Derivatives oxazolyl or triazolylmethyl, methods for their production (options), pharmaceutical preparation and method for the treatment of neuro-degenerative disorders

 

(57) Abstract:

Describes the new derivatives oxazolyl or triazolylmethyl General formula (1), where X represents O or S; R1represents H; R2represents H or lower alkyl; W represents O or NH; R3represents H, lower alkyl or lower acyl; AG represents phenyl, furyl, thienyl, naphthyl, pyridyl or pyrrolyl possibly substituted R6; R6represents one or more groups selected from lower alkyl, halogen, lower alkoxy, CF3, OH, NO2or NR4R5where R4and R5independently represent H, lower alkyl or lower acyl, and their pharmaceutically acceptable acid salt additive, provided that the following five compounds are not included in the present invention: 1-(4-methyl-5-thiazolyl)-1-phenylethanol; 1-(2,4-dimethyl-5-oxazolyl)-1-phenylethanol; 1-(5-thiazolyl)-1-phenylethanol; 1-(4-oxazolyl)-1-phenylethanol; 1-(2,4-dimethyl-5-thiazolyl)-1-(2-chlorophenyl)methanol. The compounds of formula 1 exhibit neuroprotective properties and may find application in medicine for the treatment of neurodegenerative disorders. Also described pharmaceutical composition based on vaselene.

The invention relates to new heterocyclic compounds having therapeutic activity, to processes for their preparation and intermediate compounds used for their production, to pharmaceutical preparations containing these compounds and to the use of such compounds in medicine.

Justification of the invention.

there is a large group of acute and chronic nervous and psychiatric pathologies, for which treatment is not known safe and clinically effective ways. This group of diverse disorders covers a wide range of initial stages, is characterized by a progressive process, which will sooner or later lead to the death or dysfunction of nerve cells. The shock, cerebral ischemia, injury, or disease causing degeneration of the nervous system such as Alzheimer's or Parkinson's disease, are a common condition associated with degeneration of nerve cells in the brain and/or spinal cord.

Search for possible methods of treatment of disorders leading to degeneration of nerve cells, includes the study of antagonists of excitatory amino acids, inhibitors perechisleniya lipids, antagonists kosina, antagonists of platelet activating factor and a variety of other agents. Currently there is no consensus about the main roles played by connections belonging to each of these major classes.

Anticonvulsants are widely used, in particular in the treatment of various types of epilepsy. In General, the mechanism of action of such drugs are poorly understood, it is necessary to develop new safe and effective anticonvulsants.

(J.Org. Chem. 1957, 22, 559-561) on the synthesis of heterocyclic amino esters related to antihistamine diphenhydramine, the compounds 1-(4-methyl-5-thiazolyl)-1-phenylethanol and 1(2,4-dimethyl-5-oxazolyl)-1 - phenylethanol described as intermediate.

In the work J.Org. Chem. 1988, 53, 1748-1761 described compound 1-(5-thiazolyl)-1-phenylethanol.

In the work J.Org. Chem 1991, 56, 449-452 described compound 1-(4-oxazolyl)-1-phenylethanol.

In the work J.Org. Chem. 1984, 27, 1245-1253 described compound 1-(2,4-dimethyl-5-thiazolyl)-1-(2-chlorophenyl)methanol in the form of intermediate compounds in the synthesis of certain heterocyclic analogues chlorcyclizine having hypolipidemic activity.

The above compounds is not prema invention, what says p. 1 claims.

In the application EP 351194 described compounds of the formula

< / BR>
Replacement group 2-naphthalenyloxy not included in the values of the radical R6according to the present invention.

Description of the invention.

The main objective of the present invention is to create a structurally new heterocyclic compounds, which, owing to their pharmacological profile, can be used as drugs that protect the nervous system, as anticonvulsants and/or as a sedative-hypnotic drugs.

Agents have a protective effect on the nervous system, used for the treatment of acute and chronic nervous and psychiatric disorders, characterized by progressive processes, which will sooner or later lead to the death or dysfunction of nerve cells. Such disorders include stroke; cerebral ischemia; dysfunction in the brain or spinal cord; hypoxia and anoxia, such as drowning, including perinatal and neonatal asphyxia hypoxic brain; dementia as a result of multiple heart attacks, dementia due to HIV; zabolevaniy, multiple sclerosis and Lou Gehrig's disease; brain dysfunction resulting surgery requiring cardiopulmonary bypass or the result of an operation on the brain, requiring carotid endarterectomy; dysfunction of the Central nervous system from exposure to neurotoxins or radiation. Such use of these compounds due to, for example, their ability to delay the death of nerve cells werbelow suffering from bilateral occlusal ischemia.

Antispasmodic drugs are used in clinical settings for the treatment of convulsive States of various types, such as, for example, epilepsy, epileptic condition, preeclampsia and delirium tremens. This ability manifests itself, for example, that these compounds can inhibit the seizures caused by various agents, such as NMDLA.

The present invention relates to compounds of General formula (1)

< / BR>
where X represents O, S;

R1represents H,

R2represents H, lower alkyl,

W represents O, NH;

R3represents H, lower alkyl or lower acyl;

AB>6represents one or more groups selected from among the following groups: lower alkyl, lower acyl, halogen, lower alkoxy, CF3, OH, NO2or NR4R5where R4and R5independently represent H, lower alkyl or lower acyl; geometric and optical isomers and racemates of these compounds, where such isomers exist, as well as pharmaceutically acceptable additive-acid salt and a solvate of these compounds; provided that the following five compounds are not included in the present invention:

1-(4-methyl-5-thiazolyl)-1-phenylethanol;

1-(2,4-dimethyl-5-oxazolyl)-1 - phenylethanol;

1-(5-thiazolyl)-1-phenylethanol;

1-(4-oxazolyl)-1-phenylethanol;

1-(2,4-dimethyl-5-thiazolyl) -1-(2-chlorophenyl) methanol.

The expression "pharmaceutically acceptable additive-sour salt" includes, among other things, such salts as hydrochloride, hydrobromide, hydroiodide, nitrates, acid sulfates, docile phosphates, ethicality, mesylates, fumarate, maleate and succinate.

Preferred embodiments of the present invention pertain to compounds of General formula (2)

< / BR>
where X represents O or S;

and R1, R2, R3and Ar is yl)-1-(4-methyl-5-selenazoline) methanol and 1-(2-forfinal)-1-(4 - methyl-5-selenazoline) methanol, specifically included in the scope of the present invention.

In the text of the description and claims given chemical formula or name connections apply to all existing geometric and optical isomers and racemates, and pharmaceutically acceptable additive acid salts and solvate of these compounds, such as hydrates.

The following definitions are used in the text of the description and claims.

Except where otherwise indicated, the term "lower alkyl" denotes an alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms. Examples of these lower Akilov include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and pentyl and hexyl straight and branched chain.

Except where otherwise noted, the term "lower acyl" refers to acyl group, straight or branched chain, containing from 1 to 6 carbon atoms. Examples of these lower atilov include formyl, acetyl, propionyl, isobutyryl, valeryl and pivaloyl.

Except where otherwise noted, the term "lower alkoxy" denotes CNS group with a straight or branched chain, containing the propoxy, p-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentox, hexose straight and branched chain.

Except where otherwise noted, the term "halogen" denotes fluorine, chlorine, bromine or iodine.

Among the most preferred compounds of formula (1) according to the present invention includes the following compounds:

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

1-(2-furyl)-1-(4-methyl-5-thiazolyl)methanol;

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

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

1-(2-forfinal)-1-(4-methyl-5-thiazolyl) methanol;

1-(3-chlorophenyl)-1-(4-methyl-5-thiazolyl) methanol;

1-(4-methyl-5-oxazolyl)-1-phenylethanol;

1-(4-forfinal)-1-(4-methyl-5-oxazolyl) methanol;

1-(2-forfinal)-1-(4-methyl-5-oxazolyl) methanol;

1-(3-AMINOPHENYL)-1-(4-methyl-5-oxazolyl) methanol;

1-(3-dimethylaminophenyl) -1-(4-methyl-5 - triazolyl)methanol,

as well as pharmaceutically acceptable additive is an acidic salt, or a solvate of these compounds.

The present invention relates also to methods of preparing compounds of General formula (1). In the description text beneath these methods are understood to include, as appropriate, suitable protective group is introduced into a variety of reagents and p clear to any expert in organic synthesis. Ordinary methods of use of such protective groups are described, for example, in the work "Protective Groups in Organic Synthesis", T. W. Greene, Wiley-Interscience, New York, 1981.

These compounds in which W represents O, can be obtained in the following way:

a) compound of General formula (3) interact with ORGANOMETALLIC derivatives ArM

< / BR>
or (b) a compound of General formula (4), interact with ORGANOMETALLIC derivative of General formula (5)

Ar CHO (4)

< / BR>
or (C) restores the compounds of General formula (6)

< / BR>
and abruptly stop the reaction by using a source of protons (R3represents H) or by adding an alkylating agent (R3represents lower alkyl) or Alliluyeva agent (R3represents a lower acyl). Or the compounds of formula (1) in which W represents O, and R3represents H, you can get the above method, and then convert this compound into the compound, where R3will be a lower alkyl or lower acyl.

Methods (a) or (b) can be performed, for example, by reacting aldehyde structural formula (3) or (4) with ORGANOMETALLIC derivatives ArM or (5) soot mixture. The above reaction should be carried out at a suitable temperature, usually from -100 to +50oC, preferably in an atmosphere of inert gas, usually nitrogen or argon. In some cases, the solution of the aldehyde of formula (3) or (4) in anhydrous diethyl ether or tetrahydrofuran drop by drop add in ORGANOMETALLIC derivative ArM or (5), respectively, in an anhydrous solvent such as diethyl ether or tetrahydrofuran, or hexane, or a mixture of these solvents, at a temperature of from about -50 to -78oC in nitrogen atmosphere. After a certain period of time, the reaction mixture was left to warm to room temperature and then the reaction is stopped by adding water or a lower alcohol. After that, the desired compound (1) where WR3represents OH, you can identify, purify and characterize using conventional techniques.

Aldehydes of General formula (3) or (4) and ketones, the General formula (6) are compounds, commercially available or described in the literature, or compounds that can be obtained by known methods.

The present invention relates also to a number of new intermediate compounds of General formula (6), namely the compound of General formet a phenyl, R1, R2and R6are not hydrogen; and with the exception of the following three compounds:

4-propenyl-5-thiazolyl ketone;

4-methyl-5-thiazolidine ketone;

4-methoxyphenyl 4-methyl-5-thiazolyl ketone.

In ORGANOMETALLIC derivative of General formula: ArM or (5) M is a metal residue, such as Li or Mg-halogen. Such compounds are produce, or described in the literature or can be obtained by known methods used in ORGANOMETALLIC chemistry.

The compounds of formula (1), where W represents NH or N - lower alkyl, can be obtained, for example,

a) by reductive amination of the ketone of General formula (6),

or (b) by converting a ketone of General formula (6) in oxime derivative, followed by reduction, or (C) by converting compounds of General formula (1) where WR3represents OH into the corresponding azide or phthalamic using, for example, reaction of Mitsunobu, followed by reduction or hydrolysis.

Compounds of General formula (1) have an asymmetric center and therefore can exist in enantiomeric forms. These enantiomers can be distinguished by using methods that horologically chromatography for example HPLC, using a chiral column;

or (ii) recrystallization diastereoisomeric salts, obtained by interaction of the base (1) with an optically active acid;

or (iii) obtaining derivatives of the compounds of formula (1) by reacting with an optically active reagent, separation obtained diastereoisomeric derivatives, for example, by crystallization or chromatography, followed by reduction of compounds of formula (1).

Otherwise the compounds of formula (1) can be obtained in optically active form using the method of asymmetric synthesis based on the use of chemical reagents or enzymes.

Pharmacological properties.

Neuroprotective properties of the compounds of formula (1) is manifested in their ability to inhibit the delayed death of the nervous system werbelow suffering from bilateral occlusal ischemia.

For tests used Mongolian werbelow male (60-80 g). Drugs were dissolved in isotonic saline solution containing dimethyl sulfoxide.

Ischemia of warbelow caused by occlusion within 5 minutes of both carotid arteries method for the establishment of blood flow after occlusion was checked visually and animals were kept alive for 4 days. After it was determined the extent of degeneration of nerve cells in the hippocampus. Test compounds (intraperitoneally) was administered in one dose after 60 minutes after occlusion. Before occlusion no drugs were introduced. The efficacy of the formula (1) reduction of the damage to the nerve cells of the hippocampal CA1/CA2 of warbelow ischemic stroke, clearly demonstrates the usefulness of these compounds in the prevention of degeneration of nerve cells. Thus, it is expected that these compounds can be used for the treatment of acute and chronic nervous and psychiatric disorders, characterized by progressive processes, sooner or later leading to death or dysfunction of nerve cells.

Antispasmodic properties of the compounds of formula (1) is manifested in their ability to protect mice from seizures caused NMDLA. Used male mice (18-30 g).

Groups of eight mice each were injected NMDLA (300 mg/kg, intraperitoneally) and recorded the number of mice which over the next 15 min manifested tonic convulsions. The drug was administered 15 min prior to the introduction of NMDLA, the data indicate a dose that was needed h the uly (1) appear in their ability to inhibit locomotor activity in mice.

Mice were administered the test compound and 20 min for the next 10 minutes were recorded locomotor activity. The activity was controlled by system interrupts the infrared beam in the cell size 40 cm x 40 cm Data reflect the dose that was required in order to reduce locomotor activity by 50% (ED-50).

Data pharmacological activity of compounds obtained using the above methods, is given in the table.

Recipes pharmaceuticals.

A new method of treatment of the present invention provides for oral, rectal, local, or the parenteral administration of doses, for example, from about 0.001 to 1000 mg/kg, preferably from about 1.0 to 500 mg/kg, preferably from about 5.0 to 200 mg/kg; the assignment can be performed in mode 1 to 4 doses or techniques per day. The dose will depend on the method of administration, and the preferred methods are oral or intravenous. It is desirable that when establishing the particular mode of administration and doses of doctor took into account the severity of the disease, the patient's age and other factors, which are usually ignored by doctors.

Pharmaceuticals, stanely for oral administration; sterile parenteral solutions or suspensions for parenteral use; candles for rectal use; or the corresponding formulations for the local destination. Conventional methods of selection and fabrication of suitable pharmaceutical preparations are described, for example, in Pharmaceuticals - The science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.

In order to produce a pharmaceutical preparation containing the compound according to the invention, in the form of dosages suitable for oral purpose, the active substance can be mixed with ancillary medicinal substance/carrier, for example lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a sliding substance such as magnesium stearate, calcium stearate, polyvinylglycol, wax, paraffin, etc., and then compressed into tablets. If you want to make pills in the wafers, then the pellets produced as described above, and cover them with a concentrated sugar solution which may contain, for example, gumarabic, gelatin, talc, titanium dioxide, etc. By another way tablets can be coated is of rastvoritelei. In this shell, you can add dyes to make it easier to distinguish between tablets containing different active substances or different number of active connections.

For the manufacture of 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 for the manufacture of which used any of the media used for the manufacture of tablets, for example lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules can be filled also active substance in a liquid or semi-liquid form.

Preparations for rectal application can be solutions or suspensions, or they can be manufactured in the form of suppositories containing the active substance in a mixture with a neutral fat, or in the form of a gelatine rectal capsules containing the active substance in a mixture with vegetable oil or paraffin oil.

Liquid preparations for oral use can be in the form of syrups or suspensions, for example in the form of solutions, Soderstrom. If desired, such liquid preparations may contain colouring agents: flavors, saccharin or carboxymethylcellulose as fillers, or other media known in the art.

Solutions for parenteral purposes can be prepared in the form of aqueous solutions of water-soluble pharmaceutically acceptable salts of the active substance, preferably in a concentration of from about 0.5 to about 10 wt.%. These solutions may also contain stabilizers and/or buffers, and surfactants to increase the solubility. The desired dose solutions can pour into vials.

The source materials for the following examples were purchased, with the exception of the following reagents:

4-methyl-5-thiazolecarboxamide (J. Amer. Chem., Soc., 1982, 104, 4934-43);

2-futility (J. Org.Chem., 1962, 27, 1216).

Example 1.

1-(3-Furyl)-1-(4-methyl-5-thiazolyl)methanol.

4-Methylthiazole (3 g) in dry diethyl ether drop added n-utility (1.6 M in hexano, 21 ml) in diethyl ether (20 ml); the additive is produced under stirring at -78oC in dry nitrogen atmosphere. After 30 minutes added trimethylsilane (3,9 ml), the mixture is then left to warm up to 0oC . The mixture is then cooled the -78oC and added 3-furaldehyde (5 g) in diethyl ether (10 ml). The mixture was left to warm to room temperature and after 30 minutes was added a saturated aqueous solution of acid sodium carbonate. The reaction mixture was extracted with diethyl ether (conventional method) to obtain the crude product which was then purified on a flash chromatography on silica gel to obtain the desired compound, melting point which was 44-46oC.

13C NMR (CDCl3) 14,8, 62,4, 108,8, 128,3, 135,7, 139,4, 143,5, 148,1, 150,9 ppm.

Found, %: C 55,0; H 4,7; N 7,0.

C9H9NO2S.

Calculated, %: C A 55.4; H 4,6; N 7,2.

The method described in example 1 but using the appropriate aldehydes were obtained compounds of examples 2-23.

Example 2.

1-(4-Methyl-5-thiazolyl) -1-(4-pyridyl) methanol.

Melting point 131-132oC.

Example 3.

1-(4-Methyl-5-thiazolyl) -1-(3-pyridyl) methanol.

The desired compound was converted into the hydrochloride with hydrogen chloride in ethanol and diethyl ether. Melting point 180-184oC (decomp.)

Example 4.

1-(4-Methyl-5-thiazolyl)-1-(2-naphthyl) methanol.

Escoer 5.

1-(2-Furyl)-1-(4-methyl-5-thiazolyl) methanol.

Melting point 50-51oC.

1H NMR (CDCl3): 2,35 (3H, s), between 6.08 (1H, s), to 6.19 (1H, dt), 6,33 (1H, dq), 7,39 (1H, q), and 8.6 (1H, s) ppm.

Found, %: C 55,1; H 4,8; N 6,8.

C9H9NO2S.

Calculated, %: C A 55.4; H 4,6; N 7,2.

Example 6.

1-(4-Methyl-5-thiazolyl)-1-(2-thienyl) methanol.

Melting point 75-77oC.

1H NMR (CDCl3): 2,4 (3H, s), of 3.46 (1H, d), 6,34 (1H, d), to 6.95 (2H, m), 7,29 (1H, m), and 8.6 (1H, s) ppm.

Example 7.

1-(4-Methyl-5-thiazolyl) -1-(5-nitro-2-furyl) methanol.

Melting point 127-129oC.

Example 8.

1-(5-Methyl-2-furyl) -1-(4-methyl-5-thiazolyl) methanol.

The melting point of 123-125oC.

Example 9.

1-(1-Methyl-2-pyrrolyl)-1-(4-methyl-5-thiazolyl) methanol.

Melting point 142-147oC.

Example 10.

1-(4-Methyl-5-thiazolyl) -1-(3-thienyl) methanol.

1H NMR (CDCl3): 2,43 (3H, s), 6,2 (1H, s), 7,06, 7.27 and 7,34 (1H, m each), to 8.62 (1H, s) ppm.

Example 11.

1-(2-Forfinal)-1-(4 - methyl-5-thiazolyl) methanol.

Melting point 100-101oC.

1H NMR(CDCl3): of 2.45 (3H, s), 2,8 (1H, d), 6.42 per (1H, d)x2">

Calculated, %: C 59,2; H 4.5; N 6,3.

Example 12.

1-(3-Forfinal) -1-(4-methyl-5-thiazolyl) methanol.

The melting point of 74-75,5oC.

Found, %: C 59,2; H 4,4; N 6,0.

C11H10FNOS.

Calculated, %: C 59,2; H 4.5; N 6,3.

Example 13.

1-(4-Forfinal)-1- (4-methyl-5-thiazolyl) methanol.

The melting temperature of 98.5-100oC.

Example 14.

1-(3-Chlorophenyl) -1-(4-methyl-5-thiazolyl) methanol.

Melting point 97-98oC.

1H NMR (CDCl3): to 2.41 (3H, s), 3,37(1H, d), 6,07 (1H, d), 7,26 (3H, m), 7,41 (1H, m), 8,59 (1H, s) ppm.

Found, %: C 55,2; H 4,25; N 5,65.

C11H10ClNOS.

Calculated, %: C 55,1; H 4.2; N 5,8.

Example 15.

1-(3-Methoxyphenyl)-1- (4-methyl-5-thiazolyl) methanol.

Melting point 87-88oC.

Found, %: C 60,0; H 5,7; N 5,75.

C12H13NOS0,25H2O.

Calculated, %: C 60,1; H 5,7; N 5,8.

Example 16.

1-(2-Methoxyphenyl) -1-(4-methyl-5-thiazolyl) methanol.

Melting point 121-122oC.

Example 17.

1-(2-Chlorophenyl) -1-(4-methyl-5-thiazolyl) methanol.

Melting point 122-123oC.

Nide CLASS="ptx2">

1-(2-Were)- 1-(4-methyl-5-thiazolyl) methanol.

Melting point 141,5-143oC.

Found, %: C, And 65.7; H 6,2; N 6,25.

C12H13NOS.

Calculated, %: C, And 65.7; H 6,0; N 6,4.

Example 19.

1-(3-Were) -1-(4-methyl-5-thiazolyl) methanol.

Melting point 103-104,5oC.

Found, %: C 65,8; H 6,25; N 6,4.

C12H13NOS.

Calculated, %: C, And 65.7; H 6,0; N 6,4.

Example 20.

1-(4-Methyl-5-thiazolyl) -1-(3-nitrophenyl) methanol.

Melting point 119,5-121oC.

Example 21.

1-(2,6-Acid)-1- (4-methyl-5-thiazolyl) methanol.

Melting point 125-126oC.

Example 22.

1-(4-Methyl-5-thiazolyl) -1-(1-naphthyl) methanol.

Melting point 115-116oC.

Example 23.

1-(4-Methyl-5-thiazolyl) -1-(3-Cryptor-were) methanol.

The melting temperature of 73.5-75oC.

Found, %: C For 52.6; H 3,5; N 5,0.

C12H13FNOS.

Calculated, %: C 52,7; H 3,7; N 5,1.

Example 24.

1-(4-Chlorophenyl)-1- (4-methyl-5-thiazolyl) methanol.

4-Methylthiazole was treated sequentially with n - butyllithium, trimetals the Noah chromatography on silica gel was obtained 4-methyl-5-trimethylsilylimidazole.

4-Methyl-5 - trimethylsilylimidazole (3 g), 4-chlorobenzaldehyde (4.9 g) and cesium fluoride (2.7 g) in dry tetrahydrofuran (150 ml) was distilled for 30 hours. The mixture was cooled, evaporated to dryness and the obtained residue was purified with flash chromatography to obtain the desired compound, melting point which amounted to 133.5-134,5oC.

Hydrochloride, melting point 167,5-172,5oC. by the Method described in example 24 by using the appropriate aldehyde was obtained compound in examples 25 and 26.

Example 25.

1-(2,4-Dichlorophenyl)-1- (4-methyl-5-thiazolyl) methanol.

Melting point 163-164oC.

Example 26.

1-(3,4-Dichlorophenyl) -1-(4-methyl-5-thiazolyl) methanol.

Melting point 143-144oC.

Hydrochloride, melting point 180-188oC (decomp.). Methanesulfonate, melting point 147-148oC.

Example 27.

1-(3,4-Dichlorophenyl) -1-(5-thiazolyl) methanol.

2-Bromothiazole (5 g) in dry diethyl ether (20 ml) drop by drop added to a solution of n-utility (1.6 M in hexane, 21 ml) in diethyl ether (20 ml); the additive is produced under stirring at - 70oC in dry nitrogen atmosphere. After 30 min added timethese n-utility (21 ml). The mixture was let warm up to 0oC and after 30 minutes, again cooled to -70 degrees and added 3,4-dichlorobenzaldehyde (5.8 g) in diethyl ether (40 ml). The mixture is then left to warm up to room temperature and after 30 minutes was added a saturated aqueous solution of acid sodium carbonate. The mixture was extracted with dichloromethane and the resulting material was purified by chromatography on silica gel to obtain the desired compound. The obtained hydrochloride with a melting point 167-170oC.

Example 28.

1-(4-Methyl-5-oxazolyl)-1-phenylethanol.

4-Methyl - 5-oxazolidinyl (600 mg) in dry tetrahydrofuran (10 ml) drop by drop added to the solution finelite (2.0 M solution in cyclohexane and diethyl ether, and 2.8 ml) in tetrahydrofuran (20 ml); the additive is produced under stirring at -70oC in dry nitrogen atmosphere. After 1 hour the mixture was allowed to warm to room temperature. Even after 1 hour was added a saturated aqueous solution of acid sodium carbonate and the mixture was extracted with ethyl acetate. The reaction product was purified with flash chromatography to obtain the desired compound, melting point which was 79-81oC.

1H NMR (CDCl3): and 2.14 (3H, s), 5,94 (1H, s), 7,3-7,5 (5H, m), 7,75 (Alcabideche (770 mg) in dry tetrahydrofuran (15 ml) drop by drop added to a solution of 4-performane bromide (1 M solution in tetrahydrofuran, 7.3 ml) in tetrahydrofuran (30 ml); the additive is produced under stirring at -70oC in dry nitrogen atmosphere. After 1 hour the mixture was allowed to warm up to room temperature, then poured it out into a saturated aqueous solution of acid sodium carbonate. After extraction with ethyl acetate and subsequent flash chromatography was obtained the desired compound, melting point which was 102,5-104oC.

1H NMR (CDCl3): of 2.09 (3H, s), 3,68 (1H, br), 5,88 (1H, s),? 7.04 baby mortality (2H, m), 7,38 (2H, m), 7,66 (1H, s) ppm.

The method described in example 29, by using the appropriate aldehyde was obtained compound in examples 30 and 31.

Example 30.

1-(4-Methyl-5-oxazolyl) -1-(2-were) methanol.

Melting point 122-123oC.

Example 31.

1-(4-Methyl-5-oxazolyl) -1-(4-were) methanol.

Melting point 125-127oC.

Example 32.

1-(4-Methyl-5-oxazolyl)-1- (3-were) methanol.

n-Utility (2.5 M solution in hexano, 3,9 ml) drop by drop added to a solution of 3-bromthymol (1.1 ml) in dry tetrahydrofuran (20 ml); the additive is produced under stirring at -70oC in dry nitrogen atmosphere. After 20 minutes the to room temperature, then it was distilled for 1 hour. The cooled solution was poured into a saturated aqueous solution of acid sodium carbonate. After extraction with ethyl acetate and flash chromatography was obtained the desired compound, melting point of which 76.5-77,5oC. by the Method described in example 32, using the appropriate approach formulated above or iodides were obtained compounds of examples 33 to 36.

Example 33.

1-(2-Forfinal)-1- (4-methyl-5-oxazolyl) methanol.

1H NMR (CDCl3): and 2.14 (3H, s), to 3.02 (1H, brs), from 6.22 (1H, s), 6,98-7,37 (3H, m), to 7.67 (2H, m) ppm.

Example 34.

1-(2,4-Differenl)-1- (4-methyl-5-oxazolyl) methanol.

Melting point 116-117,5oC.

Example 35.

1-(4-Methyl-5-oxazolyl) -1-(2-trifluoromethyl-phenyl) methanol.

The melting temperature of 105.5-107,5oC.

Found, %: C 56,2; H 3,7; N 5,4.

C12H10F3NO2.

Calculated, %: C 56,0; H 3,9; N The 5.45.

Example 36.

1-(2-Chlorophenyl)-1- (4-methyl-5-oxazolyl) methanol.

Melting point 127-128oC.

Example 37.

Methyl 1-(4-methyl-5-thiazolyl)-1-fenilmetilovy ether.

Sodium hydride (80% dispersion in mineral malg produced under stirring at a temperature of 0oC. After 10 minutes, added methyliodide (0.15 ml). The mixture is then left to warm up to room temperature and after 30 minutes the mixture was evaporated to dryness. The residue was purified flash chromatography to obtain the desired compound.

1H NMR (CDCl3): 2,46 and 3,39 (each 3H, s), 5,52 (1H, s), 7,28 to 7.4 (5H, m), 8,64 (1H, m) ppm.

The method described in example 37, using the corresponding starting materials were obtained compounds of examples 38 to 43.

Example 38.

Methyl 1-(3,4-dichlorophenyl)-1-(4-methyl-5 - thiazolyl) methyl ether.

Hydrochloride, melting point 170 - 176oC (decomp.).

Example 39.

Methyl 1-(2,4-dichlorophenyl)-1-(4-methyl-5-thiazolyl) methyl ether.

Melting point 55-56oC.

Example 40.

Methyl 1-(3-furyl)-1-(4 - methyl-5-thiazolyl)methyl ether.

13C NMR (CDCl3): 15,1, 15,3, 64,3, 69,6, 109,0, 126,4, 133,1, 139,9, 143,6, 149,5, 151,3 ppm.

Example 41.

1-(3-Furyl)-1-(1-methyl-5-thiazolyl)methyl methyl ether.

1H NMR (CDCl3): 2,45 and 3,36 (each 3H, s), 5,52 (1H, s), 6,34 (1H, m), 7,38 (2H, m), 8,68 (1H, s) ppm.

Example 42.

1-(2-Furyl)-1-(4-methyl-5 - thiazolyl)methyl methyl ether.

1H NMR (CDCl3): 21-(4-methyl-5-thiazolyl)methyl methyl ether.

1H NMR (CDCl3): 2.48 and 3,39 (each 3H, s), 5,86 (1H, s), 6,98-to 7.35 (3H, m), 7,52 (1H, m), 8,65 (1H, s) ppm.

Example 44.

1-(4-Methyl-5-thiazolyl)-1-phenylethyl acetate.

Acetylchloride (0.6 ml) was added to a solution of 1-(4-methyl-5-thiazolyl)- 1-phenylethanol (800 mg) and pyridine (0.5 ml) in dichloromethane (30 ml) at 0oC in dry nitrogen atmosphere. The mixture was left to warm to room temperature and then was stirred overnight. After evaporation and purification of the residue with flash chromatography was obtained the desired compound.

1H NMR (CDCl3): 2,15 and 2.51 (each 3H, s), 7,16 (1H, s), 7,35 (5H, m), 8,66 (1H, s) ppm.

Example 45.

1-(2-Forfinal)-1- (4-methyl-5-thiazolyl)methyl acetate.

Using as the starting material 1-(2-forfinal) -1-(4-methyl-5-thiazolyl) methanol in the manner described in example 44, was obtained the desired compound, melting point which was 53-56oC.

Example 46.

1-(3-AMINOPHENYL)-1- (4-methyl-5-thiazolyl) methanol.

1-(4-Methyl-5-thiazolyl)-1-(3-nitrophenyl)methanol (2 g) and 10% palladium on carbon (200 ml) in ethanol (60 ml) during the night was stirred in the vibrator in the atmosphere of hydrogen. The mixture was filtered and the filtrate evaporated to dryness. The residue was converted into hydro is UP>oC.

1H NMR (CDCl3): of 2.38 (3H, s), 2,44 (1H, d), the 3.65 (2H, br), 5,95 (1H, d), 6,56 (1H, m), 6,7 (2H, m), was 7.08 (1H, m), to 8.57 (1H, s) ppm.

Found, %: C To 59.9; H Of 5.55; N 12,4.

C11H12N2OS.

Calculated, %: C 60,0; H 5,5; N 12,7.

Example 47.

1-(3-Dimethylaminophenyl) -1-(4-methyl-5-thiazolyl) methanol.

The desired compound was obtained from 4 - methyl-5-thiazolecarboxamide and 3-bromo-N, N-dimethylaniline according to the method described in example 32. Melting point 135-138oC.

1H NMR (CDCl3): of 2.44 (3H, s), 2,75 (1H, s), 2,96 (6H, s), 6,04 (1H, s), 6,65 - 6,8 (3H, m), 7.23 percent (1H, t), at 8.60 (1H, s) ppm.

Example 48.

1-(3-Hydroxyphenyl)-1- (4-methyl-5-thiazolyl) methanol.

1-(3-Methoxyphenyl)-1-(4-methyl-5-thiazolyl)methanol (1 g) in dry dichloromethane (10 ml) drop by drop added in tribromide boron (1 M solution in dichloromethane, 25 ml); the additive produced at 0oC. the Mixture is left to warm up to room temperature, then was stirred for 15 minutes. The mixture is poured on ice (40 g) with ammonia (10 ml). The precipitate was filtered and purified by chromatography to obtain the desired compound.

Melting point 181-184oC.

Example 49.

1-(2-Furyl)-1- (4-methyl-5-thiazolyl) methanol.

Isomere 28. Melting point 52-54oC.

1H NMR (CDCl3): 2,16 (3H), 2,7 (1H, br), of 5.92, 6,32, 6,40, 7,44 and 7,80 (1H).

Found, %: C 60,0; H 5,1; N 7,9.

C9H9NO3.

Calculated, %: C, 60,3; H 5,1; N 7,8.

Example 50.

Separation of 1-(4-methyl-5-thiazolyl) -1-phenylethanol.

1-(4-Methyl-5-thiazolyl)-1-feniletilamin, suspended in buffer pH 7.5 at 37oC, was treated with pork liver esterase. The obtained product was subjected to flash chromatography to obtain after crystallization of 1-(4-methyl-5-thiazolyl) -1-phenylethanol, which, as shown by chiral HPLC, contained more than 98% of one enantiomer.

1-(4-methyl-5-thiazolyl)-1 - feniletilamin, which was obtained after flash chromatography, was subjected to alkaline hydrolysis, and product recrystallization to another enantiomer of the desired connection.

Example 51.

Separation of 1-(2-forfinal)-1- (4-methyl-5-thiazolyl) methanol.

The desired compound was separated by using preparative HPLC on a column Chiralcel OD using 2-propanol in hexane as solvent.

Enantiomers: []2D0+61oand -60orespectively.

Example 52.

oC three-tert-butoxylated lithium (1 M solution in tetrahydrofuran). Processing the usual way possible to get the connection.

1H NMR (CDCl3): to 2.55 (3H, s), 8,03 (1H, s), 9,92 (1H, s) ppm.

Example 53.

1 azido-1-(3-furyl)-1- (4-methyl-5-thiazolyl) methane.

Boron TRIFLUORIDE, diethylether (8 mmol) was added to a mixture of the reaction product of example 1 (4 mmol) and trimethylsilane (8 mmol) in dry benzene (4 ml). The mixture was stirred at room temperature for 4 days, and then was diluted with ethyl acetate (50 ml). After washing with an aqueous solution of acid sodium carbonate and water, the organic phase is separated and dried. After evaporation got the desired compound in the form of oil.

13C NMR (CDCl3): 15,1, 53,9, 108,8, 123,9, 129,9, 140,0, 143,9, 150,3, 151,4 ppm.

Example 54.

1 azido-1- (4-methyl-5-thiazolyl) -1-phenylmethane.

Using as starting material 1-(4-methyl-5-thiazolyl)-1-phenylethanol according to the method described in example 53, received the desired connection.

13C NMR (CDCl3): 15,4, 61,4, 126,7, 128,5, 128,8, 131,0, 138,5, 150,1, 151,6 ppm.

Example 55.

1-(4-Methyl-5-thiazolyl) -1-(N-phthalimido)-1 - phenylmethane hydrochloride.

1-(4-Methyl-5-thiazole is in dry tetrahydrofuran (15 ml) was stirred at room temperature for 3 days. The mixture is evaporated to dryness and the residue was purified column chromatography on silica gel. The material obtained was converted into the hydrochloride in the standard way. Melting point 194-196oC.

13C NMR (CDCl3): 12,6, 49,1, 124,1, 127,0, 129,2, 129,4, 131,2, 134,7, 135,0, 135,8, 144,8, 154,7, 167,2 ppm.

Example 56.

1-(4-Methyl-5-thiazolyl) -1-phenylethylamine.

The reaction product from example 55 (1.3 mmol) and hydrazinehydrate (1.8 mmol) was heated to a temperature of distillation in ethanol (10 ml) for 2 hours. Fallen in sediment phthalimide was filtered and the filtrate evaporated to dryness. The obtained residue was purified with flash chromatography to obtain the desired compound.

13C NMR (CDCl3): 15,4, 53,1, 126,4, 127,5, 128,6, 137,8, 143,9, 147,6, 150,2 ppm.

Example 57.

-(1-(4-Methyl-5-thiazolyl) -1-phenylmethyl) ndimethylacetamide.

Acetylchloride added into the solution of the reaction product from example 56 and triethylamine in dry dichloromethane. The mixture was stirred at room temperature overnight, then washed with an aqueous solution of acid sodium carbonate. The organic phase was separated, dried and evaporated, and the residue was purified flash chromatography to obtain the desired compound.

13C NMR (CDCl3<) -methylamine.

The reaction product from example 53 in ethanol was stirred at the vibrator with 10% palladium on carbon in a hydrogen atmosphere for 3 hours. The catalyst was filtered and the filtrate evaporated to dryness. The residue was subjected to flash chromatography to obtain the desired compound.

13C NMR (CDCl3): 14,7, 44,9, 108,6, 120,9, 137,0, 138,4, 142,9, 147,2, 149,7 ppm.

Examples of pharmaceutical compositions.

Composition No. 1 tablets.

Connection example 33 10 grams

Lactose - 94 g

Microcrystalline cellulose - 86 g

Polyvinylpyrrolidone - 8 g

Magnesium stearate 2 g

Connection example 33, lactose, cellulose and polyvinylpyrrolidone were sifted and mixed. Magnesium stearate was sieved and added to the above mixture. By pressing the appropriate stamps received 1000 tablets, each of which contained 10 mg of the active ingredient. If desired, the resulting tablets can be coated membranes.

Composition N 2 tablets.

Connection example 11 - 50 g

Lactose - 80 g

Microcrystalline cellulose - a 20 g

Potato starch - 40g

Polyvinylpyrrolidone - 8 g

Magnesium stearate 2 g

Connection example 11 is isusually and mixed with the remainder of the starch, polyvinylpyrrolidone and sifted magnesium stearate. By pressing the appropriate stamps received 1000 tablets, each containing 50 mg of active ingredient.

Composition N 3 capsules.

Connection example 1 - 100 grams

Pre gelatinising starch - 98 g

Magnesium stearate 2 g

The compound of example 1 and starch were sieved, mixed and then mixed with sifted magnesium stearate. The mixture used for filling 1000 hard gelatin capsules of suitable size. Each capsule contained 100 mg of the active ingredient.

Song # 4 - solution for injection.

Connection example 46 is 0.5 - 10 g

Polyethoxysiloxane castor oil - 15 g

Water for injection ad 100 g

You can add sodium chloride to increase tonic effect solution, and also change the pH in order to increase the stability and/or to strengthen the solution of the compounds according to the invention using a dilute acid or alkali or by adding the appropriate buffer salts. You can also include antioxidants and salt, contributing to the formation of chelate complexes of metals.

Solution prigotavlivaya in the autoclave. Otherwise the solution can be sterilized by filtration, after which it is poured into sterile vials under aseptic conditions. Spill solution can be performed in a nitrogen atmosphere.

Composition No. 5 - a solution for injection.

The compound of example 1 and 0.5 - 10 g

Polyethoxysiloxane castor oil - 15 g

Propylene glycol - a 20 g

Block copolymers of polyoxyethylene and polyoxypropylene (Pluronic F68) - 10 g

Water for injection ad 100 g

The connection according to the invention is added to the mixture palafoxiana castor oil, propylene glycol and polyoxypropylene (Pluronic F68). The mixture is gently heated to obtain a clear solution. Then the solution was sterilized by heating in an autoclave. Otherwise the solution can be sterilized by filtration. Thus is obtained a concentrated sterile solution that is acceptable to dilute with sterile water to form a composition that would be acceptable for parenteral use.

Composition No. 6 - a solution for injection.

Connection example 5 and 0.5-10 g

Hydroxypropyl-8-cyclodextrin - 10 g

Water for injection ad 100 g

To a mixture of the claimed compounds were added to water for injection and Gilkey, which was then sealed and sterilized by heating in an autoclave, otherwise the solution can be sterilized by filtration.

1. Derivatives oxazolyl or triazolylmethyl General formula I

< / BR>
where X represents O or S;

R1represents H; R2represents H or lower alkyl;

W represents O or NH;

R3represents H, lower alkyl or lower acyl;

Ar represents phenyl, furyl, thienyl, naphthyl, pyridyl or pyrrolyl possibly substituted R6;

R6represents one or more groups selected from lower alkyl, halogen, lower alkoxy, CF3, OH, NO2or NR4R5where R4and R5independently represent H, lower alkyl or lower acyl,

optical isomers and racemates of the compounds, where such isomers exist, as well as their pharmaceutically acceptable acid salt additive, except for the five compounds listed below:

1-(4-methyl-5-thiazolyl)-1-phenylethanol;

1-(2,4-dimethyl-5-oxazolyl)-1-phenylethanol;

1-(5-thiazolyl)-1-phenylethanol;

1-(4-oxazolyl)-1-phenylethanol;

1-(2,4-dimethyl-5-thiazolyl)-1-(2-chlorophenyl)methanol.

2. With the t value, specified in paragraph 1.

3. The compound of formula I, including:

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

1-(2-furyl)-1-(4-methyl-5-thiazolyl)methanol;

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

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

1-(2-forfinal)-2-(4-methyl-5-thiazolyl)methanol;

1-(3-chlorophenyl)-1-(4-methyl-5-thiazolyl)methanol;

1-(4-methyl-5-oxazolyl)-1-phenylethanol;

1-(4-forfinal)-1-(4-methyl-5-oxazolyl)methanol;

1-(2-forfinal)-1-(4-methyl-5-oxazolyl)methanol;

1-(3-AMINOPHENYL)-1-(4-methyl-5-thiazolyl)methanol;

1-(3-dimethylaminophenyl)-1-(4-methyl-5-thiazolyl)methanol,

and their pharmaceutically acceptable acid additive salt.

4. Connection on p. 1, showing a sedative effect.

5. Connection on p. 1, showing a neuroprotective effect.

6. Connection on p. 1, showing anticonvulsant action.

7. The method of obtaining derivatives oxazolyl or triazolylmethyl formula I on p. 1, where W = O, R3= H, has a therapeutic activity, characterized in that the compound of General formula III interacts with ORGANOMETALLIC derivatives ArM

< / BR>
where R1, R2, X and Ar are set under item 1, and M - represents - or triazolylmethyl formula I on p. 1, where W = O, R3= H, has a therapeutic activity, characterized in that the compound of General formula IV interacts with an ORGANOMETALLIC derivative of General formula V

Ar - CHO,

< / BR>
where M represents a metal residue, such as Li or Mg-halogen, and R1, R2and X have the meanings specified in paragraph 1.

9. The method of obtaining derivatives oxazolyl or triazolylmethyl formula I on p. 1, where W is NH; R3- H, has a therapeutic activity, characterized in that the compound of General formula I, where R3HE is a converted into the corresponding azide or phthalimide using, for example, reaction of Mitsunobu, and then respectively obtained product restore or hydrolized.

10. Pharmaceutical drug exhibiting neuroprotective property when bilateral occlusive ischemia, anticonvulsant and sedative effect, containing derived oxazolyl or triazolylmethyl General formula I

< / BR>
where X represents O or S;

R1represents H; R2represents H or lower alkyl;

W represents O or NH;

R3represents H, lower alkyl or lower acyl;

Ar before whom represents one or more groups, selected from lower alkyl, halogen, lower alkoxy, CF3, OH, NO2or NR4R5where R4and R5independently represent H, lower alkyl or lower acyl, except for the five compounds listed in paragraph 1,

and their pharmaceutically acceptable acid additive salt as an active ingredient and a pharmaceutically acceptable carrier.

11. A method for the treatment of neuro-degenerative disorders in bilateral occlusive ischemia, and/or convulsive States, and/or the excited state by assigning to a patient in need of such treatment, a sufficient amount of the compounds of General formula

< / BR>
where X represents O or S;

R1represents H;

R2represents H or lower alkyl;

W represents O or NH;

R3represents H, lower alkyl or lower acyl;

Ar represents phenyl, furyl, thienyl, naphthyl, pyridyl or pyrrolyl possibly substituted R6;

R6represents one or more groups selected from lower alkyl, halogen, lower alkoxy, CF3, OH, NO2or NR4R5where R4and R5independently represent H, the Oh of the acid additive salt.

 

Same patents:

The invention relates to compounds of the following formula 1, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

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 new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes

The invention relates to 4-aryloxy - or 4-aaltio-piperidinyl derivative of the formula (I):

< / BR>
where

R1and R2each, independently of one another, signify unsubstituted or one - or twofold substituted with A, OH, OA, aryloxy with 6-10 C atoms, aralkylated with 7-11 C atoms, -O-(CH2)n-O-, Gal, CF3, NO2, NH2, NHA, NA2, NHAc, NAAc, NHSO2A and/or NASO2A phenyl residues;

X denotes O, S, SO or SO2;

"m" denotes 1, 2 or 3;

"n" represents 1 or 2;

A stands for an alkyl residue with 1-6 C-atoms;

Gal denotes F, Cl, Br or iodine;

and Ac denotes alkanoyl with 1-8 C-atoms, arkanoid with 1-10 C-atoms or aroyl with 7-11 C atoms, and their physiologically acceptable salts

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof
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