Derivatives pianolasociety or their pharmaceutically acceptable salts.

 

(57) Abstract:

Usage: in medicine as protivogipertonicheskoe, antisemitische and vasodilator. The inventive product derivatives pianolasociety f-ly 1, where A is OH or-OC/O/CH3or A and B together-relationship, B - H; if R1- H, R2= H, C/O/CH3nXnor C/O/NHCH3-nABOUTnwhere X= F, CI, Br or methyl, n=0-3, or R1or R2together denote (CH2)m(CH2)m-1C/O/, NR3/CH2/2/C/O/, (CH2)m-2NHC,O/ or (CH2)m-2OC/O/, where m= 4 or 5, R3-H or methyl, or their pharmaceutically acceptable salts. LD (50)600 mg/kg is 43-56%. Connection structure 1:

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5 table.

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions.

In Japanese laid patent publication N Sho 58-67683 (67683/1983) [1] indicate that the connection (code number BRL-34915) of the formula (A)

Prowse the 1 [2] reported perhaps the connection BRL-34915 activates TO+channel and shifts the resting membrane potential to hyperpolarization.

In Br.J.Pharmac (1986), 89, S. 395-403 [3] it is shown that the connection BPI-34915 weakens the trachea of the Guinea pig, and made the assumption that it may be useful as drugs for the treatment of asthma.

Br. Angiolohy (1987), 27, S. 423-431 [4] suggested that the composition for activation+channel is effective for the treatment of arrhythmia and angina pectoris.

In Br.J.Pharmac (1987), 91, S. 804-813 [5] it is shown that the connection BRL-34915 weakens the uterus of the rat. Consequently, it may be effective to prevent premature birth.

In DLO News ROUND-UP N 312 (1987) indicate that the connection BRL-34915 effectively for medical treatment of incontinence and pain.

However, in EP-A-28 449 [6] and EP-A-28 064 [7] indicated that the derivatives of benzopyran, which include the connection BRL-34915, may adversely affect cardiac function.

In this regard, we conducted intensive studies of new compounds, and the present inventors have found that new derivatives of pianolasociety are a great activity for lowering blood pressure. Then the real inventor is derived pianolasociety;

development of methods of obtaining these derivatives;

creating protivogipertonicheskoe, vasodilator (coronary or cerebral) and asthma compositions containing as the active ingredient in these proceedings;

development of methods for the treatment of hypertension, serdechnososudistyh disorders, diseases of the brain vessels and asthma.

New derivatives of pianolasociety according to the present invention represented by the formula:

O (1)

in which And indicates HE or OS(O)CH3-nXnwhere X denotes a fluorine atom, chlorine atom, bromine atom, methyl or metaxylene group, n represents 0 or an integer from 1 to 3, or a and b together represent a bond;

In denotes the atom H, or M - together with a link;

if R1denotes a hydrogen atom, R2denotes a hydrogen atom, C(Z)CH3-nXnor(Z)NHCH3-nXnwhere Z represents an oxygen atom or a sulfur atom;

if R1does not denote a hydrogen atom, R1and R2together denote (CH2)m, (CH2)m-1C(Z), N(R3)(CH2)2C(Z), (CH2)m-2NHC(Z) or (CH2)m-2OC(Z), where m is an integer of 4 or 5, and R3the seat shall denote a hydrogen atom and indicates IT, and pharmacologically acceptable salts of the compounds which can form salts, are very active in the lowering of blood pressure.

The compounds of formula (1) are new compounds, and the fact that these compounds, with the exception of compounds in which R1and R2represent simultaneously a hydrogen atom and indicates IT, they are very active to lowering blood pressure, it is totally unexpected.

The compounds of formula (1) exist in the form of stereo and optical isomers, and the present invention covers all of these isomers.

Each of the substituents in the formula (1) representing the connection active low blood pressure, are described in detail.

And may constitute, for example, HE, OC(O)CH3, OS(O)CH2F, OC(O)CH2Cl, OC(O)CH2Br, OC(O)CF3, OC(O)CH2OCH3or OS(O)CH2CH3.

And may indicate a relationship with Century

The preferred example As HE is.

If R1represents a hydrogen atom, R2may be, for example, a hydrogen atom, C(O)CH3C(O)CH2F, C(O)CH2CL, C(O)CH2Br, C(O)CF3, OC(O)CH2OCH3C(O)CH2CH3C(O) preferred.

If R1does not denote a hydrogen atom, R1and R2together denote (CH2)4, (CH2)5, (CH2)3C(O), (CH2)4C(O) NH(CH2)2C(O) N(CH3)(CH2)2C(O), (CH2)2NHC(O) and (CH2)2OC(O), preferably (CH2)4, (CH2)5, (CH2)3C(O), (CH2)4C(O) NH(CH2)2C(O) and N(CH3)(CH2)3C(O).

The method of obtaining compounds of formula (1).

Reaction scheme I

O

O

The compound of formula (II) result in the interaction with ammonia in an inert solvent in order to obtain the compounds of formula (III). Preferred solvents are methanol, ethanol and isopropanol. The reaction temperature may be in the range 0-90aboutWith, preferably in the range of 15-60aboutC. If desired and if necessary, the reaction can be carried out at high pressure. The molar ratio of the reaction may be an excess of moles of ammonia per mol of compound of formula (II), preferably 2-5 moles of ammonia per mole.

Reaction scheme 2

(III) OV)

Reaction scheme 3

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Reaction scheme 4

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Reaction scheme 8

(II)

(1) CH2=SNCO2(primary or secondary1-C4alkyl)

(2) NaOH

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(1) (Boc)2O or BocCl

(2) acetic anhydride/sodium acetate anhydrous sodium

(3) N+< / BR>
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In the reaction shamah Y denotes the usual, easily leaving group such as halogen atom (chlorine atom, bromine atom or iodine atom), acetoxy or triptoreline. Y' represents a chlorine atom, a bromine atom, an iodine atom, o-toluensulfonate, n-toluensulfonate or m-toluensulfonate. The symbols m, n and X have the meanings given for formula (I).

In the formula (1) compounds (compounds of formula (IV) or (V)), where R1denotes a hydrogen atom, can be obtained by the method shown in reaction schemes 2 and 3.

That is, the compound of formula (III) result in interaction with YC(O)CH3-nXnorder to obtain compounds of the formula (IV) (see reaction scheme 2).

The molar ratio YC(O)CH3-nXnbased on the compounds of formula (III) is in the range of 1.0 to 1.5 moles, preferably 1,01-,05 moles per mole.

The reaction solvent is an inert solvent, for example, halogenated, dichloromethane, chloroform or carbon tetrachloride, benzene, toluene, ethyl shall ritilin and pyridine, potassium carbonate and sodium carbonate. The molar ratio of these substances may be redundant in the calculation of the YC(O)CH3-nXn, preferably 1.0 to 2.0 moles per mole.

The reaction temperature is in the range of 0-90aboutWith, predpodtitelno 0-30aboutC.

The duration of reaction is sufficient such that it provides sufficient reaction of acylation. She is 0.5 to 20 hours, preferably from 1 to 2 o'clock

The compounds of formula (III) is carried out in interaction with C(O)NCH3-nXnorder to obtain the compounds of formula (V) (see reaction scheme 3).

The molar ratio C(O)NCH3-nXnbased on the compounds of formula (iII) is in the range of 1.01 to 1.5 mol, preferably of 1.01-1.05 moles per mole.

The solvents are the same as those used according to the reaction scheme 2.

Can be applied catalyst to accelerate the reaction. As examples of the catalyst can lead triethylamine and trimethylamine. The molar ratio of these substances is in the range of 0.01 to 0.05 moles per mole per the compound of formula (III).

The reaction temperature is in the range of 0-90aboutWith, preferably 5-30aboutC.

As for Podolskii acylation. She is 0.5 to 20 hours, preferably 1-2 hours

In the case when R1and R2together are (CH2)m(in accordance with the method according to reaction scheme 4, compounds of formula (II) result in interaction with pyrrolidine or piperidine order to obtain compounds of the formula (VI).

Reaction conditions are the same as described above for reaction scheme I.

The compounds of formula (I) in which R1and R2together are (CH2)m-1C(O), (CH2)m-2NHC(O) and (CH2)m-2OC(O), get the reaction schemes 5, 6 and 7, respectively.

That is, the compounds of formula (III) result in the interaction, respectively, with YC(O)(CH2)m-1Y', Y'(CH2)m-2NC(O) or YC(O)O(CH2)m-2Y' and then the obtained compound is subjected to a cyclization reaction by removing HY' in accordance with the traditional methods commonly used to obtain the corresponding compounds of formulas (VII), (VIII) and (IX).

Reaction conditions are the same as for the reaction of scheme 2, when the compounds of formula (III) result in the reaction with the acid chloride of the acid. Reaction conditions are the same as for the reaction of scheme 3 in the case when sedimentrelated acid after the reaction of acylation of the amino group. Solvents in the reaction of cyclization are the same solvents that in reaction scheme 2.

As the acid acceptor can be applied potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. Their molar ratio is in excess based on the compound of the formula (iII), preferably 1.5 to 3 moles per mole.

The temperature of the cyclization reaction is from 0aboutWith up to reflux temperatures of the reaction solution cyclization, preferably from 30aboutC to the reflux temperature of the reaction solution.

The duration of the reaction is 0.5 to 24 hours, preferably 0.5 to 5 hours

The compounds of formula (I) in which R1and R2together denote NH(CH2)m-2C(O), can be obtained according to the method represented by reaction scheme 8.

Hydrazine, which lead into an interaction with compounds of the formula (II) may be either anhydrous or gidratirovannym.

The molar ratio of hydrazine per the compounds of formula (II) is in the range of 1.01 to 3.0 moles per mole, preferably of 1.01-1.05 moles per mole.

Solvents are alcohols, such as methanol, ethanol and isopropanol.

The temperature of the reactions is sufficient such duration, which provides sufficient reaction. As a rule, it can be from 10 min to 10 h, preferably 0.5 to 2 hours

The molar ratio of primary or secondary1-C2alkyl (lower Alky)acrylate, which lead into an interaction with compounds of the formula (X) obtained by bringing into the interaction of hydrazine with compounds of the formula (II), 0.7-1.0 moles per mole. For this reaction the solvent can be used methanol, ethanol or isopropanol, etc.

The reaction temperature is 0-150aboutC, preferably from 15aboutC to the reflux temperature of the solvent.

As for the duration of the reaction, it should provide sufficient reaction. As a rule, it should be 0.5-20 hours, preferably 2-3 hours

Ester (lower) alkyl thus obtained compounds of the formula (XI) result in interaction with sodium hydroxide or potassium hydroxide to obtain compounds of the formula (XI).

The molar ratio used above sodium hydroxide or potassium hydroxide per alkilany ester as the starting material is 1.05 to 1.5 moles per mole, pressage of alkyl, are alcohols, such as methanol, ethanol and isopropanol.

The reaction temperature is in the range of 0-100aboutWith, preferably 15-30aboutC.

The duration of reaction is 1-20 hours, preferably 2-3 hours,

The compounds of the formula (XI) first lead in the interaction with di-tertbutylbenzene or tertbutyloxycarbonyl, and the amino group (the relevant parts of hydrazine powered group), adjacent to the methylene chain in the compound (XI), protect tertbutoxycarbonyl group. The molar ratio of di-tertbutylbenzene or tertbutyloxycarbonyl in the calculation of the compound of formula (XI) is from 1.0 to 1.05 moles per mole.

As solvents can be used inert solvents such as dichloromethane, chloroform, tetrahydrofuran (THF) and ethyl ether.

As catalysts for the reaction can be used basic catalysts such as triethylamine, trimethylamine, DBU (1,8-diazabicyclo/5.4.0/undec-7-ene) and pyridine.

The reaction temperature is in the range of 0-150aboutWith, preferably 10-30aboutC.

The duration of the reaction is 0.5 to 20 hours, preferably 1-2 hours

After centuries is Yes and sodium acetate.

Acetic anhydride, used as a reagent in the reaction of cyclization, can be used also as a solvent. The amount of sodium acetate is 0.1-3 equivalents per acetic anhydride, preferably 0.1 to 0.3 equivalents.

Then the compound of formula (XII) can be obtained by removal of the protective group (tertbutyloxycarbonyl) of the above compounds.

The removal of the protective groups is carried out by adding the acid, for example triperoxonane acid. Other acids can be n-toluensulfonate or sulphuric acid.

Usually the acid is used in excess, based on the connection from which to remove the protective group, for example 1.5 to 10 moles per mole, preferably 1.5 to 5 moles per mole.

The reaction temperature is in the range 0-30aboutWith, preferably 0-15aboutC.

The duration of reaction is 0.5-10 h, preferably 0.5 to 3 hours

The compounds of formula (I) in which R1and R2together denote N(CH3)(CO2)m-2C(O), can be obtained by methylation of the compounds of formula (XI) or (XII) using commonly used meteorologi agent, for example under the conditions and the volume of oxygen. In the case when Z is a sulfur atom, the desired compound can be obtained by sulfonation of the corresponding compounds reagent (HOWESSON'a). In addition, the compounds of formulas (V) and (VIII) in which Z represents a sulfur atom, can be obtained by casting in the interaction of the compounds of formula (III) c XmCH3-nNC(S) or Y'(CH2)m-2NC(S), respectively.

Compounds represented by formula (1) in which a and b together denote a bond, can be obtained by treating compounds of formula (1), And in which IT denotes, and denotes a hydrogen atom, an alkali, such as sodium hydride, sodium hydroxide and sodium carbonate, in an inert solvent, such as THF, dimethylformamide (DMF) and chloroform.

In this case, it is not necessary to isolate the compound of formula (1), where IT denotes and denotes a hydrogen atom.

The compounds of formula (II), which is the starting material can be obtained according to the following reaction scheme.

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After the action on the known compounds of formula (XIII) with sodium hypochlorite order to obtain compounds of the formula (XIV) compounds of the formula (II) can be obtained by Ostankino group of compounds of formula (XV) is obtained through the reaction of epoxiconazole the compounds of formula (XIV) with ammonia, pyrrolidine or piperidine suitable reducing agent, such as triethylphosphite and nutriasia, the compound of formula (XV) may be introduced into the compound of the formula (1-2). However, it is preferable to carry out the reaction of compounds (II) with amines.

O

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As mentioned above, the active compounds according to the present invention (referred to as more "real connection"), except for compounds in which R1and R2simultaneously denote a hydrogen atom and indicates IT, have a great sosudorasshiryayuschey activity and blood pressure-lowering activity. Therefore, these compounds are useful as pharmaceuticals in the treatment of hypertension, angina pectoris, arrhythmia, diseases of the brain vessels and asthma in mammals, including humans. Therefore, in accordance with the present invention offers a pharmaceutical composition containing an effective amount of these compounds to treat the aforementioned diseases.

As a way of introducing these connections, you can specify parenteral administration by injection (subcutaneous, intravenous, intramuscular or intraperitoneally injection), the use of ointments, candles suspense.

The above-mentioned pharmaceutical or veterinary compositions containing these compounds in amounts of about 0.1-to 99.5 wt. preferably in quantities of 0.5 to 95 wt. calculated on the total weight of the composition. These compounds or compositions containing these compounds, can be added to any other pharmaceutically or veterinary active compounds. In addition, the composition according to the present invention can contain a variety of these compounds.

Clinical dose of these compounds varies depending on age, body weight, sensitivity or symptoms, etc. of the patient. However, the effective daily dose is usually 0.1-100 mg, preferably from 0.5% -% 10 mg for adults. If necessary, can be applied to amounts outside the specified interval.

These compounds can be prepared in the form of various suitable compositions depending on the method of administration, in accordance with a commonly used traditional methods of preparing pharmaceutical compositions.

Namely, tablets, capsules, granules or pills for oral administration can be prepared using excipients, such as sugar, lactose, glue, the tragakant, methylcellulose or polyvinylpyrrolidone; a dispersing agent, for example, starch, carboxymethyl cellulose or its calcium salt, crystalline powdery cellulose or polyethylene glycol; lubricants, for example talc, magnesium stearate or calcium, colloidal silicon dioxide, laurate sodium or glycerin.

Injectable liquids, solutions, emulsions, suspensions, syrups or aerosols can be obtained with the use of a solvent for the active ingredient, for example water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol or polyethylene glycol; surfactants such as esters of fatty acids and of sorbitol, esters of fatty acids and polyoxyethylenesorbitan, esters of acids and polyoxyethylene, polyoxyethylene ether, hydrogenated castor oil or lecithin; a suspending agent, for example, sodium salt carboxymethyl, cellulose derivatives, e.g. methyl cellulose, or natural rubber, for example, tragacanth or gum Arabic; and if contorversy means, for example, n-oksibenzoynoy acid, benzalkonium chloride or a salt of sorbic acid. Similarly ointment can hydrophilinae ointments or hydrogel base. Candles can be prepared using, for example, cocoa butter, polyethylene glycol, lanolin, triglycerides of fatty acids, coconut oil or Polysorbate.

Examples of tests.

Protivogipertonicheskoe action.

Compound dissolved or suspended in a solvent (PEG 400* H2About 3:1 volume/volume)) and administered orally to spontaneously hypertensive rats-males (SHP, 11 weeks).

* Polyethylene glycol with an interval of molecular weight 380-420.

Systolic blood pressure (ACS) is measured by the method tailcuff (Natsame Seisakusho CO. Ltd. KN-210-1) before oral introduction and one hour after administration of the tested compounds. Rats SHP pre-heated at a temperature of 50aboutC for 3-5 min in a warm box and placed in a cage on a hot plate (37about(C) 5-15 minutes

In table.1 presents the percentage decrease in systolic blood pressure within one hour after administration of the tested compounds. Each value is the average of three animals.

Test for acute toxicity.

Used mouse-male-IGR (6 weeks). Compound (examples 8 and 11), suspended in ineni. 't died, none of the mouse that received the test compound at a dose of 600 mg/kg (n 3). Both compounds showed low toxicity.

Examples (including reference examples and examples, the compositions)

Examples of the present invention are described in detail, but they in no way limit the present invention.

In the reference examples and the examples of the present invention abbreviations "NMR" and "MS" means "spectrum of nuclear magnetic resonance and mass+spectrum", respectively.

With s l o h n m s p R I m e R 1. 7,8-Dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano (2,3-f)-benzo-2,1,3-oxadiazol-3-oxide

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To the mixture to 4.41 g (to 19.9 mmol) 6-amino-3,4-dihydro-2,2-dimethyl - 3,4-epoxy-7-nitro-2H-benzo(b)of Piran, 1.29 g (32 mmol) of sodium hydroxide, 400 ml of ethanol and 40 ml of water is slowly added dropwise, with stirring to 32.2 g )26 mmol) of 6% sodium hypochlorite solution at room temperature.

Upon completion of the reaction, the solution mixture was added 1 l of brine and extracted three times with ethyl acetate. Connected to an ethyl acetate layer was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent the residue is subjected to chromatography on a column of silica gel with skin is Yellow crystals, so pl. 144-145aboutC.

With s l o h n m s p R I m m e R 2. 7,8-Dihydro-6,6-dimethyl-7,8-epoxy-6G-pyrano (2,3-f)benzo - 2,1,3-oxadiazol

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To a mixture of 1.0 g (4.27 mmol) 7.8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano(2,3-f)Ben - zo - 2,1,3+oxadiazol 3-oxide and 6 ml of benzene is added dropwise with stirring to 0.80 ml (4,70 mmol) triethylphosphite for 15 min at 60aboutC. Then the mixture is stirred for three hours. After removal of the solvent under reduced pressure the residue is subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate/hexane (1:1 (volume/volume)) and gain of 0.82 g of target compound (yield 88%). Part of the resulting product is re-crystallized from hexane and get yellow crystals (so pl. 97-99aboutC).

With s l o h n th p R I m e R 3. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazol

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of 0.82 g of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazole (3.8 mmol) dissolved in 25 ml of 16.7% ammonia solution in ethanol, lead interaction in a glass tube high pressure at 60aboutC for 48 hours the Reaction solution is distilled off, the residue is subjected to chromatography on a column of silica gel using cachestore substance brown. Part of the resulting connection is re-crystallized from ethanol and obtain the target product as colourless crystals. So pl. 159-162aboutC.

NMR (l3+ DMCO-6//(M. D.):

OF 1.26 (3H), 1,49 (3H), 2,80-3,30 (5H), TO 3.33 (1H), 3,78 (1H), PC 6.82 (1H), 7,98 (1H).

MS: 133 (50%), 163 (100%), 235 (M+, 3%).

P R I m e R 1. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-methylurea-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazol

O

To a mixture of 200 mg (0,850 mmol) 7.8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano(2,3-f)benzo - 2,1,3+oxadiazole and 20 ml dichloromethane added under stirring at room temperature, 55 μl (0,935 mmol) of methyl isocyanate, followed by stirring for 23 hours

Precipitated precipitated crystals are separated by filtration and obtain 227 mg (yield 92%) of colorless crystals of the target compound.

So pl. 213-215aboutC.

M. S. 44, 202, (30%), 274 (M+-N2Oh, 6%).

P R I m m e R 2. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylthiourea - 6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

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To a mixture of 200 mg (0,850 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy - 8-amino-6N-pyrano(2,3-f)benzo-2,1,3+oxadiazole and 20 ml dichloromethane added under stirring at room temperature 68 mg (0,935 mmol) methylisothiocyanate, followed by stirring tcvetnyh crystals (yield 47%).

So pl. 213-215aboutC.

M. S. 91 (62%), 202 (67%), 290, 308 (M+, 27%).

P R I m e R 3. (Intermediate compound to obtain the compound according to example 3).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(2 - chloroethylamino)-6N - pyrano(2,3-f)benzo-2,1,3-oxadiazol

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To a mixture of 400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole and 40 ml dichloromethane added under stirring at room temperature, 200 ál (of 1.87 mmol) 2-chlorotriazine, followed by stirring for 6 hours Precipitated precipitated crystals are separated by filtration and obtain 480 mg (yield 83%) of the desired product as colorless crystals.

So pl. 178-180aboutC.

M. S. 87 (57%), 163, 304 (78%), 340 (M+, 8%).

(The compound of example 3).

7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-OK - solidsolid-1-yl)- 6H-pyrano(2,3-f)benzo-2,1,3-oxadiazol

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To 410 mg (1.2 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-chloroethylamino)-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole obtained above, the type of 3.32 g (24 mmol) of potassium carbonate, 400 mg (2.4 mmol) of potassium iodide and 50 ml of absolute acetone and the mixture is heated under reflux for 13 h under nitrogen atmosphere. The impurities separated by filtration at room temperature. Then Phi is I and dried over anhydrous magnesium sulfate. Then the solvent is distilled off. The residue is re-crystallized from ethyl acetate and obtain 102 mg (yield 34% ) of pure desired product as colorless crystals.

P R I m e R 4. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-isopropylamino - 6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

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To a mixture of 200 mg (0,850 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole and 20 ml dichloromethane added under stirring at room temperature 92 μl (0,935 mmol) isopropylmalate, followed by stirring for 6 hours the Precipitated crystals filtered off and obtain 120 mg (yield 44%) of target compound as colorless crystals.

So PL; 201-203aboutC.

M. S. 43 (40%), 202, 302 (20%), 320 (M+, 12%).

P R I m e R 5. (Intermediate compound to obtain the compound of example 5).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(2 - chlorocarbons-amino)- 6N-pyrano(2,3-f)benzo-2,1,3-oxazol

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To a mixture of 400 mg (1,79 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo+2,1,3-oxadiazole, 260 μl (to 1.87 mmol) of triethylamine and 40 mg dichloromethane added under stirring at room temperature 193 μl (to 1.87 mmol) of 2-chloroethylphosphonic, followed by stirring for 21 hours, the Reaction is IntelliTouch again from chloroform and receive 507 mg (yield 87%) of target compound as pale yellow crystals.

So pl. 164-166aboutC.

M. S. 133 (48%), 235, 307 (M+, 25%).

(The compound of example 5),

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(2-OK - isoxazolin-3-yl)-6N - pyrano(2,3-f)benzo-2,1,3-oxadiazol

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To 400 mg (1,17 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2 - chlorocarbonate)-6N-pyrano(2,3-f)benzo-2,3,1-oxadiazol - La, obtained above, add 3,24 g (23,4 mmol) of potassium carbonate, 388 mg), 2.34 mmol) of potassium iodide and 50 ml of absolute acetone and the mixture is heated under reflux for 26 h under nitrogen atmosphere. The insoluble matter is filtered off at room temperature. To the filtrate add ethyl acetate, washed three times with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off. The residue is subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate/methanol (10:1 vol/vol) and obtain 339 mg (yield 94%) of target compound in a solid brown color. Part of the obtained compound re-crystallized from ethyl acetate and get yellow crystals.

So pl. 177,5-180aboutC.

M. S. 43 (25%), 272, 287 (65%), 305 (M+, 8%).

P R I m e R 6. (Intermediate compound to obtain the compound of example 6).

7,8-Dihydro-6,6-dimethyl-7-oceti-3-hydroxy-4- (1-piperidinyl)-6-amino-7-nitro-2H-benzo(b)of Piran, 0.7 ml of 50% aqueous potassium hydroxide solution, 4 ml of methylene chloride and 10 mg Bu4N+Br-add equal to 4.97 g (a 4.03 mmol) of 6% aqueous sodium hypochlorite solution under stirring at room temperature and the reaction continued for 9 hours the Organic layer was separated and the aqueous layer was extracted twice with methylene chloride. Connected methylenchloride layer washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is subjected to chromatography on a column with silicagel using as eluent a mixture of ethyl acetate/hexane (1:3 volume/volume) and get 297 mg (yield 43%) of the desired product as oil. Part of the obtained compound was dissolved in ethanol and added dropwise to the resulting solution a solution of hydrogen chloride in ethanol and dry ether, receive hydrochloric salt of the target compound as yellow crystals.

So pl. 210-213aboutC.

(The compound of example 6).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1 - piperidinyl)-6N-pyrano- (2,3-f)benzo-2,1,3-oxadiazol

< / BR>
A mixture of 297 mg (0,93 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperidinyl)-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol-hydroxy - Yes, 6 ml of ethylene glycol and 60 mg (0,93 mmol) NaN3heated to a temperature which xtraceroute twice with chloroform. After drying, the United chloroformic layers over anhydrous sodium sulfate, the solvent is banished so the Residue is subjected to chromatography on a column of silica gel using as eluting agent a mixture of ethyl acetate/hexane (1:3 volume /volume) and obtain 84 mg (yield 30%) of target compound in the form of oil. Part of the obtained compound was dissolved in a mixture of ethanol/ethyl ether, add a mixture of hydrogen chloride/ethyl alcohol and get a hydrochloric salt of the target compound as yellow crystals.

So pl. 202-205aboutC.

P R I m e R 7. (Intermediate compound for producing compounds of examples 7 and 8).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-/n- (1-oxo-4-chloro)butyl/amino - 6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 80 mg (0.34 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy - 8-amino-6H-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 14 mg (0,374 mmol) of sodium hydroxide, 6 ml of methylene chloride and 3 ml of water is added 42 ml (0,374 mmol) of 4-chlorobutyrate under stirring at room temperature, followed by stirring for 30 minutes At the end of the reaction methylenchloride layer is separated and the aqueous layer was extracted twice with methylene chloride. United methylenchloride layers washed with diluted SATELNODE and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is subjected to preparative thin-layer chromatography on silicagel using as eluent a mixture of ethyl acetate/ethanol (10:1 vol/vol) and obtain 194 mg (yield 37%) of target compound.

Pale-yellow crystals. So pl. 160-161aboutC.

(The compound of example 7).

6,6-Dimethyl-8-(2-oxo-1-pyrrolidinyl) -6N-pyrano(2,3-f)benzo - 2,1,3-oxadiazol

< / BR>
A mixture of 116 mg of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-oxo-4-chloro) butyl-amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 940 mg of potassium carbonate and 113 mg of potassium iodide are suspended in 20 ml of acetone and heated under reflux in nitrogen atmosphere for 24 hours After cooling impurities filtered through a suction filter and separated, the solvent is distilled off. The residue is subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate/methanol (5: 1 vol/vol) and get the target connection. The resulting connection will recrystallized from ethanol and irradiated with 72 mg (yield 74%) of pure target compound as colorless crystals.

So pl. 238-240aboutC.

P R I m e R 8. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-1 - pyrrolidinyl)-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

< / BR>
A mixture of 150 mg (0,441 g mmol of potassium and 146 mg (0,882 mmol) of potassium iodide are suspended in 20 ml of acetone and heated under reflux for 17 h under nitrogen atmosphere. After cooling, any insoluble matter is filtered off. Then, the filtrate is diluted with ethyl acetate and washed three times with water. After drying the obtained product over anhydrous sodium sulfate and evaporation of the solvent to obtain 33 mg (yield 25%) of target compound as colorless crystals.

So pl. 242-244aboutC.

NMR (DCl3+ DMSO-6) (M. D.):

OF 1.35 (3H), AND 1.54 (3H), 1,94-2,78 (4H), 3,05-3,61 (3H), OF 3.77 (1H), 5,33 (1H), 6,97 (1H), 7,39 (1H).

M. S. 86 (100%), 270 (95%), 285 (60%), 303 (M+, 12%).

P R I m e R 9. (Intermediate compound to obtain the compound of example 9).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-/n- (1-oxo-5-chloro)pencil/ amino-6N-pyrano(2,3-f)benzo-2,1,2-oxadiazol

< / BR>
200 mg (0.85 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N - pyrano(2,3-f)benzo-2,1,3-oxadiazole and 37 mg (0,94 mmol) of sodium hydroxide dissolved in a solution mixture of 10 ml of chloroform and 5 ml of water and to this add 120 ál (0,94 mmol) 5-chlorovaleryl-chloride.

After mixing the solution mixture for 15 min chloroform layer is separated and the aqueous layer was washed twice with chloroform. The United chloroform layers are washed with saturated sodium bicarbonate solution and dried with anhydrous sodium sulfate. The solvent is distilled off and otesi ethyl acetate/methanol (10:1 volume/volume), obtain 56 mg of the target compound as crystals (yield 16%). The compound obtained is used as starting material in example 9 without further purification.

(Compound of example 9).

7,8-Digi draw-6,6-dimethyl-7-hydroxy-8-(2-oxo-1-piperidinyl)-6N - pyrano(2,3-f)benzo-2,1,3-oxadiazol

O

A mixture of 56 mg of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-/n-(1-hydroxy-5 - chloro)pencil/amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 440 mg (3,16 mmol) of potassium carbonate and 52 mg (0,316 mmol) of potassium iodide are suspended in 10 ml of acetone and heated under reflux for 22 hours After cooling, the undissolved substance was separated by filtration and the filtrate diluted with ethyl acetate. The resulting solution was washed twice with water and once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent the residue is subjected to preparative thin-layer chromatography with silica gel using as eluent a mixture of ethylacetate/methanol (10;1 volume/volume) and receive 30 mg (yield 54%) of target compound. Part of the resulting connection is re-crystallized from a mixture of ethyl acetate/hexane and obtain pale yellow crystals.

MP. 192-194aboutC.

P R I m e R 10. 7,8-Dihydro-6,6-dimethy-7,8-epoxy-6N-pyrano(2,3-f)Ben - zo-2,1,3 - oxadiazole, 63 μl (0,756 mmol) pyrrolidine and 2 ml of ethanol is heated under reflux with stirring for 31 hours After removal of the solvent the residue is subjected to preparative thin-layer chromatography with silica gel using as eluent a mixture of ethyl acetate/methanol (1:1 vol/vol) and obtain 120 mg (yield 60%) of target compound. Part of the obtained compound was dissolved in dry ether and added dropwise to the resulting solution a solution of hydrogen chloride in ethanol, receive hydrochloric salt of the desired product as pale yellow crystals.

So pl. 208-209aboutC.

P R I m e R 11. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-acetylamino-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 200 mg (0,850 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy - 8-amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 128 μl (0,917 mmol) of triethylamine and 17 ml of methylene chloride added with stirring at a temperature of 0about128 μl (0,917 mmol) acetylchloride, followed by stirring for 30 minutes At the end of the reaction the precipitated crystals are separated by filtration. The crystals are washed successively with methylene chloride and water and dried under reduced pressure and a temperature of 80aboutTo get 223 kg (yield 88%) of target compound. Then, after prosout again from ethylacetate and obtain 7 mg of the target compound as pale yellow needle crystals.

So pl. 241,0-242,0aboutC.

P R I m e R 12. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-chloroacetamido-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 200 mg (0.85 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano(2,3-f) benzo - 2,1,3-oxadiazole, 130 μl (0,935 mmol) of triethylamine and 20 ml of methylene chloride added with stirring at room temperature 74 μl (0,935 mmol) chloracetamide, followed by stirring for 30 minutes

Upon completion of the reaction, the precipitated crystals are separated by filtration and obtain 201 mg (yield 76% ) of target compound. Colourless crystals, so pl. 232,0-234,0aboutC.

P R I m e p 13. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-paulolino-6N-pyrano(2,3-f)benzo-2,1,3-about xad

O

To a mixture of 200 mg (0.85 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 130 μl (0,935 mmol) of triethylamine in 20 ml of methylene chloride added with stirring at room temperature 115 μl (0,935 m mol) of pivaloate, followed by stirring for 3.5 hours. Upon completion of the reaction solution mixture is washed three times with water and dried over anhydrous magnesium sulfate. After removal of the solvent the residue will recrystallized from ethanol and pure target compound (yield 191 mg, 70%). Pale-the-pyrano(2,3-f) benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 200 mg (0.85 mmol) of 7.6-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 130 μl (0,935 mmol) of triethylamine and 20 ml of dichloromethane added under stirring at room temperature 98 μl (0,935 mmol) isobutyramide, followed by stirring for four hours. Upon termination of the reaction mixture is washed three times with water and dried over anhydrous magnesium sulfate. After removal of the solvent the residue will recrystallized from ethanol and obtain 109 mg (yield 42%) of pure target compound.

Pale-yellow crystals, so pl. 194,0-196,5aboutC.

P R I m e R 15. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-triptorelin-6N-p - early- (2,3-f)benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 300 mg (1.28 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano(2,3 - f)benzo - 2,1,3-oxadiazole and 3 ml of pyridine, add 180 μl (1.28 mmol) of anhydrous triperoxonane acid with stirring for three hours at a temperature of 0aboutC, followed by stirring for three hours at room temperature. Upon termination of the reaction mixture is washed three times with water and dried over anhydrous sodium sulfate. After removal of the solvent the residue is subjected to chromatography on a column of silica gel using as the aqueous connections will recrystallized from ethanol and pure target compound.

Pale yellow crystals; so pl. 257,0-259,0aboutC.

P R I m e R 16. 7,8-Dihydro-6,6-dim ethyl-7-hydroxy-8-propionamido-6N-pyrano(2,3-f)benzo-2,1,3 - oxadiazol

< / BR>
To a mixture of 200 mg (0.85 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano(2,3-f)benzo - 2,1,3-oxadiazole, 130 ml (0,935 mmol) of triethylamine and 20 ml of methylene chloride added with stirring at room temperature 81 μl (0,935 mmol) propionitrile, followed by stirring for 6 hours At the end of the reaction the solution mixture is washed three times with water and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is re-crystallized from ethanol and obtain 77 mg (yield 31%) of the pure target compound.

Pale yellow crystals; so pl. 203,0-205,0aboutC.

P R I m e R 17. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-bromoacetamide-6N-pyrano(2,3-f) benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 180 mg (0,765 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 117 μl (0,842 mmol) of triethylamine and 20 ml of methylene chloride add 73 μl (0,842 mmol) bromoacetanilide under stirring at room temperature, followed by stirring for 1 hour At the end of the reaction the precipitated crystals are separated by filtration and obtain 199 mg (vychodil-7-acetoxy-8-acetylamino-6N-pyrano (2,3-f)benzo-2,1,3-oxadiazol

< / BR>
A mixture of 100 mg (0.36 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-acetyl - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole, 2 ml of pyridine and 34 μl (0.36 mmol) of acetic anhydride was stirred at room temperature for 24 hours after the reaction mixture was diluted with ethyl acetate, washed with water and saturated water solution of sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is re-crystallized from chloroform and obtain 58 mg (yield 26%) of target compound.

Pale-yellow crystals. so pl. 236,0;6,0-238,5aboutC.

P R I m e R 19. 6,6-Dimethyl-8-acetylamino-6H-pyrano(2,3-f) benzo-2,1,3-oxadiazol

O

To a mixture of 80 mg (0,289 mmol) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - acetylamino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole and 5 ml dry tetrahydrofuran added 25 mg of sodium hydride (oil containing more than 55%) with stirring for 1 h at room temperature. Then the mixture gently add water and extracted three times with ethyl acetate. United an ethyl acetate layers are washed sequentially with 0.5 G. hydrochloric acid, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is subjected to fractional jam/volume) and obtain 24 mg (yield 32%) of target compound. The resulting connection will recrystallized from ethanol and pure target compound.

So pl. 218,0-220,0aboutC.

P R I m e R 20. (Intermediate compound I to obtain a compound of example 20).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-guide - razine-6N-pyrano (2,3-f)benzo-2,1,3-oxadiazol

< / BR>
To 1.0 g of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano(2,3, -f) benzo-2,1,3-oxadiazole add 10 ml of ethanol and 250 mg Hijazi hydrate and heated under reflux for 16 hours the Solvent is distilled off under reduced pressure and add ethylacetat. The precipitated crystals are separated by filtration and receive intermediate compound 1 in the form of pale yellow crystals.

(Yield 1.0 g, 89%).

So pl. 126,0-127,0aboutC.

(Intermediate compound 2 for obtaining compound of example 20).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-2-(2 - oxycarbonyl) hydrazino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

O

To 1.0 g of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-hydrazino-6N-pyrano (2,3-f)benzo-2,1,3-oxadiazole add 10 ml of ethanol and 300 mg of acrylate and heated under reflux for 3 hours the Solvent is distilled off under reduced pressure and to the residue add 10 ml of ethanol and 3 ml of 1 n sodium hydroxide solution and stirred at the slots and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is distilled off. To the residue add a solution of chloroform/ethyl acetate (1: objem/volume) and the precipitated crystals are separated by filtration, to obtain the intermediate compound 2 in the form of pale yellow crystals (yield 250 mg, 20%).

(Intermediate compound 3 for obtaining compound of example 20).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-tertbutoxycarbonyl-3 - oxopyrrolidin-2-yl)-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazol

< / BR>
To a mixture of 250 mg of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-2-(2-oxycarbonyl)hydrazino-6N-pirano(23-f10 ml of chloroform and 100 mg triethylamine add under stirring for 1 h at room temperature, 200 mg of di-tertbutylbenzene. To the mixture are added 20 ml of a saturated aqueous solution of ammonium chloride and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is distilled off. To the residue add 2 ml of acetic anhydride and 100 mg of anhydrous sodium acetate and heated at a temperature of 60aboutC for 10 minutes the Solvent is distilled off and to the mixture was added 30 ml of water and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is distilled off. To the residue add mixture is offered by compound 3 in the form of pale yellow crystals. Output 200 mg, 65%

So pl. 190,0-191,0aboutC.

(Compound of example 20).

7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(3 - oxopyrrolidin-2-yl-6N - pyrano(2,3-f)benzo-2,1,3-oxadiazol

< / BR>
To 200 mg of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-tertbutoxycarbonyl-3-oxapyrazon - lidin-2-yl)-6N-pyrano(2,3-f)benzo-2,1,3-OK - cavasola added under ice cooling, 2 ml triperoxonane acid and stirred for 1 h at room temperature. The resulting solution was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is distilled off. To the residue is added a mixture of ethyl acetate/diethyl ether (1:1) and the precipitated crystals are separated by filtration, to obtain the target compound as colorless crystals. Yield 130 mg, 84%

So pl. 230,0-233,0aboutC.

P R I m e R 1 on the composition of

Tablet Compound of example 8 10 G. of Lactose 260 g of Crystalline powder - crustacean leaves cellulose 600 g Corn starch 350 g Oxypropylation 100 g of CMC-CA* 150 g of magnesium Stearate and 30 g total 1500 g

* Calcixerollic

The above components are mixed in the usual way and tabletirujut, get 10,000 tablets containing each 1 mg sports is Skye powder - crustacean leaves pulp 1000 g magnesium Stearate 50 g total of 1500 g

The above components are combined in the usual way, then placed in gelatin capsules and receive 10,000 capsules with each capsule 1 mg of the active ingredient.

P R I m e R 3 composition

Soft capsules of the Compound of example 8 10 g of PEG (polyethylene glycol) 400 479 g Triglyceride saturated fatty acids 1500 g of Pepper-mint oil, 1 g of Polysorbate 80 10 g total 2000

The above components are mixed and placed in a soft gelatin capsule No. 3 in the usual way, get 1000 soft capsules with each capsule 1 mg of the active ingredient.

P R I m e R 4 on the composition of

Ointment Compound of example 8 1.0 g Liquid paraffin 10.0 g Cetyl alcohol 20,0 g White vaseline to 68.4 g Ethylparaben (Ethylparaben) 0.1 g L-menthol 0.5 g total 100.0 g

The above components are mixed in the usual way and get 1% ointment.

P R I m e R 5 on the composition of

Candles Compound of example 8 1 g Witepsol n* 478 g of Witepsol W35* 520 g of Polysorbate 80 1 g total 1000 g

* (Trade name connection triglycerides)

The above components are mixed in the molten state in the usual way and poured into molds for candles, then cooled to harden and get 1000 candles weighing 1 g each with soderzhaniya example 8 1 mg Distilled water for injection 50 ml

A solution prepared by dissolving the compounds in distilled water when it is required.

P R I m e R 21. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo - tetrahydropyrimidin-1-yl)-6N-pyrano(2,3-f)benzo-2,1,3-oxa - diazol (compound No. 21).

< / BR>
To 400 m (1.7 mmole) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole was added 40 ml of dichloromethane and stirred at room temperature. To the solution mixture was added 192 μl (to 1.87 mmol) 3-chloropropionate and everything was mixed for 26 hours Precipitated precipitated crystals were filtered to obtain colorless crystals. Then the crystal was added 4,70 g (34 mmol) of potassium carbonate, 0.56 g (3.4 mmole) iodotope potassium and 120 ml of absolute acetone, and the mixture was heated under reflux for 12 h under nitrogen atmosphere. At room temperature the reaction mixture was filtered. The filtrate was converted, to the residue was added ethyl acetate, was washed with water and saturated aqueous NaCl, and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled. Then the residue was precrystallization of ethyl acetate, and was 73 mg (yield: 13%) of the pure target compound as colorless crystals.

So the hydroxy-8-(2-oxo - 1,3-tetrahydroxide-1-yl)-6N-pyrano(2,3-f)benzo-2,1,3 - oxadiazole (compound 22)

< / BR>
To 700 mg (2,98 mmole) 7,8-dihydro-6,6-dimethyl)-7-hydroxy-8 - amino-6N-pyrano(2,3-f)benzo-2,1,3-oxadiazole was added 540 μl (a 3.87 mmole) of triethylamine and 80 ml of chloroform, and the mixture was mixed at room temperature. To the solution mixture was added to 0.61 g (3,88 mmole) 3-chloropropionate, and the mixture was mixed for 1 h the Reaction solution was washed three times with water and dried over anhydrous sodium sulfate. The solvent was distilled and turned out the oil. Then oil was added 8,24 g (59,6 mmole) of potassium carbonate, 0,99 g (5,96 mmol) iodotope potassium, and 140 ml of absolute acetone, and the mixture was heated under reflux for 7 h under nitrogen atmosphere. At room temperature the reaction mixture was filtered. The filtrate was distilled, to the residue was added ethyl acetate, and the mixture was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled. Then the residue was subjected to chromatogaphy on silicagel column using as a developing solvent of ethyl acetate, giving a colorless oil. Part of the obtained oil was precrystallization from ethanol and then ethyl acetate giving the pure target compound in the form of colorless crystals Dihydro-6,6-dimethyl-7-hydroxy-8-(ethoxymethylene) amino-6N-pyrano(2,3-f)benzo-2,1,3-Arcadia evil

< / BR>
To 200 mg of 0.85 mmole) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole was added 130 μl (0,94 mmole) of triethylamine and 20 ml of methylene chloride and the mixture is stirred at room temperature. To the resulting solution was added 85 μl (0,94 mmole) of methoxyacetanilide and the mixture is stirred for 2 hours the Precipitated crystals were filtered, rinsed with methylene chloride and dried at 80aboutWith under reduced pressure, giving 176 mg (yield 67%) of the desired compound.

So pl. 217-219aboutC.

Mass spectrometry: 45 (100%), 235 (30%), 307 (M+, 15%).

Indicators antigipertenzivnoe activity are presented in table.2.

Data of biological testing in comparison with the known analogues are presented in table.3.

The compounds used in the tests are as follows:

< / BR>
< / BR>
< / BR>
Example 1 application Japan N 5867683,

< / BR>
Example 7 application of Japan N 5867683.

< / BR>
Anti-asthma activity.

Method.

Male white Guinea pigs, Hartley (250-450 g) was scored by decapitation and the trachea was removed. Each trachea was cut spirally and was divided into 2-3 segments. Each segment was suspenderbelt with the tense is>TheC, in an atmosphere of 95% O2and 5% CO2. The composition of the modified mortar Tirade was as follows, mm: NaCl 137, KCl 2.7, And CaCl21,8, MgCl21,0, NaHCO320, NaH2PO40.32 and glucose 11. Mechanical responses were recorded as a result of isotopically (Nihon Kohden, type TD-112S). In order to determine the relaxation of spontaneous tone, the compounds of this invention cumulative added to the bath after the repeated reaction of relaxation on the addition of isoproterenol (1 Microm). The reaction relaxation was expressed as a percentage of the maximum response to be added to the bath 1 mmole of aminophylline at the end of the experiment. Some indicators EU50(concentration giving 50% of maximum response) were calculated using linear regressional analysis on the linear part of the curve dose-response. As reference compounds used BRL-34915 (see formula A). The compounds of this invention and the reference compound were dissolved and diluted in 100% dimethyl sulfoxide. Aminophylline was dissolved in distilled water.

The results of the experiments are presented in table.4.

Vasodilatatory activity.

Method.

Portal wenene bodies, containing modified Krebs solution at 37aboutC. in the atmosphere ABOUT2with 5% CO2. Was given a load of 1.0 g, and encountered the voltage was recorded by isothermal transduction power offset (company Nihon Kohden, TV T). The strips are brought into equilibrium within 60-90 min in wash solution when changing the solution every 20 minutes After reaching equilibrium compounds represented by the invention and the reference connection BRL-34915 (see formula A) was added to the drug every 15 min with an increase of one third log units. Since this experiment was undertaken to study the reduction in the frequency of spontaneous contractions caused by the test compound, the frequency of contractions was counted for 10 min at the end of each 15-minute interval. The activity of the potassium channel opening, which is associated with vasorelaxation (cook, 1988), was expressed in percent frequency of spontaneous contractions in the period before drug administration. Some indicators pic30(negative logarithmic concentrations of the drug, giving a 30% response compared to the baseline condition) was calculated using linear regression analysis of the linear part of each curve reactions from osteoarthritis of General formula I:

< / BR>
where A is OH or-OC(O)CH3-group;

B is hydrogen,

or A and B together denote a bond, if R1is hydrogen, R2is hydrogen, C(O)CH3-nXnor C(O)NHCH3-nXnwhere X is fluorine, chlorine, bromine or methyl, n=0-3-integer

or R1and R2together denote (CH2)m, (CH2)m-1C(O) NR3(CH2)2C(O), (CH2)m-2NHC(O) or (CH2)m-2OC(O), where m = 4 or 5, R3is hydrogen or methyl,

or their pharmaceutically acceptable salts.

Priority signs

03.02.88 - A-OH or A and B together represent a bond, B is hydrogen or together with A connection, provided that R1is hydrogen, R2is hydrogen, R1and R2together - (CH2)m, (CH2)m-1C(O), where m is 4 or 5, or its pharmaceutically acceptable salt.

01.03.88 - A-OH, B is hydrogen when uslovii that R1is hydrogen, R2is hydrogen or C(O)NHCH3, R1and R2together - (CH2)2OC(O), or its pharmaceutically acceptable salt.

29.03.88 - A - OH, B is hydrogen, R1and R2together - NH(CH2)2C(O), or its pharmaceutically acceptable salt.

25.05.88 - A - R2- C(O)CH3-nXnwhere X is fluorine, chlorine, bromine or methyl; A Is O or 1-3-an integer R1and R2together - (CH2)m, (CH2)m-1C(O), where m= 4 and 5, or its pharmaceutically acceptable salt.

 

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< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl

The invention relates to medicine, namely to urology, and pulmonology, and can be used in the treatment of tuberculosis of the urinary system

FIELD: oncological diseases.

SUBSTANCE: invention is designed for use in complex treatment of urinary bladder cancer in case of propagation of tumor to sub-epithelium connective tissue. Method comprises transurethral resection and introduction of immune preparations and furacillin solution. Once transurethral resection completed, three-way Foli catheter is transurethrally introduced to patient, through which mixture of standard furacillin solution with 10·106 ME interferon α-2β is injected from the first postoperative day and over following 3-5 postoperative days bringing summary dose of interferon to 50·106 ME.

EFFECT: prevented traumatism of urinary bladder due to single introduction of catheter and assured continuous action of drugs without development of immune complications.

FIELD: veterinary science.

SUBSTANCE: the suggested preparation contains the following ratio of components, weight%: dioxidine 0.48-0.52, furacrylin 0.021-0.027, dimethylsulfoxide 38-50, distilled water - the rest.

EFFECT: higher therapeutic efficiency.

3 ex, 3 tbl

FIELD: veterinary medicine.

SUBSTANCE: the present innovation deals with ways and preparations for treating and preventing acute and chronic endometritis, vaginitis, balanoposthitis. One should introduce froth-forming suppositories into cavity of affected organ, moreover, suppositories contain in their composition different medicinal substances, foaming agents, a filler, foam stabilizers and other crystalline substances reduced up to amorphous state. Moreover, components of suppositories are in the following ratio, g (weight%): potassium iodide 1.5 (6.8), furacillin 0.7 (3.2), Trikhopol (Metronidazole) 2.0 (9.0), lidocaine hydrochloride 0.8 (3.6), calcium carbonate (precipitated chalk) 2.6 (11.8), sodium bicarbonate 9.0 (41.0), calcium stearate 0.2 (0.9), common salt 1.0 (4.6), citric acid 3.0 (13.6), 20%-alcoholic solution of MGD-2 emulsifier 1.2 (5.5). The method provides prolonged complex bactericidal and antiprotozoan, antiphlogistic, local anesthetizing impact upon animal and activation of body protective system.

EFFECT: higher efficiency of prophylaxis and therapy.

1 tbl

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