Derivative (1-heteroatom-1-heterocyclyl)alkane, or a geometric or optical isomers or racemates, or its pharmaceutically acceptable acid salt of accession, or its solvate, the means of obtaining it, acetamidine compounds, pharmaceutical composition having neuroprotective properties

 

(57) Abstract:

Derivative (1-heteroatom-1-heteroseksualci)alkane of General formula I where X is oxygen or sulfur, Z Is O, S, N-R2or C=N; R1- H, alkyl, halogen, or R1and the ring together represent benzofuranol system rings; R2- H, lower alkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl or CF3; A - WR3-C-R4or C=C(R5R6W IS O, NH, R3- H, lower alkyl or acyl; R4- alkyl, cyclopropyl or perfluoroalkyl, or R3and R4together form a ring in which n=4, R5and R6- H or lower alkyl, or a geometric or optical isomers or racemates, except 1-(4-pyridyl)-1(2-thiazolyl)ethanol and 1-(2-pyridyl)-1-(2-thiazolyl)ethanol. The compounds of formula I are valuable in the treatment of acute and chronic neuropsychiatric disorders characterized by progressive processes that will sooner or later lead to the death and dysfunction of nerve cells. 8 C. and 4 h.p. f-crystals, 1 table. about

The present invention relates to new heterocyclic compounds having therapeutic activity, methods and intermediate products for their production, medicines containing named onionskin neuropsychiatric disorders, for which reliable and clinically effective treatment is available. This is different from the other group of disorders covers a wide range of initial cases, which are characterized by the promotion of progressive pathological processes that will sooner or later lead to the death and dysfunction of nerve cells. Seizures, cerebral ischemia, injury, or neurodegenerative diseases such as Alzheimer's or Parkinson's disease are common conditions that are associated with neurodegeneration of the brain and/or spinal cord. Stubbornly continuing the search for possible cures neurodegerative diseases includes studies of antagonists of excitatory amino acids, inhibitors of lipid perechisleniya, calcium channel antagonists, inhibitors of specific pathways of the arachidonic acid cascade, Kappa-opioid agonists, adenosine agonists, antagonists of PAF and other other agents. Currently there is no consensus concerning the importance of the role played by connections belonging to any of these major classes.

The number of articles relating to chemistry perlovich dyes, A. Treibs and employees (Leibig's Ann.Chem., 1/BR>< / BR>
where

n=1 or 2;

R - a different group.

In the article concerning the reactions of fulvenes with 1,3-bipolar compounds. ((Leibig's Ann.Chem.. 1981, 491-501) presents the following link:

< / BR>
The pharmacological activity is not associated with any of the above compounds. The above compounds are not included in the scope of the present invention.

In the application for the European patent EP 293220 and J. Heterocyclic Chem., 1990, 27, 1933-40 presents 1,5 - diarylpyrazole formula:

< / BR>
where

X is O or S.

The mentioned compounds are possible anti-inflammatory drugs. This activity depends on the presence of 1,5-dialling deputies, which prevents these compounds from the scope of the present invention.

In the application for the European patent EP 351194 as inhibitors of 5-limes-shenasi presented compounds of General formula

< / BR>
in which

Q is thiazolium;

Ar1aryl containing up to 10 carbon atoms;

Ar26-clenney aryl, including pyridyl;

X is O, S, SO, SO2; or NH;

A is a direct link to X, or represents (1-6C)alkylene, (3-6C)albaniles, (3-6C)akinyan or cyclo(3 - 6C)alkylene. Deputy Ar1-A-X - is represented by the compound formula

< / BR>
in J. Heterocyclic Chem., 1989, 26, 1869-1873 described compounds of formulas

< / BR>
or

< / BR>
The pharmacological activity of these compounds is not known. These three compounds are excluded from the scope of the present invention.

In Zh. Obshch. Khim. 1962, 32, 2664-26 70 (Chem. Abs. 58: 9057h) described 1-(4-pyridyl)-1-(2-thiazolyl)ethanol. In Zh. Obshch. Khim. 1963, 33, 825 - 828 (Chem. Abs. 59: a) described 1-(2-pyridyl)-1-(2-thiazolyl)ethanol. The pharmacological activity is not known for these two compounds. These two compounds are excluded from the scope of the present invention.

The main purpose of the present invention is the provision of a structurally new heterocyclic compounds, which are assumed to be due to their pharmacological profile, will be valuable in the treatment of acute and chronic neuropsychiatric disorders characterized by progressive processes that will sooner or later lead to the death and dysfunction of nerve cells. Such disorders include seizures: cerebral ischemia; dysfunction resulting from injury of the brain and/or spinal cord; hypoxia and anoxia, for example, when drowning, and including perinatal and neonatal hypoxic anfictionica cerebrally, AIDS, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, horey's disease, epilepsy, multiple sclerosis and amyotrophic lateral sclerosis; brain dysfunction due to surgery involving cardiopulmonary bypass, or in connection with the operation of the brain, including endarterectomy carotid arteries; and the dysfunction of the CNS (Central nervous system) due to exposure to neurotoxins or radiation. Useful properties shown, for example, by the ability of these compounds to inhibit delayed cell death in models of ischemia in gerbils induced by bilateral occlusion.

The present invention relates to a compound of General formula I

< / BR>
where

X is O, S, Se or NR2;

Y1, Y2, Y3, Y4independently represent N or CR2;

Z Is O, S, Se. NR2or C=N;

R1represents one or more groups selected from H, lower alkyl, lower acyl, halogen, lower alkoxy or CF3or R1together with the ring

< / BR>
represents a condensed benzene ring, optionally substituted:

R2is H, lower alkyl, CF3and when there is more than one R2group they can be chosen independently:

A is

< / BR>
in which

W is O, S, NH or N-lower alkyl;

R3- H, lower alkyl or lower acyl;

R4- lower alkyl, aryl-lower alkyl, cyclopropyl or lower perfluoroalkyl,

or

R3and R4together form a ring

< / BR>
in which

n = 3 or 4;

R5and R6independently are hydrogen, lower alkyl or aryl-lower alkyl, provided that at least one of X, Y1, Y2, Y3or Y4is nitrogen and which ring

< / BR>
is not 1-methyl-2-imidazolyl;

its geometric and optical isomers and racemates, where there are such isomers, as well as its pharmaceutically acceptable acid salts of accession and their solvate:

and provided that excluded the following five compounds:

1-(C-indolyl)-1-(2,5-dimethyl-3-pyrrolyl)Aten;

1-(1-methyl-2-indolyl)-1-(1-methyl-2-pyrrolyl)Aten;

1-(1-methyl-2-indolyl)-1-(1-methyl-2-pyrrolyl)ethanol;

1-(4-pyridyl)-1-(2-thiazolyl)ethanol;

1-(2-pyridyl)-1-(2-thiazolyl)ethanol;

"Pharmaceutically acceptable acid salt of the merger include, but are not limited to such salt, etandisulfonat, mesilate, fumarate, maleate and succinate.

For the preferred compounds of the invention include compounds having the formula II

< / BR>
in which

X is O or S;

A, Z, R1and R2are as previously defined above. More preferred compounds of this invention relate to compounds having the General formula III

< / BR>
in which

X and Z independently are O or S;

W represents O;

R1, R2, R3, R4are as previously defined above;

and to compounds of General formula IV

< / BR>
in which

X and Z independently represent O or S;

R1, R2, R5and R6are as previously defined above.

Analogous compounds in which X is Se, for example, 1-(3-furyl)-1-(4-methyl-5-selenazoline)ethanol and 1-(2-selenazoline)-1-(3-thienyl)ethanol is most preferred.

Throughout the description and appended claims, a given chemical formula or name, will cover all geometric and optical isomers and racemates where such isomers and their pharmaceutically acceptable acid salts attached is ormula invention. If you have not installed or not stated otherwise, the term "lower alkyl" means a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and pentyl, and hexyl straight or branched chain.

If you have not installed or not stated otherwise, the term "lower perfluoroalkyl" means a straight or branched alkyl group having from 1 to 4 carbon atoms, a fully substituted by fluorine. Examples of the lower performanceline groups include trifluoromethyl, pentafluoroethyl and heptafluoropropyl.

If you have not installed or not stated otherwise, the term "lower acyl" means a straight or branched alllow group having from 1 to 6 carbon atoms. Examples of the lower acyl include formyl, acetyl, propionyl, out-butyryl, valeryl and pivaloyl.

If you have not installed or not stated otherwise, the term "lower alkoxy" means a straight or branched CNS group having from 1 to 6 carbon atoms. Examples of the lower alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert - butoxy, pentox, and hexose straight and branched chain.

the who defined above, substituted by a hydroxy-group. Examples of hydroxy-lower alkyl include hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.

If you have not installed or not stated otherwise, the term "lower acyloxy-lower alkyl" means a lower alkyl as defined above, substituted by an oxygen atom which carries the group, lower acyl, which is defined above. The examples mentioned lower acyloxy-lower alkyl include acetoxymethyl, propionylacetate, 1-acetoxyethyl and 2-acetoxyethyl.

If you have not installed or not stated otherwise, the term halogen means fluorine", "chloro", "bromo" or "iodine".

If you have not installed or not stated otherwise, the term "lower alkoxy-lower alkyl" means a lower alkyl as defined above, substituted by a group of lower alkoxy, which is defined above. The examples mentioned lower alkoxy-lower alkyl include methoxymethyl, ethoxymethyl, methoxy-ethyl, and ethoxyethyl.

If you have not installed or not stated otherwise, the term "aryl" means phenyl, naftalina, follow, thienyl, pyridyloxy or pyrrolidino group, optionally substituted. If you have not installed or not stated otherwise, the term "aryl-lower alkyl" means a group of nisga aryl-lower alkyl include benzyl, phenethyl, phenylpropyl, 4-performer, furfuryl, Z-furyl-methyl, triletal and Tennille.

If you have not installed or not stated otherwise, the term "condensed benzene ring" means a fully saturated five-membered heterocyclic ring containing one heteroatom, condensed to the benzene ring. Examples of condensed benzene rings include benzofuranyl, benzo[b]thienyl and indolyl.

The most preferred compounds of formula (I) in accordance with the present invention are:

1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol;

1-(4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol;

1-(3-furyl)-1-(4-methyl-5-thiazolyl)ethanol;

1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)ethanol;

1-(2,4-dimethyl-5-thiazolyl)-1-(3-furyl)ethanol;

1-(4-methyl-5-thiazolyl)-1-(3-thienyl)ethanol;

1-(2-ethyl-4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol;

1-(2,5-dimethyl-4-oxazolyl)-1-(3-furyl)ethanol;

1-(4-methyl-5-thiazolyl)-1-(2-thienyl)ethanol;

1-(5-thiazolyl)-1-(3-thienyl)ethanol;

1-(3-furyl)-1-(4-methyl-5-oxazolyl)Aten;

1-(3-furyl)-1-(4-methyl-5-oxazolyl)-1-propene;

1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)Aten;

1-(2-furyl)-1-(4-methyl-5-oxazolyl)ethanol;

1-(2-thiazolyl)-1-(2-thienyl)ethanol;

1-(2-thiazolyl)-1-(3-Tien is R>
1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)-2,2,2-triptorelin;

1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethylamine;

1-(2-thiazolyl)-1-(3-thienyl)ethylamine;

and their pharmaceutically acceptable acid salts of joining or solvate.

The present invention also relates to methods of producing compounds having the formula I. throughout the subsequent General descriptions of such methods should be understood that, if necessary, to various reagents and intermediate products add and later remove the corresponding protective group by a method known to experts in the field of organic synthesis. Generally accepted methods of use of such protective groups are described, for example, in "Protective Groups in Organic Synthesis", T. W. Greene, Wiley-Interscience, New York, 1981.

The above compound in which A is

< / BR>
can be obtained by:

a) interaction of the compounds of General formula V with an ORGANOMETALLIC derivative of General formula VI

< / BR>
or (b) the interaction of compounds of General formula VII

< / BR>
with ORGANOMETALLIC VIII

< / BR>
or (C) the interaction of compounds of General formula IX

< / BR>
ORGANOMETALLIC derivative of General formula

R4M,

and clearing reactio) or allermuir (R3represents a lower acyl) reagent.

or (d) interaction, particularly in cases where R4is a perfluoroalkyl, compounds of General formula IX with a derivative Silla General formula

RiSiMe3.

Alternative compounds of formula I in which A is

< / BR>
and R3is hydrogen, can be first obtained as above, and then converted into a compound in which R3is lower alkyl or lower acyl.

Methods (a), (b) or (c) can be implemented, for example, by reacting the ketone of structure V, or VII, or IX with a pre-formed ORGANOMETALLIC derivative VI or VIII or R4M, respectively, in a suitable anhydrous diethyl ether or tetrahydrofuran, or hexane, or mixtures thereof. The above reaction should be carried out at an appropriate temperature, typically between -100 and +50oC and preferably in an inert atmosphere, usually nitrogen or argon. In a particular embodiment, to ORGANOMETALLIC derivative VI or VIII or R4M, respectively, in anhydrous diethyl ether or tetrahydrofuran, or hexane, or their mixtures at a temperature of from about -50 to -78oC and under nitrogen atmosphere is added dropwise obvestilo period of time the mixture is brought to room temperature and then quenched by adding water or a lower alcohol.

Necessary product I in which A represents A

< / BR>
can then be isolated and purified, and characterized using standard techniques.

Method (d) can be performed, for example, by treatment of a solution of ketone IX and derivative silila R4SiMe3in an appropriate anhydrous solvent, for example diethyl ether or tetrahydrofuran, tetrabutylammonium. This reaction should be carried out at an appropriate temperature, typically between -100 and +50oC and preferably in an inert atmosphere, usually nitrogen or argon. After an appropriate period of time, the reaction mixture is brought to room temperature and then treated with 6M hydrochloric acid.

Necessary product I in which A is

< / BR>
can then be isolated and purified, and characterized using standard techniques.

Ketones of General formula V, or VII, or IX are compounds that are commercially available or have been previously described in the literature, or compounds that can be obtained by direct use of known methods.

The present invention also relates to new intermediate products, and and is is About, S or Se;

Yiis C-H, C-lower alkyl or C-CF3;

Y2is N;

or Y3or Y4present CR2and acyl group attached to the other of these conditions:

R4represents C2-C6is alkyl or perfluoroalkyl;

R1, R2and Z are as defined above,

provided that when X is Oh, acyl group is not attached to Y3and excluded the following four compounds ethyl-4-thiazoleacetic; tert-butyl-5-thiazoleacetic; tert - butyl-5-oxazolidinone; tert-butyl-4-tert-butyl-2-methyl-5-oxazolidinone.

In ORGANOMETALLIC derivative of General formula (VI or VIII, or R4M, m represents a metal residue, for example, halide Li or Mg. Such compounds are commercially available or have been previously described in the literature, or they can be obtained by direct use of known methods of ORGANOMETALLIC chemistry.

Derivatives silila formula R4SiMe3are either commercially available, for example, CF3SiMe3or were previously described in the literature, or they can be obtained by direct use of known methods.

HWR3of the compounds of formula I in which A is

< / BR>
or (b) the use of the compounds of formula IX as a substrate for standard alkenes reacts, for example, the reaction of the Wittig reaction Peterson or reaction poppy-Marri.

Method (a) can be realized, for example, by treatment of a solution of the compounds of formula I in which A is

< / BR>
in a suitable inert solvent with an acid or a base, or with a reagent such as thionyl chloride or phosphorus oxychloride. The above reaction should be conducted at an appropriate temperature, usually between -20oC and the boiling point of the solvent. In a preferred embodiment, a solution of the compounds of formula I in which A is

< / BR>
in a solvent, for example dichloromethane or chloroform, at a temperature of from 0oC to 10oC is treated with acid, for example, anhydrous hydrogen chloride or p-toluensulfonate acid or thionyl chloride. Then the reaction mixture is brought to room temperature or above. Necessary product I in which A is

< / BR>
can then be isolated and purified, and characterized using standard techniques.

The compounds of formula I in which A is
as a substrate for the implementation of Ritter reaction, or (b) use of compounds of General formula I in which A is

< / BR>
as a substrate for the implementation of the response type Mitsunobu, or (C) the interaction of compounds of General formula I in which A is

< / BR>
with trimethylsilylmethyl, Me3SiN3in the presence of a Lewis acid, for example, the TRIFLUORIDE of diethylether boron to obtain azide of the formula I in which A is

< / BR>
and then restore the azide using, for example, hydrogen in the presence of a palladium or platinum catalyst.

Some compounds of General formula I contain an asymmetric center and can therefore exist in enantiomeric forms. These enantiomers can be separated using methods that are well known to specialists in this field. Such methods include, for example:

(i) direct separation by chiral chromatography, for example, by high performance liquid chromatography (HPLC) using a chiral column: or

(ii) the recrystallization of the diastereomeric salts formed by interaction of the base I with an optically active acid:

x diastereomeric derivatives, for example, by crystallization or chromatography, followed by recovery of the compounds of formula I.

Alternative compounds of formula I can be obtained in optically active form by using a chemical or enzymatic method of asymmetric synthesis.

Some compounds of General formula I in which A is

< / BR>
can exist as E and Z (TRANS - and cisisomers). Such isomers can be separated using standard techniques, for example, crystallization or chromatography, which are well known to the specialists in this field.

Neuroprotective properties of the compounds of formula I are illustrated by their ability to inhibit the slow death of nerve cells in the model of ischemia in gerbils induced by bilateral occlusion.

Used male Mongolian gerbils (60 - 80g). Drugs were dissolved in isotonic saline solution containing dimethyl sulfoxide.

Caused ischemia in gerbils by 5-minute occlusion of both carotid arteries, followed by the procedure described by R. Grill, A. C. Foster, and G. N. Woodruff, J. Neuroscience, 1987, 7, 3343-3349. Body temperature all the time was maintained equal to 37"C. In Which the assessed degree of degeneration of nerve cells in the hippocampus. Compound was administered intraperitoneally in the form of a single dose after 60 minutes after occlusion. Before occlusion introduction did not. The effectiveness of compounds of the formula I in reducing damage to the CA1/CA2 nerve cells in the hippocampus of gerbils after ischemic stroke clearly illustrates the usefulness of these compounds in the prevention of neurodegeneration (table). Therefore, it is expected that these compounds will have value in the treatment of acute and chronic neuro-psychiatric disorders, characterized by progressive processes that will sooner or later lead to the death and dysfunction of nerve cells.

The administration of a medicinal product in a new method of treatment of this invention may be oral, rectal, local, or parenterally at dose level, for example, from about 0.01 to 1000 mg/kg, preferably from about 1.0 to 500 mg/kg and, mainly, from about 5.0 to 200 mg/kg, while it can be administered in the treatment regimen of 1 to 4 doses or treatments per day. The dose will depend on the method of use of the medicinal product, with the preferred methods of application are oral or intravenous. It should be understood that individual losest patient and other factors, normally considered by the attending physician of the hospital.

Drugs, including compounds of this invention may be in the form of tablets, pills, capsules, syrups, powders or granules for oral administration, in the form of sterile parenteral solutions or suspensions for parenteral administration; in the form suppositories for rectal administration: or in the form of suitable local drugs. Conventional methods of selection and preparation of suitable medicines described for example in Pharmaceuticals - The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.

To obtain a drug containing the compound in accordance with the present invention in the form of dosage units for oral administration, the active substance can be mixed with adjuvant/carrier, e.g. lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder, for example, gelatin or polyvinylpyrrolidone and lubricants, e.g. magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc., and then compressed into tablets. If necessary coated tablets, the inner content is et to contain, for example, gum Arabic, gelatin, talc, titanium dioxide, etc., Alternative tablet may be coated with polymer, known to specialists in this field, dissolved in a volatile organic solvent or mixture of organic solvents.

In order to easily distinguish between tablets containing different active substances or different amounts of the active compounds, these coatings can be added dyes. To obtain soft gelatin capsules, the active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance the use or the above-mentioned excipients for tablets, for example, lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin) cellulose derivatives or gelatin. Liquid or semi-solid contents of the medication can also be placed in hard gelatin capsules.

Dosage units for rectal application can be in the form of solutions or suspensions, or they can be obtained in the form suppositories containing the active substance in a mixture with a neutral fat base, or what asle.

Liquid pharmaceutical preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from about 0.02% to about 20% by weight described here, the active substance, while the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid medications may not necessarily contain coloring substances, substances that give flavor, saccharin, and as a thickener carboxymethylcellulose or other fillers, is well known to specialists in this field.

Solutions for parenteral administration by injection can be obtained in the form of an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizers and/or buffers can be enabled to improve the solubility of the surfactant. They can be in capsules with different units of dosage. The necessary starting materials for all songs and examples are commercial product, except for the following substances:

4-methyl-5-oxazolepropionic (Indian J. Chem., Sect.In., 1985, >5-acetyl-4-methylthiazole (J. Agr.Food Chem., 1974, 22, 264-9);

5-acetyl-2,4-dimethyloxazole(Chem.Ber., 1960,93,1998-2001);

5-acetyl-2,5-dimethyloxazole (J. Am.Chem. Soc., 1975, 97, 6484-6491);

5-acetyl-C-methylisoxazole and C-acetyl-5-methylisoxazole (J.Org. Chem., 1989,54,2646-2650).

Preparation 1. N-Methoxy-N-methyl-4 - methyl-5-oxazolinone.

4-Methyl-5-oxazolepropionic (15 g) and N, O-dimethylhydroxylamine (11 g) in dry chloroform (100 ml) was cooled to 0oC and added dry pyridine (28.5 g). Then, the mixture was heated to room temperature, After 30 minutes was added an aqueous solution of acid sodium carbonate and separated the organic layer. Dichloromethane was extracted water layer. Mixed organic layers were washed, dried and evaporated. The residue was purified flash chromatography to obtain the titled compound as a white solid. The melting point of 59-60oC.

1H NMR (CDCl32,5, 3,34 and 3,82 (each 3H, s) and 7,86 (1H, s) frequently. in a million.

Found: C, 49,0; H, 5,6; N, 16,4. For C7H10N2O3< / BR>
Calculated: C, 49,4; H, 5,9; N, 16.5 Per Cent.

Preparation 2. N-Methoxy-N-methyl-2,4-dimethyl-5-oxazolinone

On the basis of 2,4-dimethyl-5-oxazolepropionic and following the General method recip is) 2,42, 2,5, 3,32, and 3.8 (each 3H, s) frequently. in a million.

Preparation of 3. 3-Furyl-4-methyl-5-oxazolidinone.

3-Bromofuran (2.5 g) in dry diethyl ether were mixed and cooled to 70oC under an atmosphere of dry nitrogen and dropwise added n-utility (2.5 M solution in hexane, 6.8 ml). After 30 minutes, dropwise added N-methoxy-N-methyl-4-methyl-5-oxazolinone (2,89 g) in dry diethyl ether. After 30 minutes the reaction mixture was heated to room temperature. Added ethanol (5 ml) and then saturated aqueous solution of sodium chloride.

The mixture was extracted with dichloromethane and the resulting substance was purified flash chromatography to obtain the titled compound. The melting point of 82-83,5oC.

1H NMR (CDCl32,62 (3H,s), 7,01, 7,52, 7.95 and 8,42 (each 1H) frequent. in a million.

Found: C, Of 60.8; H, 4,4, N, 8,0. For C9H7NO3< / BR>
Calculated: C, 61,0; H, 4,0; N, 7.9 Per Cent.

Preparation 4. 5-Acetyl-2-ethyl-4-methoxazole.

3-Chloropentane-2,4-dione (46,5 g), propionamide (50 g) and propionic acid (151 g) was heated at 145oC for 5 hours. The mixture was cooled to room temperature, then 10 m aqueous solution of sodium hydroxide brought the pH to 10 and were extracted dieth also brown oil, which was purified by vacuum distillation, boiling point 70oC at 2 millibars.

13C NMR (CDCl3) 10,6, 13,4, 21,6, 27,2, 144,7, 145,0, 166,4 and 187,2 frequent. in a million.

Preparation 5. 4-Methyl-5-propionyloxy.

N-Methoxy-N-methyl-4-methyl-5-oxazolinone (5 g) in dry tetrahydrofuran at -40oC was stirred under a nitrogen atmosphere and dropwise added ethanmariat (1M solution in tetrahydrofuran, 35 ml). After 30 minutes, provided the heating of the mixture to room temperature and then stirred for another one hour. Added an aqueous solution of acid sodium carbonate: separated the organic layer and the aqueous layer was extracted with diethyl ether.

Thus obtained substance was purified flash chromatography to obtain a pale yellow liquid that is cured by cooling.

1H NMR (CDCl3) to 1.22 (3H, t), of 2.53 (3H, s), 2,85 (2H, Quartet) and to 7.84 (1 H, s) frequently. in a million.

Preparation 6. 2,4-Dimethyl-5-propionyloxy.

Following the General method of obtaining 5, but starting from N-methoxy-N-methyl-2,4-dimethyl-5-oxazolinone, has been named connection in the form of low-melting solids.

1H NMR (CDCl3) to 1.21 (3H, t), 2,48 (3H, s) and 2.52 (to the evil.

n-Utility (2.5 M solution in hexane, 1.1 EQ.) added dropwise to a solution of 4-methylthiazole (1 EQ.) in dry diethyl ether at -70oC under an atmosphere of dry nitrogen. After 30 minutes, dropwise added trimethylsilane (1.0 equivalent). The mixture was heated to room temperature and then repaid by adding a saturated solution of acid sodium carbonate. In the usual way by means of vacuum distillation, has been named connection, the boiling point of the 42oC at 1 mm Hg.

Preparation 8. 2,4-Dimethyl-5-oxazolyl-3-furillen.

Following the method of preparation 3, but using N-methoxy-N-methyl-2,4-dimethyl-5-oxazolinone, has prepared a named connection. The melting point of 73.5-74,oC.

Found: C, And 62.6; H, 4,7, N, 7,45. For C10H9NO3< / BR>
Calculated: C, Of 62.8; H, 4.75 V; N, 7.3 Per Cent.

Preparation 9. Cyclopropyl-4-Methyl-5-oxazolidinone.

Following the method of preparation 3, but using cyclopropylamine - bromide, has been named connection.

1H NMR (CDCl3) of 1.06 and 1.25 (each 2H, m), of 2.53 (3H, s), 2,65 (1 H, m) and to $ 7.91 (1H, s), frequent. in a million.

Preparation 10. Tert-butyl-2,4-dimethyl-5-oxazolidinone.

Based on the M-label is a named connection.

13C NMR (CDCl3) 13,7, 13,9, 26,0, 43,3, 144,2, 147,1, 160,8 and 195,1 frequent. in a million.

Preparation 11. 2,4-Dimethyl-5-oxazolyl-2-propylketone.

On the basis of N-methoxy-M-methyl-2,4-dimethyl-5-oxazolidinone and 2-propylaniline and following the General method of preparation 3, has been named connection.

13C NMR (CDCl3) 13,3, 13,9, 17,9, 36,8, 144,3, 145,3, 161,6 and 193,8 frequent. in a million.

Preparation 12. 3-Trifurcation.

3-Bromofuran (20 g) was added to a solution of n-utility (2.5 M in hexane, 60 ml) in diethyl ether (200 ml) at -70oC. After 30 minutes, slowly added ethyltryptamine (28.6 g). After 1 hour the mixture was allowed to warm to room temperature and then stirred overnight. Added 1M hydrochloric acid (100 ml) and the mixture was stirred for 5 minutes. Separated the organic layer, washed, dried and evaporated. The rest drove to obtain these compounds. Boiling point 118oC.

13C NMR (CDCl3) 109,0, to 116.2 (Quartet, J 290 Hz), 121,0, 144,9, 150,6, 175,5 (Quartet, J 37 Hz) frequent. in a million.

Preparation 13. 3-Triptorelin.

The named compound was obtained following the method of preparation 12, but using C-bromothiophene. Boiling point 48o

Preparation 14. 5-Acetyl-2-amino-4-cryptomaterial.

Hydroxy-(tosyloxy)iadanza (78,5 g) was added to a solution of 1,1,1-triterpene-2,4-dione in acetonitrile (500 ml). The mixture was heated under phlegm for 45 minutes, then cooled and added thiourea (15.2 g). The mixture was heated under phlegm for 4 h and then left to stand overnight. By evaporation and crystallization of the residue from dichloromethane got a named connection.

13C NMR (d6-DMSO) 29,5, 120,1 (Quartet, J 270 Hz), output reached 125.5, 141,1 (the Quartet. J 35 Hz), 170,3 and 187,2 frequent. in a million.

Preparation 15. 5-Acetyl-4-cryptomaterial.

The product from preparation 14 (7 g) was added to a mixture of nitric acid (69%, 10 ml) and phosphoric acid (85%, 48 ml). The suspension was mixed and cooled to -20oC and dropwise added sodium nitrite (3.6 g) in water (30 ml). After another 30 minutes, at -20oC dropwise added hypophosphorous acid (50%, 19,5 ml). After 15 minutes, the mixture was left to warm to 0oC. After 1 hour, using 40 aqueous solution of sodium hydroxide, and the mixture was podslushivaet and was extracted with dichloromethane. The extracts were washed, dried and evaporated, and the residue was purified flash chromatography to obtain the above connection is Lyon.

Preparation 16. 4-Bromo-1,3,5-trimethylpyrazole.

To a stirred suspension of sodium hydride (1.8 g) in dry dimethylformamide at 0oC was added 4-bromo-3.5-dimethylpyrazol (10 g) in dry dimethylformamide. When the evolution of hydrogen has ended, dropwise added itmean in (8.9 g). Ensured the heated mixture to room temperature and after 30 minutes was added a saturated aqueous solution of acid sodium carbonate (5 ml). After evaporation under high vacuum, the residue was purified column chromatography to obtain the titled compound.

1H NMR (CDCl3) 2,2, 2,22, and to 3.73 (each 3H, s) frequently. in a million.

Preparation 17. 4-Methyl-2-triftoratsetilatsetonom.

To 4-methyl-2-trimethylsilyloxy (J. Chem. Soc., Chem. Commun., 1984, 258) (9.95 g) in diethyl ether (100 ml) at 0oC under an atmosphere of dry nitrogen dropwise added 1 - cryptomaterial (10 g). The mixture was stirred overnight at room temperature. Added water and the separated organic layer was washed, dried and evaporated. Flash chromatography got a named connection.

13C NMR (d6-DMSO) (as hydrate) 11,0, 89,5 (Quartet, J 33 Hz), 122,3 (Quartet, J 287 Hz), 136,0, 136,1 and 158,6 frequent. in a million.

Cooking is whether using isopropoxide aluminum in 2-propanol. The resulting alcohol was treated with sodium hydride in dimethoxyethane and added itmean. Distillation has been named connection.

13C NMR (CDCl3) 14,2, 57,0, 64,9, 127,2, 149,9 and 150,5 frequent. in a million.

Example 1. 1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol.

a) 3-Bromofuran (7.6 g) in dry tetrahydrofuran (25 ml) at -70oC under a nitrogen atmosphere was treated dropwise with n-butyllithium (2.5 M solution in hexane, 20.8 ml).

After 30 minutes, dropwise added 5-acetyl-4-methoxazole (5 g). After 30 minutes, keeping the mixture at -70oC, the reaction mixture was warmed to room temperature and then was stirred for 30 minutes. Added ethanol (12 ml) and then the reaction mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with dichloromethane. Thus obtained product was purified by chromatography on silica gel or neutral alumina. Then by crystallization from diethyl ether was obtained 1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol as a white solid, melting point 102-103oC.

1H NMR (CDCl3) to 1.9 (3H, s), and 2.1 (3H, s), 6,36 (1H, Quartet), 7,37-7,41 (2H, m) and to 7.67 (1H, s) frequently. in a million.

13C NMR (CDCl3) 12,4, 28,9, 68,4, 108,8, 130,7, 131,1, 138,8, 143,5, 142,2; H, 5,7; N, 7.25 PERCENT.

b) 3-Furyl-4-methyl-5-oxazolidinone (1 g) in dry diethyl ether (15 ml) at -70oC under a nitrogen atmosphere was treated dropwise with methyllithium (1.5 M solution in diethyl ether. 4.1 ml). After 45 minutes, allowed to warm the reaction mixture to room temperature and added ethanol (2 ml). The mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with dichloromethane. Then by chromatography and crystallization of the obtained 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol, identical with the substance obtained above in 1(a).

Example 2. To n-butyllithium (2.5 M solution in hexane, 10.4 ml) in dry diethyl ether (20 ml) at -70oC under nitrogen atmosphere was added dropwise 3-bromothiophene (to 4.23 g) in diethyl ether (10 ml). After 3 hours, was added dropwise 5-acetyl-4-methoxazole (2.5 g). After keeping the mixture for 2.5 hours at -70oC she is allowed to warm to room temperature and then left it on all night. The mixture was poured into water and was extracted with simple ether. Thus obtained product was led from diethyl ether to obtain 1-(4-methyl-5-oxazolyl)-1-(3-trilateral, melting point 87-89oC.

1H NMR (CDCl3) of 1.93 (3H, s), 2,0 (3H, s), 7,05 (1H, m), a 7.2 to 7.35 (2H, m) and 7,66 (1H, s) frequently. on minigene: C, 57,2; H, 5,3, N, 6,6. For C10H11NO2S

Calculated: C, 57,4; H, 5,3, N, 6,7; S 15.3 Per Cent.

Example 3. 1-(4-Methyl-5-oxazolyl)-1-(2-thienyl)ethanol.

Thiophene (3,36 g) in dry tetrahydrofuran (20 ml) were mixed and cooled to -40oC under an atmosphere of dry nitrogen and dropwise added n-utility (2.5 M solution in hexane, 16 ml). Given the heated mixture to a temperature of -20oC and then, after 1 hour, it was cooled to -70oC. was Added dropwise 5-acetyl - 4-methoxazole (5 g) in dry tetrahydrofuran (15 ml). After another 1 hour and allowed to warm the mixture to room temperature and was stirred for another 2 hours. Added an aqueous solution of acid sodium carbonate and the mixture was extracted with diethyl ether. Thus obtained substance was purified flash chromatography to obtain the titled compound. The melting point of 84-85oC

1H NMR (CDCl3) 2,04 and 2.1 (each 3H, s), 2,87 (1H, broad s) of 6.96 (2H, m), 7,29 (1H, m) and 7,72 (1H, s) frequently. in a million.

Found: C, To 57.1; H, 5,2; N, 6.5 In. For C10H11NO2S

Calculated: C, 57,4; H, 5,3; N, 6.7 Percent.

Example 4. To n-butyllithium (2.5 M solution in hexane, to 18.4 ml) in diethyl ether (20 ml) at -70oC under nitrogen atmosphere was added dropwise 3-bromofuran (6.8 g) in diethyl ether (15 UP>o
C, she was allowed to warm to room temperature and then left it for the night. The mixture was poured into water and was extracted with diethyl ether. Thus obtained product was led from diethyl ether. The melting point of 102-104oC.

1H NMR (CDCl3) was 1.94 (3H, in), 2.25 (3H, s), 6.35mm (1H, m), 7,35 (2H, m) and of 8.47 (1H, s) frequently. in a million.

13C NMR(CDCl3) 15,9, 30,2, 69,2, 109,0, 131,9, 139,0, 139,7, 143,5, 147,3 and of 149.0 frequent. in a million.

Found: C, 57,4; H, 5,4, N, 6,7. For C10H11NO2S

Calculated: C, 57,4; H, 5,3; N,6.7%.

Example 5. 1-(2,4-Dimethyl-5-oxazolyl)-1- (3-furyl)ethanol.

The named compound was obtained following the General method of example 4, but starting from 5-acetyl-2,4-dimethyloxazole. The melting point of 93-95oC.

1H NMR (CDCl3) a 1.88 (3H, s), 2,0 (3H, s) to 2.35 (3H, s), 3,5 (1H, s), 6,36 (1H, m) and 7.4 (2H, m) frequent. in a million.

13C NMR(CDCl3) 12,3, 13,6, 29,0, 68,3, 108,9, 130,8, 131,4, 138,8, 143,3, 148,4, and 158,8 frequent. in a million.

Found: C, To 63.8; H, 6,4, N, 6,7. For C11H13NO3< / BR>
Calculated: C, 63,75; H, 6,3; N, 6.8%.

Example 6. 1-(2,4-Dimethyl-5-thiazolyl)-1-(3-furyl)ethanol.

The named compound was obtained following the General method of example 4, but starting from 5-acetyl-2,4 - dimethylthiazole. Point plave million.

13C NMR (CDCl3) 15,95, 18,5, 30,6, 69,3, 108,95, 132,1, 138,3, 138,9, 143,4, 146,25, and 161,9 frequent. in a million.

Found: C, A 59.2; H, 5,9, N, 6,1; S, 14,2. For C11H13NO2S

Calculated: C, A 59.2; H, 5,9; N, 6,3; S To 14.4%.

Example 7. 1-(4-Methyl-5-thiazolyl)-1-(3-thienyl)ethanol.

The named compound was obtained following the General method of example 4, but using 3-bromothiophene. The melting point 149-151oC.

1H NMR (d6-DMSO) to 1.96 (3H, s) of 2.16 (3H, s), 6,2 (1H, s), was 7.08 (1H, m) and 7.5 (2H, m) and 8.8 (1H, s), frequent. in a million.

13C NMR (d6-DMSO) 15,8, 30,5, 70,4, 120,6, 125,95, 126,8, 140,8, 146,3, 148,8, and 149.2 frequent. in a million.

Found: C, To 52.9; H, 5,0; N, 6,0. For C10H11NOS2< / BR>
Calculated: C, 53,3; H, A 4.9; N, 6.2 Percent.

The above compound in dry tetrahydrofuran was treated with dry hydrogen chloride in diethyl ether to obtain 1-(4-methyl-5-thiazolyl)-1-(3 - thienyl)ethanolgasoline. The melting point 111-112oC.

1H NMR (d6-DMSO) 2,04 and 2.26 (each 3H. C) 6,0 (broad, s), 7,16 (1H. m), a 7.62 (2H, m) and 9.5 (1H, s) frequently. in a million.

Example 8. 1-(2,4-Dimethyl-5-oxazolyl)-1-(3-thienyl)ethanol.

Based on 3-bromothiophene and 5-acetyl-2,4-dimethyloxazole and following the General method of example 4, has been named is connected to the 5, 7.27 and 7,31 (each 1H, m) frequent. in a million.

13C NMR (CDCl3) 12,2, 13,8, 29,4, 71,0, 120,8, 126,1, 126,2, 131,3, 147,1, 148,6, and 158,9 frequent. in a million.

Example 9. 1-(2-Ethyl-4-methyl-5-oxazolyl)- 1-(3-thienyl)ethanol.

Based on 3-bromothiophene and 5-acetyl-2-ethyl-4-methoxazole and following the General method of example 4, has been named connection. The melting point of 77.5-79oC.

1H NMR (CDCl3) of 1.23 (3H, t), is 1.77 (3H, s), and 1.9 (3H, s), and 2.6 (2H, Quartet), of 5.15 (1H, s), 7,01 (1H, m), 7.23 percent (2H, m), frequent. in a million.

13C NMR (CDCl3) 10,7, 11,5, 20,9. 29,0, 70,1, 120,1, 125,4, 125,8, 130,3, 147,3, 148,5 and 162,6 frequent. in a million.

Example 10. (1-(3-Furyl)-1-(4-methyl-5-oxazolyl)propanol

Based on 3-bromofuran and 4-methyl-5-propionyloxy and following the General method of example 4, has been named connection.

1H NMR (CDCl3) to 0.92 (3H, t), 2,0-2,3 (2H, m), of 2.15 (3H, s), 6,36 (1H, m), and 7.4 (2H, m) and 7,66 (1H, s) frequently. in a million.

Example 11. 1-(2-Ethyl-4-methyl-5-oxazolyl)-1-(3-furyl)ethanol.

Based on 3-bromofuran and 5-acetyl-2-ethyl-4-methoxazole and following the General method of example 4, has been named connection.

1H NMR (CDCl3) to 1.32 (3H, t), of 1.88 and 2,04 (each 3H, s), 2,73 (2H, Quartet), 2,82 (1H, broad, s) 6,38 (1H, m) and 7.4 (2H, m) frequent. in a million.

13C I is oxazolyl)-1-(3-thienyl)propanol.

Based on 3-bromofuran and 2,4-dimethyl-5-propionyloxy and following the General method of example 4, has been named connection.

By cleaning HPLC (high performance liquid chromatography) was obtained white solid. The melting point of 81-83oC.

13C NMR (CDCl3) 8,0, 12,4, 13,8, 35,1, 74,5, 124,0, 124,9, 126,8, 132,5, 147,7, 149,9 and 159,0 frequent. in a million.

Found: C, To 60.6; H, 6,2, N, 5,7. For C12H15NO2S

Calculated: C, Of 60.7; H, 6,4, N,5,9%.

Example 13. 1-(2,5-Dimethyl-4-oxazolyl)-1-(3-furyl)ethanol.

Based on 3-bromofuran and 4-acetyl-2,5-dimethyloxazole and following the General method of example 4, has been named connection.

1H NMR (CDCl3) 1,8, 2,12 and 2,34 (each 3H, s), 3.6 (H, broad s) 6,38 (1 H, m) and to 7.32 (2H, m) frequent. in a million.

13C NMR (CDCl3) 11,1, 13,6, 29,2, 68,1, 109,1, 132,1, 138,7, 142,4, 143,1 and 158,2 frequent. in a million.

Example 14. (1-(2,5-Dimethyl-4-oxazolyl)-1-(3-thienyl)ethanol.

Based on 3 - bromothiophene and 4-acetyl-2,5-dimethyloxazole and following the General method of example 4, has been named connection.

1H NMR (CDCl3) 1,88, 1,98, and 2,35 (each 3H, s), 3,85 (H, broad s), was 7.08 (1H, m) and 7,26 (2H, m) frequent. in a million.

13C NMR (CDCl3) 10,8, 13,5, 29,6, 70,6, 120,4, 1LASS="ptx2">

4-Methylthiazole (6,51 g) in dry tetrahydrofuran (50 ml) were mixed under an atmosphere of dry nitrogen, cooled to -70oC and dropwise added n-utility (2.5 M solution in hexane, 29 ml). After 30 minutes added trimethylsilane (7,14 g) and gave the mixture to warm to room temperature. After 30 minutes the mixture was cooled to -70oC and dropwise added n-utility (2.5 M solution in hexane, 29 ml). After 30 minutes, was added dropwise 3-acetyl-2,5-dimethylfuran (10 g). The mixture was mixed at -70oC for 1 hour and then gave it to warm to room temperature. After 30 minutes, was added an aqueous solution of acid sodium carbonate and the mixture was extracted with diethyl ether. Mixed extracts washed, dried and evaporated to obtain these compounds, which recrystallize from diethyl ether. The melting point of 100.5 is 101.5oC.

1H NMR (CDCl3) 1,9, to 2.06 2.24 (each 3H, s), 2,42 (H, broad s) 5,94 (1H, s), and to 8.57 (1H, m) frequent. in a million.

Found: C, To 60.6; H, 6.5; The N, 5,9. For C12H15NO2S

Calculated: C, Of 60.7; H, 6,4; N, 5.9 Per Cent.

Example 16. (1-(2-Furyl)-1-(4-methyl-5-thiazolyl)ethanol.

On the basis of 4-methylthiazole and 2-acetylfuran and following the General method of example 15, has been named connected and 7,41 (each 1H, m), and 8,56 (1H, s) frequently. in a million.

Found: C, 57,3; H, 5,2, N, 6,6. For C10H11N02S

Calculated: C, 57,4; H, 5,3; N, 6.7 Percent.

Example 17. 1-(4-Methyl-5-thiazolyl)-1-(2-thienyl)ethanol.

On the basis of 4-methylthiazole and 2-acetylthiophene and following the General method of example 15, has been named connection. The melting point 146,5 - 147,5oC.

1H NMR (CDCl3) 2,08, and of 2.23 (each 3H, s), 3,14 (1 H, broad s) of 6.96 (2H, m), 7,31 (1H, m), and 8,54 (1H, s) frequently. in a million.

Found: C, To 53.0; H, 5,0; N, 6,0. For C10H11NOS2< / BR>
Calculated: C, 53,3; H, A 4.9; N,6,2%.

The above compound in dry tetrahydrofuran was treated with dry hydrogen chloride in diethyl ether to obtain 1-(4-methyl - 5-thiazolyl)-1-(2-thienyl)ethanolgasoline. The melting point 109,5 - 110,5oC.

1H NMR (d6-DMSO) of 1.84 and 1.95 (each 3H, s), a 3.87 (broad, s), 6,65, 6.73 x and 7,13 (each 1H, m), and 8,84 (1H, s) frequently. in a million.

Example 18. 1-(5-Thiazolyl)-1-(3-thienyl)ethanol.

n-Utility (2.5 M solution in hexane, 5.6 ml) in dry diethyl ether (25 ml) was mixed at -70oC under nitrogen atmosphere and dropwise added 2 - trimethylsilylimidazole (2 g) in diethyl ether (25 ml). After 30 minutes, dropwise added 3-acetylthiophene (1,93 g) in dietro the cation for another 1 hour. Added a saturated aqueous solution of acid sodium carbonate and separated the organic layer. The aqueous layer was extracted with diethyl ether. Organic layers were mixed, washed, dried and evaporated, and the residue was purified flash chromatography to obtain the titled compound in the form of butter.

1H NMR (CDCl3) 2,02 (3H, s), 3,82 (1H, broad, s), 7,07 (1H, m) and 7,28 (2H, m), 7,56 (1H, s) and 8,63 (1H, s) frequently. in a million.

13C NMR (CDCl3) 32,3, 71,8, 120,8, 126,0, 126,4, 139,3, 147,9, 148,3 and 152,9 frequent. in a million.

Example 19. 1-(3-Furyl)-1-(4-methyl-5-oxazolyl)Aten.

1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (900 mg) in dry chloroform was treated with 1 M anhydrous hydrogen chloride in diethyl ether (1.1 equivalent). After 10 minutes at room temperature was added an aqueous solution of acid sodium carbonate and the mixture was extracted with dichloromethane. Thus obtained substance was purified flash chromatography to obtain the titled compound in the form of almost colorless liquid.

1H NMR (CDCl3) 2,22 (3H, s), and 5,42 5,59 (each 1H, s), 6,55 and 7,44 (each 1H, m), 7,52, and 7,81 (each 1H, s) frequently. in a million.

13C NMR (CDCl3) 13,0, 109,2, 115,0, 123,9, 128,1, 133,2, 140,9, 143,2, 145,4 and 148,9 frequent. in a million.

Example 20. 1-(3-f the teaching of example 19, got a named connection in the form of a mixture of E and Z-isomers.

1H NMR (CDCl3) 1,8 and 1.92 (total 3H, d), represented 2.02 and 2.12 (total 3H, s), 6,1-6,3 (total 1H, m), 6,37 and 6.5 (total 1H, m), 7,18 and 7,43 (total 1H, s), 7,38 and 7.5 (total 1H, m) and 7,74 and 7,89 (total 1H, s) frequently. in a million.

Example 21. Hydrochloride of 1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)Atena.

1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)-1-methoxyethane (790 mg) in dry diethyl ether was treated with 1 M anhydrous hydrogen chloride in diethyl ether (1.2 equivalent). The named compound was obtained as a white solid, which was filtered, washed and dried. The melting point 128,5 - 130oC.

13C NMR (d6-DMSO) 12,7, 13,7, 109,5, 114,8, 123,8, 127,8, 132,7, 141,5, 144,0, 144,6 and 159,7 frequent. in a million.

Found: C, A 58.3; H, 5,3, N, 5,9. For C11H11N02HCl

Calculated: C, 58,5; H, 5,4; N, 6.2 Percent.

Example 22. 1-(2-Furyl)-1-(4-methyl-5-oxazolyl)ethanol.

To a stirred solution of 2-leciaferna (1 equivalent), in diethyl ether at -20oC was added dropwise 5-acetyl-4-methoxazole (4 g) in dry diethyl ether. Gave the mixture to warm to room temperature and then left it on all night. Then by flash chromatography, has been named connection in the form of a white (C), 6,30 (1H, m), 6,38 (1H, m), 7,41 and 7,71 (each 1H, s) frequently. in a million.

Example 23. (1-(2,4-Dimethyl-5-thiazolyl)-1-(3-pyridyl)ethanol.

To a stirred solution of 3-licimeriya (from 3.5 g of 3-bromopyridine), in diethyl ether at -70oC dropwise added 5-acetyl-2,4-dimethylthiazole (2.5 g) in dry diethyl ether. After 3 hours the mixture allowed to warm to room temperature. Even after 1 hour was added an aqueous solution of acid sodium carbonate and separated the organic layer. The aqueous layer was extracted with diethyl ether. The substance obtained from the mixed organic layers were purified instant flash chromatography to obtain the above compound, melting point of 107.5 - 109oC.

13C NMR(CDCl3) 16.3, 18,7, 32,7, 71,9, 123,1, 133,5, 137,9, 142,4, 146,9, 148,0 and 162,2 frequent. in a million.

Example 24. 1-(2,4-Dimethyl-5-thiazolyl)-1-(2-pyridyl)ethanol.

Using the General method of example 23, but using 2-litiere, has been named connection. The melting point of 104 - 105oC.

13C NMR(CDCl3) 16,2, 18,8, 31,9, 72,5, 120,1, 122,4, 136,9, 137,2, 147,3, 148,6 161,8 and 163,5 frequent. in a million.

Example 25. 1-(3,5-Dimethyl-4-isoxazolyl)-1-(3-furyl)ethanol.

The named compound was obtained following the General method of example 4, n is/SUP>H NMR (CDCl3) 1,83, 2,11 and 2,33 (each 3H, s), 6,33 and 7,38 (each 1H, DD) and 7,42 (1H, t) are frequent. in a million.

Example 26. 1-(3,5-Dimethyl-4-isoxazolyl)-1-(3-thienyl)ethanol.

The named compound was obtained following the General method of example 4, but on the basis of 4 - acetyl-3.5-dimethylisoxazole and 3-bromothiophene. The melting point of 93.5 - 95oC.

13C NMR (CDCl3) 11,8, 12,7, 30,3, 70,1, 119,3, 120,8, 126,4, 126,5, 148,4, 158,9 and 164, 8mm frequent. in a million.

Example 27. 1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)utilmately ether.

To a stirred suspension of sodium hydride (80%, 300 mg) in dry N,N-dimethylformamide (10 ml) at 0oC was added 1-(3-furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol (2 g). After 20 minutes, was added dropwise methyliodide (1.5 g). Gave the mixture to warm to room temperature and after 30 minutes was added an aqueous solution of acid sodium carbonate. The mixture is then evaporated to dryness. The residue was treated with water and was extracted with diethyl ether. Thus obtained substance was purified flash chromatography to obtain the titled compound.

13C NMR (CDCl3) 12,5, 13,8, 24,8, 50,9, 73,4, 109,3, 129,1, 132,7, 139,7, 143,1, 146,5 and 159,2 frequent. in a million.

Example 28. 1-(3-Furyl)-1-(4-[methyl-5-oxazolyl) utilmately ether.

Named soudn NMR (CDCl3) 1,81, 2.14 and 3,16 (each 3H, s), 6,32, and 7,74 (each 1H, broad, s) and 7.4 (1H, m) frequent. in a million.

Example 29. 1-(2-Thiazolyl)-1-(2-thienyl)ethanol.

To a stirred solution of 2-bromothiazole (5 g) in diethyl ether (50 ml) at -70oC under an atmosphere of dry nitrogen was added dropwise n-utility (2.5 M solution in hexane, 13.4 ml) in dry diethyl ether (25 ml). After 30 minutes, was added dropwise 2 - acetylthiophene (of 3.85 g) in diethyl ether (25 ml). After another 1 hour gave the mixture to warm to room temperature and left under stirring overnight. Added water. The mixture was extracted with diethyl ether to obtain the titled compound, which was recrystallize from diethyl ether. The melting point of 112 - 113oC.

13C NMR(CDCl3) 31,6, 74,8, 119,7, 124,1, 125,3, 126,8, 142,2, 150,5 and 177,1 frequent. in a million.

Example 30. 1-(2-Furyl)-1-(2-thiazolyl)ethanol.

The melting point of 91 - 92oC.

13C NMR(CDCl3) 28,3, 72,7, 106,4, 110,3, 119,7, 142,1, 142,4, 150,6 and 175,4 frequent. in a million.

Example 31. 1-(2-Thiazolyl)-1-(3-thienyl)ethanol.

The melting point of 107 - 108oC.

13C NMR(CDCl3) 30,6, 74,6, 119,3, 121,1, 126,0, 126,1, 142,2, 147,3 and of 177.8 frequent. in a million.

The hydrochloride. The melting point 120 - 122oC1-(1-Methyl-2-pyrrolyl)-1-(2-thiazolyl)ethanol.

The melting point of 143 - 144oC.

13C NMR(CDCl3) 31,8, 35,4, 72,9, 106,3, 108,4, 119,9, 124,9, 134,2, 141,7 and 177,6 frequent. in a million.

Example 33. 1-(2-Benzofuranyl)-1-(2-thiazolyl)ethanol.

The melting point 120 - 121oC.

13C NMR (CDCl3) 28,3, 73,2, 103,0, 113,3, 119,9, 121,3, 122,9, 124,5, 128,0, 142,1, 155,0, 159,3 and 174,7 frequent. in a million.

Example 34. 1-(2-Thiazolyl)-1-(3-thienyl)-2,2,2-triptorelin.

The melting point of 96 - 97oC.

Found: C, 40,6; H, 2,1; N, 5,2. For C9H6NOS2< / BR>
Calculated: C, 40,75; H, 2,3; N, 5.3% OF

Example 35. 1-(3-Furyl)-1-(2-thiazolyl)-2,2,2 - triptorelin.

The melting point of 106 - 107oC.

Found: C, By 43.6; H, 2,3; N, 5,5. For C9H6F3NO2S

Calculated: C, A 43.4; H, 2,4; N, 5.6 Percent.

Example 36. 1-(4,5-Dimethyl-2-thiazolyl)-1-(2-thienyl)ethanol.

To a stirred solution of 4,5-dimethylthiazole (2.5 g) in dry diethyl ether (30 ml) at -70oC under an atmosphere of dry nitrogen was added dropwise n-utility (2.5 M solution in hexane, 9.7 ml). After 30 minutes, was added dropwise 2-ametiliit (3.1 g) in diethyl ether 20 ml). After 1 hour the mixture allowed to warm to room temperature and then the usual way has been named connection.

Point PL is Lyon.

Example 37. 2-(4-Methyl-2-thiazolyl)-2-(2-thienyl)tetrahydrofuran.

Using the General method of example 36, 4-methylthiazole and 4-chloro-1-(2-thienyl)-1-butanone got a named connection.

The melting point of 59 - 60oC.

13C NMR (CDCl3) 17,4, 26,2, 41,2, 69.3, 86,2, 113,9, 124,2, 124,7, 126,8, 148,9, 153,1 and covers 175.6 frequent. in a million.

Example 38. 1-(4,5-Dimethyl-2-thiazolyl)-1-(3-thienyl)-2,2,2-triptorelin.

Based on 3-(2,2,2-TRIFLUOROACETYL)thiophene and using the General method of example 36, has been named connection.

The melting point 90 - 92oC.

Found: C, 45,1; H, 3,2, N, 4,6. For C11H10F3NOS2< / BR>
Calculated: C, 45, 0mm; H, 3,4; N, 4.8 Percent.

Following the General method of example 4 and using the appropriate ketone, obtained compounds of examples 39-45.

Example 39. 1-(3-Furyl)-1-(3-methyl-5-isoxazolyl)ethanol.

13C NMR (CDCl3) 11,3, 28,4, 68,5, 101,2, 108,5, 130,2, 139,0, 143,3, 159,6 and 175,9 frequent. in a million.

Example 40. 1-(3-Furyl)-1-(5-methyl-3-isoxazolyl)ethanol.

The melting point of 49 - 52oC.

13C NMR (CDCl3) 12,2, 29,1, 68,7, 99,8, 108,7, 131,4, 138,8, 143,3, 169,3 and 169,6 frequent. in a million.

Example 41. (1-(3-Furyl)-1-(4-trifluoromethyl-5-thiazolyl)ethanol.

Point plavan.

Example 42. 1-Cyclopropyl-1-(3-furyl)-1-(4-methyl-5-oxazolyl)methanol.

The melting point of 85-86oC.

13C NMR (CDCl3) 1,3, 1,5, 12,5, 20,4, 70,3, 109,3, 129,9, 131,5, 139.8, 143,2, 148,4 and of 148.6 frequent. in a million.

Example 43. 2,2-Dimethyl-1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)-1-propanol.

The melting point 163 - 164oC.

13C NMR(CDCl3) 13,2, 13,8, 25,3, 40,2, 78,2, 111,0, 128,6, 132,9, 140,3, 141,8, 147,3 and of 158.4 frequent. in a million.

Example 44. 1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)-2-methyl-1-propanol.

13C NMR (CDCl3) 12,6, 13,8, 16,9, 36,9, 75,3, 109,3, 129,5, 132,0, 139,6, 142,8, 148,0 and 158,9 frequent. in a million.

Example 45. 1-(3-Furyl)-1-(4-methyl-2-oxazolyl)-2,2,2-triptorelin.

1H NMR (CDCl3) to 2.18 (3H, s). 6,16 (IH, s), and 6.67, 7.42, 7.46 and to 7.68 (each 1H, m) frequent. in a million.

Example 46. 1-(4-Methyl-2-oxazolyl)-1-(3-thienyl)ethanol.

Following the General method of example 2 and using 2-acetyl - 4-methoxazole, has been named connection.

13C NMR (CDCl3) 11,4, 28,5, 71,7, 120,8, 125,7, 126,1, 134,8, 136,3, 146,1 and 166,8 frequent. in a million.

Example 47. 1-(2-Benzofuranyl)-1-(4-methyl-5-thiazolyl)ethanol.

To a solution of 4-methyl-2-trimethylsilylimidazole (1 equivalent) in dry diethyl ether at -70oC under the atmosphere albenzabuy (1 equivalent) in diethyl ether. After 1 hour, the mixture allowed to warm to room temperature and then repaid by the addition of saturated aqueous solution of acid sodium carbonate. Then, by column chromatography on silica gel, has been named connection. The melting point of 139 - 140oC.

Found: C, 64,65; H, 5,0; N, 5,3. For C14H13NO2S

Calculated: C, 64,85; H, 5,1; N, 5.4 Per Cent.

Following the General method of example 47 and using the appropriate ketone, obtained compounds of examples 48-50.

Example 48. 1-(5-Methyl-2-furyl)-1-(4-methyl-5-thiazolyl)ethanol.

The melting point 120 - 123oC.

13C NMR (CDCl3) 13,4, 15,8, 28,5, 70,3, 106,2, 107,5, 138,3, 147,9, 149,3, 152,3 and 155,0 frequent. in a million.

Example 49. 1-(1-Methyl-3-pyrrolyl)-1-(4-methyl-5-thiazolyl)ethanol.

The melting point of 116 - 117oC.

13C NMR (CDCl3) 16,2, 30,2, 36,4, 70,9, 106,5, 119,2, 122,2, 130,4, 141,4, 147,0 and 148.5 frequent. in a million.

Example 50. 2-(4-Methyl-5-thiazolyl)-2-(2-thienyl)tetrahydrofuran.

This compound is obtained using 4-chloro-1-(2-thienyl)-1-butanone.

1H NMR (CDCl3) 2,0-of 2.16 (2H, m), of 2.33 (3H, s), 2,5-2,62 and $ 2.68-2,8 (each 1H, m) 4,06 (2H, m), 6,9 (2H, m), 7,24 (1H, m) and to 8.57 (1H. C) frequent. in a million.

Following the General sposoby-5-oxazolyl)-1-(3-furyl)teletravel ether.

13C NMR (CDCl3) 12,4, 13,8, 15,5, 25,4, 58,6, 72,9, 109,3, 129,5, 132,4, 139,5, 143,0, 146,9 and 158,9 frequent. in a million.

Example 52. 1-(2-Thiazolyl)-1-(2-thienyl)utilmately ether.

13C NMR (CDCl3) 25,3, 51,3, 79,8, 119,5, 125,5, 125,7, 126,5, 142,3, 147,8 and 176,2 frequent. in a million.

Example 53. 1-(4-Methyl-5-thiazolyl)-1-(2-thienyl)utilmately ether.

The melting point of 49 - 50oC.

Found: C, Up 55.1; H, 5,2, N, 5,8. For C11H13NOS2< / BR>
Calculated: C, To 55.2; H, 5,5; N, 5.8 Percent.

Connection examples 54-57 obtained by acid-catalyzed dehydration of the corresponding tertiary alcohols using a technique similar to the one used in examples 19-21.

Example 54. 1-(3,5-Dimethyl-4-isoxazolyl)-1-(3-thienyl)Aten.

The melting point of 35 - 36oC.

Found: C, And 64.5; H, 5,4, N, 6,7. For C11H13NOS

Calculated: C, Up 64.4; H, 5,4; N, 6.8 Per Cent.

Example 55. 1-(2,4-Dimethyl-5-thiazolyl)-1-(1-methyl-2-pyrrolyl)Aten.

13C NMR (CDCl3) 15,5, 19,0, 34,7, 107,5, 110,2, 117,5, 123,9, 131,7, 132,0, 133,4, 148,8 and 163,3 frequent. in a million.

Example 56. 1-(1-Methyl-3-pyrrolyl)-1-(4-methyl-5-thiazolyl)Aten.

13C NMR (CDCl3) 16,1, 36,2, 106,6, 112,7, 121,2, 122,7, 125,1, 131,9, 133,6, 149,8 and 149,9 frequent. in a million.

The use of the LASS="ptx2">

13C NMR (CDCl3) 9,2, 13,4, 22,6, 23,1, 111,0, 112,1, 122,0, 125,4, 141,3, 143,4, 145,0, 149,4 and 162,4 frequent. in a million.

Example 58. 1-(2-furyl)-1-(1,3,5-trimethyl-4-pyrazolyl)ethanol.

4-Bromo-1,3,5-trimethylpyrazole transformed into the corresponding compound 4-lithium compound, which then interact in situ with 2-acetylfuran.

The melting point of 102 - 105oC.

Found: C, A Total Of 65.1; H, 7,4, N, Of 12.5. For C12H16N2O2< / BR>
Calculated: C, And 65.4; H, 7,3; N, 12.7 Per Cent.

Example 59. 1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)-2,2,2-triptorelin.

To a stirred solution of 2,4-dimethyl-5-oxazolyl-3-furaltadone (1.7 g) and (trifluoromethyl)trimethylsilane (1.9 g) in dry tetrahydrofuran (30 ml) at -10oC was added tetrabutylammonium fluoride (250 mg). Gave the mixture to warm to room temperature. After 45 minutes added 6M hydrochloric acid. After 1 hour by adding a saturated aqueous solution of acid sodium carbonate changed the basicity of the mixture and then was extracted with dichloromethane. Thus obtained substance was purified flash chromatography by recrystallization from diethyl ether.

The melting point 129 - 130,5oC.

Found: C, 50,45; H, 3,7; N, 5,3. For C11H10F3NO3

n-Utility (2.5 M solution in hexane, 20 ml) in dry diethyl ether was cooled to -70oC under an atmosphere of dry nitrogen, and was added TMEDA (5.8 g). After 5 minutes dropwise added 1-methylpyrrole (5,4 g). Even after 15 minutes dropwise added 5-acetyl-2,4-dimethylthiazole (4,5 ml). After 30 minutes gave the mixture to warm to room temperature and then processed in the usual way.

The melting point 194 - 197oC (decomposition).

13C NMR (CDCl3) 14,4, 18,8, 31,6, 35,5, 70,7, 106,1, 108,0, 124,7, 135,0, 137,5, 147,5 and 162,5 frequent. in a million.

Example 61. 1-(5-(2-Hydroxyethyl)-4-methyl-2-thiazolyl)-1-(3-GANIL)ethanol.

To a stirred solution of 5- (2-hydroxyethyl)-4-methylthiazole (35 mmol) in dry tetrahydrofuran (80 ml) at -70oC under an atmosphere of dry nitrogen was added n-utility (2.5 M solution in hexane, 75 mmol). After 30 minutes, was added dropwise 3-acetylthiophene (38 mmol) in dry tetrahydrofuran (10 ml). After 1 hour, the mixture allowed to warm to room temperature and then stirred overnight. By normal processing, followed by column chromatography, has been named connection.

The melting point of 127 to 129oC.

13C NMR (d6-DMSO) 15,7, 30,3, 30,8, 62,1, 74,5, 120,9, 126,4, 127,4, 12LASS="ptx2">

The product from example 61 was treated at room temperature with acetylchloride in dichloromethane in presence of triethylamine.

13C NMR (CDCl3) 14,9, 20,9, 26,0, 30,7, 64,0, 74,4, 121,1, 126,0, 126,1, 127,5, 147,5, 148,6, 170,7 and 173,7 frequent. in a million.

Found: C, 54,1; H, 5,6; N, 4,45. For C14H17NO3S2< / BR>
Calculated: C, 54,0; H, 5,5, N, 4,5%.

Example 63. 1-(4-Bromo-3-furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol.

Following the General method of example 1a, but using 5-acetyl-2,4 - dimethyloxazole and 4-bromo-3-lititure (Liebigs Ann.Chem.. 1986, 625 - 637), has been named connection.

The melting point of 124 - 125oC.

13C NMR (CDCl3) 12,3, 13,7, 27,6, 68,5, 99,0, 129,9, 132,0, 140,4, 142,7, 146,9 and 159,0 frequent. in a million.

Example 64. 1-(5-Methoxymethyl-4-methyl-2-thiazolyl)-1-(3-thienyl)ethanol.

The named compound was obtained following the General method of example 36, but using 3-acetylthiophene and 5-methoxymethyl-4-methylthiazole.

The melting point of 71 - 73oC.

13C NMR(CDCl3) 15,1, 30,7, 57,9, 65,9, 74,4, 121,1, 125,9, 126,0, 128,5, 147,3 and of 149.5, 175,4 frequent. in a million.

Example 65. 1 Azido-1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethane.

1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (1 g) was suspiciously in benzene (4 ml). Debatinator all night, then poured into water and was extracted to obtain the titled compound.

13With NMR (CDCl3) 12,4, 25,9, 59,9, 108,8, 127,4, 132,5, 139,6, 143,9, 146,1 and of 149.0 frequent. in a million.

Example 66. 1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethylamine.

The product from example 65 in ethanol was first made in the presence of 10% palladium on coal to obtain these compounds.

The melting point of 82.5 - 83,5oC.

13C NMR (CDCl3) 12,7, 29,9, 50,5, 109,0, 129,5, 132,4, 138,4, 143,3, 148,0 and to 150.6 frequent. in a million.

Example 67. 1 Azido-1-(2 - thiazolyl)-1-(3-thienyl)ethane.

A named connection received on the basis of 1-(2-thiazolyl)-1-(3-thienyl)ethanol and following the General method of example 65.

13C NMR (CDCl3) 26,8, 66,2, 119,8, 122,4, 126,0, 126,6, 143,0, 143,2 and 173,4 frequent. in a million.

Example 68. 1-(2-Thiazolyl)-1-(3-thienyl)ethylamine.

Recovery of the product from example 67, as in example 66, has been named connection.

13C NMR (CDCl3) 31,6, 57,4, 118,8, 120,3, 125,8, 126,0, 142,4, 148,4 and to $ 179.7 frequent. in a million.

Example 69. 1-(2,4-Dimethyl-5-oxazolyl)-1-(3-furyl)-2,2,2-triptorelin.

In benzene (2 ml) at room temperature is added 1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)-2,2,2-triptoreline (160 mg). Added the WPPT is diluted with ethyl acetate and water. Treatment as usual got 1 azido-1-(2,4-dimethyl-5 - oxazolyl)-1-(3-furyl)-2,2,2-trifluoroethane. The restoration of this azide, using the method of example 66, has been named connection.

13With NMR (CDCl3) 12,4, 13,8, 58,0, (Quartet, J 30 Hz), 109,9, 122,8, 125,7, (Quartet, J 286 Hz), 135,0, 141,0, 141, 3mm, 143,4 and 159,8 frequent. in a million.

Example 70.

N-[1-(1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethyl)]ndimethylacetamide.

The product of example 66 was treated with acetylchloride in the presence of triethylamine to obtain these compounds.

13C NMR (CDCl3) 12,6, 23,8, 25,6, 52,5, 108,9, 129,4, 130,8, 139,5, 143,6, 147,1, 148,0 and 168,9 frequent. in a million.

The following examples illustrate pharmaceutical preparations used in the method of the invention.

Preparation 1. Tablets.

The compound of example 5, g - 10

Lactose, g - 94

Microcrystalline cellulose, g - 86

Polyvinylpyrrolidone, g - 8

Magnesium stearate, g - 2

The compound of example 5, lactose, cellulose and polyvinylpyrrolidone sifted and mixed. Sifted magnesium stearate and then it was mixed with the above mixture. Then, by pressing, using appropriate drills, received 1000 tablets, each of which sod is apart 2.Tablets.

The compound of example 46, g - 50

Lactose, g - 80

Microcrystalline cellulose, g - 20

Potato starch, g - 40

Polyvinylpyrrolidone, g - 8

Magnesium stearate, g - 2

The compound of example 46, lactose, cellulose and part of the starch were mixed and granulated with 10 % starch paste. The resulting mixture was dried and mixed with the remaining starch, polyvinylpyrrolidone and sifted magnesium stearate. Then the resulting mixture was extruded to obtain 1000 tablets, each containing 50 mg of active ingredient.

Preparation 3. The capsule.

The compound of example 31, g - 100

Pre gelatinising starch, g - 98

Magnesium stearate, g - 2

The compound of example 31 and starch sifted, mixed together and then smeared sifted magnesium stearate. The mixture used for filling 1000 hard gelatin capsules of appropriate size. Each capsule contained 100 mg of the active ingredient.

Preparation 4. The composition of the medicinal product for injection.

The compound of example 66, g - 0,5 - 10

Polyethoxysiloxane castor oil, g - 15

Water for injection, g - 100

To regulate the tone of solution may be added to the sodium chloride and the pH to sostavit to obtain a solution of the compound of the invention when using a dilute acid or alkali or by adding an appropriate buffer salts. May also include antioxidants and metal salts, causing the formation of chelate compounds.

The resulting solution, gave an introduction and filled in the vessels of the appropriate size. Medicines were sterilized by heating in an autoclave. An alternative solution can be sterilized by filtration and filled in sterile vessels under aseptic conditions. The solution can be packaged under a protective layer of nitrogen.

The drug 5. The composition of the medicinal product for injection.

The compound of example 5, g - 0,5 - 10

Polyethoxysiloxane castor oil, g - 15

Propylene glycol, d - 20

Polyoxyethylene-polyoxypropylene block copolymers (Pluronic F 68), g - 10

Water for injection, g - 100

The connection according to the invention was added to the mixture polyethoxyethanol castor oil, propylene glycol and Pluronic F 68. The mixture is gently heated to obtain a clear solution. This solution was sterilized by heating in an autoclave or alternative by filtering. Thus, there has been a concentrated sterile solution, which is suitable for dilution with sterile water in order to form the product, suitable for p is the gathering of example 59, g - 0,5 - 10

Hydroxypropyl-beta-cyclodextrin, g - 10

Water for injection, g - 100

To a mixture of compounds of the invention and hydroxypropyl-beta-cyclodextrin was added water for injection. The mixture is gently mixed to obtain a transparent solution. The solution is filled in the vessel, which was then sealed and sterilized by heating in an autoclave or an alternative method of filtration.

1. Derivative (1-heteroatom-1-heterocyclyl)alkane of General formula II

< / BR>
where X is O or S;

Z IS O, S, NR2or C = N;

R1represents one or two groups selected from H, lower alkyl or halogen, or R1and the ring

< / BR>
together represent benzofuranol system rings;

R2is H, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl or CF3and when there is more than one R2group, they can be chosen independently;

And is

< / BR>
where W is O, NH;

R3- H, lower alkyl or lower acyl;

R4- lower alkyl, cyclopropyl or lower perfluoroalkyl,

or R3and R4together form a ring

< / BR>
in which n = 4;

R5and R6

2. Connection on p. 1, having the General formula III

< / BR>
in which X and Z are independently O or S;

W is O or NH;

R1- R4defined in paragraph 1 of the formula.

3. Connection on p. 1, having the General formula IV

< / BR>
in which X and Z are independently O or S;

R1, R2, R5and R6defined in paragraph 1 of the formula.

4. Connection on p. 1, which is 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol; 1-(4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol; 1-(3-furyl)-1-(4-methyl-5-thiazolyl)ethanol; 1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)ethanol; 1-(2,4-dimethyl-5-thiazolyl)-1-(3-furyl)ethanol; 1-(4-methyl-5-thiazolyl)-1-(3-thienyl)ethanol; 1-(2-ethyl-4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol; 1-(2,5-dimethyl-4-oxazolyl)-1-(3-furyl)ethanol; 1-(4-methyl-5-thiazolyl)-1-(2-thienyl)ethanol; 1-(5-thiazolyl)-1-(3-thienyl)ethanol; 1-(3-furyl)-1-(4-methyl-5-oxazolyl)Aten; 1-(3-furyl)-1-(4-methyl-5-oxazolyl)-1-propene; 1-(2,4-dimethyl-5-oxazolyl)-1-(3-furyl)Aten; 1-(2-furyl)-1-(4-methyl-5-oxazolyl)ethanol; 1-(2-thiazolyl)-1-(2-thienyl)ethanol; 1-(2-thiazolidine-5-oxazolyl)-1-(3-furyl)-2,2,2-triptorelin; 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethylamine; 1-(2-thiazolyl)-1-(3-thienyl)ethylamine, or its pharmaceutically acceptable acid salt of prisoedinenia, or its solvate.

5. The method of obtaining profsoznogo (1-heteroatom-1-heterocyclyl)alkane of General formula II under item 1, when A is

< / BR>
where R3and R4are specified in paragraph 1 values

characterized in that the compound of General formula V

< / BR>
where R2and R4are specified in paragraph 1 values

subjected to interaction with ORGANOMETALLIC derivative of General formula VI

< / BR>
where Z and R1are specified in paragraph 1.

6. The method of deriving (1-heteroatom-1-heterocyclyl)alkane of General formula II under item 1, when A is

< / BR>
where R3and R4have the values listed in paragraph 1,

characterized in that the compound of General formula VII

< / BR>
where R1, R4and Z are specified in paragraph 1 values

subjected to interaction with ORGANOMETALLIC derivative of General formula VIII

< / BR>
where X, R2have the values listed in paragraph 1.

7. The method of deriving (1-heteroatom-1-heterocyclyl)alkane of General formula II under item 1, when A is

< / BR>
where R < / BR>
where X, Z, R1and R2are specified in paragraph 1 values

subjected to interaction with ORGANOMETALLIC derivative of General formula R4M and quenched the reaction mixture with a proton source (R3is H), or alkylating, (R3is lower alkyl) or allermuir (R3represents a lower acyl)reagent.

8. The method of deriving (1-heteroatom-1-heterocyclyl)alkane of General formula II under item 1, when A is

< / BR>
where R3and R4have the values listed in paragraph 1,

characterized in that the compound of General formula IX

< / BR>
where X, Z, R1, R2are specified in paragraph 1 values

subjected to interaction with the derived Silla General formula

R4SiMe3.

9. The method of deriving (1-heteroatom-1-heterocyclyl)alkane of General formula II under item 1, when A is

< / BR>
where R3and R4have the values listed in paragraph 1,

characterized in that the compound of General formula II in which A is

< / BR>
subjected to interaction with trimethylsilylmethyl and Lewis acid, followed by reduction of the obtained azide.

10. Acetamidine compounds of General formula ( 4
- C2-C6the alkyl or cyclopropyl;

R1is hydrogen;

R2is hydrogen, lower alkyl or CF3;

Z is O,

provided that when X is O, acyl group is not attached to, C4and that the following four compounds are excluded: ethyl-4-thiazoleacetic; tert-butyl-5-thiazoleacetic; tert-butyl-5-oxazolidinone; tert-butyl-4-tert-butyl-2-methyl-5-oxazolidinone.

11. Pharmaceutical composition having neuroprotective properties, including an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of the compounds of General formula II

< / BR>
where X Is O or S;

Z IS O, S, NR2or C=N;

R1represents one or two groups selected from H, lower alkyl or halogen, or R1and the ring

< / BR>
together represent benzofuranol system rings;

R2- H, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl, aryl-lower alkyl or CF3and when there is more than one R2group, they can be chosen independently;

A is

< / BR>
where W is O, NH;

R3- H, lower alkyl 3
and R4together form a ring

< / BR>
in which n = 4;

R5and R6independently are H or lower alkyl,

or its geometric or optical isomers or racemates, where there are such isomers, or pharmaceutically acceptable acid salt of accession or its solvate.

12. Connection on p. 1, having neuroprotective properties.

 

Same patents:

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to 3-/1-diazolidinyl butyl-4-piperazinil/ 1H-indazols formula I

< / BR>
where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R5is hydrogen or lower alkyl;

X is halogen;

m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures

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

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to novel condensed heterocyclic compounds or their salts
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