

The task is. The aim of the research was to find the nitrates capable of a longer time to preserve its action, therapeutic effect and benefits which would have consisted in the fact that they were taken once a day and gave the necessary therapeutic effect. If this were coming from the fact that disposable daily intake instead of multiple leads to increased "flexibility" of the patient, and may thus be influenced by pharmacokinetic profile of the active substance, i.e. the assumption that the difference between the maximum and minimum level due to low concentrations fall significantly favorable.

Method. To identify generirovaniya representing the activity profile of all nitrates, had determined the rate of denitration ratio to the corresponding value for a known ISDN metabolites IS-5MN. For this purpose, rats users the solution IS-5-MN or investigational substance within 4 minutes The perfusion solution was determined by eye-catching number of NO2. To provide comparative conditions for monitoring, perfusion with IS-5-MN (standard substance, ethanol) three times conducted in such a manner as if a third perfusion was an unknown substance (thus able to determine a modified experimental conditions, liver function and, accordingly, to consider it). The values of YRel.(the relative velocity denitration) suggest that the rate of denitration is significantly higher in comparison with IS-5-MN. High values indicate fast denitration low, respectively, on slow.

Results.

It was found that the rate of denitration through perpendicularly liver of rats using the analyte is significantly higher than the introduction of isosorbid-5-Mononitrate, and is equal to VRel.= 0,95, i.e., were set lower values speed denitration than in the case of isosorbid-5-Mononitrate.

The results of the method presented below:

Example - YRel.< / BR>
1 - 0,45

5/3 - 0,49

7/7 - 0,49

10 - 0,28

12/1 - 0,36 l

1. Cyclohexylacetate General formula I

< / BR>
where A is a bond or C1- C6-Allenova chain;
-alkyl;

R2is hydrogen, OH, C1- C6-alkyl, C2- C6alkenyl, hydroxy-(C1- C6)-alkyl;

Z is hydrogen, C1- C6-alkyl, C2- C6alkenyl or C2- C6-quinil, which may contain one or two substituent selected from the group OH, C1- C6-alkylcarboxylic, C1- C6-alkoxy, halogen, cyano, carboxy, C1- C6-alkoxycarbonyl, -CONR3R4C1- C6-alkylcarboxylic, pyridinyl, N-oxypyridine, pyrrolidinyl, or Z and R2together with the nitrogen atom to which they are attached, form a six-membered heterocyclic ring, optionally containing oxygen, R3and R4-C1- C6is alkyl, hydrogen, as well as their optically active forms.

2. Cyclohexylacetate under item 1, characterized in that a communication or1- C3-accelerograph, in particular-CH2group.

3. Cyclohexylacetate under item 1 or 2, wherein R1is a hydrogen atom or a C1- C3is an alkyl group, in particular, were marked or heterogroup.

4. Cyclohexylacetate on PP.1 to 3, wherein R2is a hydrogen atom, hydroxy, hydroxy-C1-farinograph.

5. Cyclohexylacetate on PP.1 to 4, wherein R3and R4- independent of each other a hydrogen atom or a C1- C3is an alkyl group, in particular methyl.

6. Cyclohexylacetate on PP. 1 to 5, characterized in that Z is a hydrogen atom, a C1- C6-alkyl, C2- C6alkenyl or2- C6-Alchemilla, and alkyl and Alchemilla group can be substituted once by halogen atom, carboxy, carboxamido-FROM1- C3-alkoxy, C1- C3-alkylcarboxylic-, hydroxy-, or cyano, or alkyl - and altergroup can be multiply substituted by hydroxy or C1- C3-alkylcarboxylic or Z represents a 3 - or 4-peridogram or N-hydroxy-peridogram or pyrolidine ring, or for the case when B is - NR2- CO - Z - group, Z is C1- C3-alkoxygroup.

7. Cyclohexylacetate under item 1 selected from the group of the following compounds: TRANS-N-acetyl-4-nitrocyclohexanone, diamid N-(TRANS-4-nitrocyclohexanone) succinic acid, N-bis-(2-hydroxyethyl)amide, TRANS-4-nitrocyclohexanone acid amide 4-hydroxy-N-(TRANS-4-nitrobenzyloxy)butyric acid, and is of nitrato formula I

< / BR>
where a is a bond or C1- C6-alkylen;

B - group-NR1- CO - Z-CO - NR2- Z, -NR1- SO2Z;

R1is hydrogen or C1- C6-alkyl;

R2is hydrogen, OH, C1- C6-alkyl, C2- C6alkenyl, hydroxy-(C1- C6)-alkyl, Z is hydrogen, C1- C6-alkyl, C2- C6alkenyl or2- C6-quinil, which may contain one or two substituent selected from the group OH, C1- C6-alkylcarboxylic,1- C6-alkoxy, halogen, cyano, carboxy, C1- C6-alkoxycarbonyl, -CONR3R4C1- C6-alkylcarboxylic, pyridinyl, N-oxypyridine, pyrrolidinyl, or Z and R2together with the nitrogen atom to which they are attached, form a six-membered heterocyclic ring, optionally containing acid, R3and R4- C1- C6is alkyl, hydrogen, characterized in that the compound of General formula II

< / BR>
where A and B are as above, is subjected to the interaction with forming the ester of nitric acid reagent.

9. Drug for the treatment of diseases of the heart and the circulatory system on the basis of nitro compounds, characterized in, and other conventional additives and auxiliary substances.

10. Cyclohexylacetate General formula I under item 1

< / BR>
where A is a bond or C1- C6- Allenova chain;

B - group NR1- CO - Z - CO - NR2- Z, -NR1- SO2Z;

R1is hydrogen or C1- C6- alkyl;

R2is hydrogen, hydroxy, C2- C6alkenyl, C1- C6-alkyl, hydroxy - C1- C6-alkyl;

Z is hydrogen, C1- C6-alkyl, C2- C6alkenyl or C2- C6-quinil, which may contain one or two substituent selected from the group of hydroxy, C1- C6-alkylcarboxylic, C1- C6-alkoxy, halogen, cyano, carboxy, C1- C6-alkoxycarbonyl, CONR3R4C1- C6-alkylcarboxylic or Z means the pyridine ring N-oxypyridine and pyrolidine ring, or Z and R2together with the nitrogen atom to which they are attached, form a six-membered heterocyclic ring, optionally containing oxygen, and R3and R4mean hydrogen or C1- C6-alkyl, as well as their optically active forms with prolonged nitratoides activity.

 

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Antihypoxic tool // 2098085
The invention relates to medicine, specifically to the creation of medicines, stamina body tissues to hypoxia by preventing disturbances of the homeostasis of energy systems and restoration in pathology, ischemic and hypoxic cell damage

FIELD: medicine, in particular ophthalmology.

SUBSTANCE: treatment of ophthalmology diseases by administration in conjunctival sac of patient eye as well as injection of medicine, in particular alkali salt of 5-amino-2,3-dihydro-1,4-phtalasindione is disclosed. Eye drops, eye ointment contain alkali salts of 5-amino-2,3-dihydro-1,4-phtalasindione or mixture thereof, wherein lithium or sodium, or potassium, or calcium salt of 5-amino-2,3-dihydro-1,4-phtalasindione is selected as alkali salt, and mixture of above mentioned salt in equal ratio is used as mixture salts of 5-amino-2,3-dihydro-1,4-phtalasindione.

EFFECT: treatment method with improved effectiveness and reduced treatment duration.

16 cl, 6 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with decreasing intraocular pressure during carrying out operative interferences in case of cataract and glaucoma. One should introduce 5%-pentamine solution together with anesthetic solution into sub-Tenon's space at the quantity of 0.1-0.4 ml and 1.0-1.5 ml, correspondingly. The method enables to achieve considerable decrease of intraocular pressure and, thus, provide decreased quantity of such complications, as prolapse of vitreous body, iris and corneal endothelium traumatization.

EFFECT: higher efficiency.

4 ex

FIELD: medicine; pharmaceutical engineering.

SUBSTANCE: pharmaceutical composition COMPRISES 5-(2-pyrazinyl)-4-methyl-1,2-dithyol -3-thion (oltipraze) and dimethyl-4,4'-dimetoxi-5,6,5',6'-dimethylene-dioxybiphenyl-2,2' dicarboxilate (DDB) as the main components. Oltipraze: DDB proportion is preferentially equal to 50-1:1-50, the most preferential being 5:1.

EFFECT: enhanced effectiveness of treatment.

6 cl, 6 dwg, 9 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with antiviral preparations that contain aliphatic alcohol C21-C28 in combination with either nucleoside or nucleotide analog or phosphoformic acid in pharmaceutically acceptable carrier. It is necessary to mention that n-docosanol is considered to be a preferable aliphatic alcohol. Concentration of aliphatic alcohol C21-C28 corresponds to 0.05% to 40% by weight. Concentration of either nucleoside or nucleotide analog or phosphoformic acid corresponds to 0.1% to 10% by weight. The innovation, also, deals with the ways to treat viral infections due to applying such compositions. Aliphatic alcohols C21-C28 synergistically intensify antiviral activity of nucleoside analogs directed against replication of several herpetic viruses and that of cow's pox.

EFFECT: higher efficiency of inhibition.

28 cl, 13 dwg, 21 ex, 6 tbl

FIELD: medicine, obstetrics, gynecology, mammology.

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EFFECT: improved method for treatment.

2 tbl

FIELD: thoracic surgery and pulmonology.

SUBSTANCE: method comprises complex therapy utilizing ecdysterone-containing preparation, namely 0.005-0.01% ecdysterone solution prepared by dissolving ecdysterone in mixture of equal portions of 70% alcoholic tinctures of calendula and eucalyptus. Preparation is administered orally in dose of 30-40 drops before meal.

EFFECT: activated formation of antibodies, function of phagocytes and T cells, protein synthesis processes, including surfactant synthesis, and stabilized alveolocyte membranes.

2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a solid pharmaceutical composition. The composition comprises tegaserod or its salts as an active component that is sensitive to acid effect and/or difficultly soluble in water, and a loosening agent taken in the amount at least 15 wt.-% as measured for the total mass of the composition. The composition is stable and can be prepared easily, it shows good rate release after its administration patients and good biological availability. The composition is designated for prophylaxis, modulation or treatment of visceral pain or discomfort, for modulation of visceral sensitivity or perception, improvement of sensory perception of rectum intestine tension and for treatment of anal dysfunction regulation.

EFFECT: improved and valuable medicinal properties of composition.

14 cl, 7 ex

FIELD: medicine.

SUBSTANCE: the present innovation should be fulfilled due to performing sclerotherapy with 96%-ethanol under ultrasound control at the dosage of 0.5-1 ml/ml of nodal volume in case of nodal neoplasms and 3-5 ml in case of cystic neoplasm after liquid aspiration. Moreover, a day before each course of sclerotherapy one should introduce Movalis for 5-10 d once daily after meals. The course of sclerotherapy should be started with introducing 96%-ethanol, then 8-10 d later it is necessary to introduce benzyl peniccilin sodium salt at the dosage of 0.5-1 ml/ml of nodal volume in case of nodal neoplasm, and 0.5 ml after liquid aspiration - in case of cystic neoplasm. The innovation enables to decrease side manifestations of complex therapy performed due to decreasing the quantity of injections.

EFFECT: higher efficiency of therapy.

1 cl, 4 ex

FIELD: medicine, proctology.

SUBSTANCE: the present innovation deals with introducing a sclerosing preparation consisting of equal parts of 96% alcohol and 2% lidocain at the quantity of 2-4 ml, for all fissures it is necessary to inject 10 ml 0.5%-novocain solution and 2 ml solcoseryl or actovegin, then one should change the direction to move a needle towards coccyx towards sphincter's external diameter to introduce 5 ml 0.5%-Novocain solution and, not shifting a needle, one should introduce a sclerosing preparation. The innovation enables to conduct simultaneously the following procedures: anesthesia, the rupture of adhesions, blocking painful and sensitive branches of pudendal nerve that innervate ulcerous area that leads then to decreased pain syndrome, decreased sphincter's spasm and better ulcer's healing.

EFFECT: higher efficiency of sclerotherapy.

2 dwg, 2 ex

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