Derivative of benzothiazole or its pharmacologically acceptable salt

 

(57) Abstract:

Usage: in the active chemistry of heterocyclic substances, in particular as anti-inflammatory substances derivatives of benzothiazole. The inventive product derivatives of benzothiazole f-crystals: (communication with gray)- CR1=C(OR2)-CR3-CR4-C (communication with nitrogen) -S-C/NR5R6/N - where R1and R2equal to or different hydrogen, lower alkyl or alkoxygroup or group f-ly: -(CH2)p-Pr p=1-4; R4is hydrogen, lower alkyl, phenyl or a group of f-crystals: -(CH2)q-Pr when q= 1, 4, or group f-ly: -C(/O-C(O)-R7/H-Pr, R7lower alkyl, or R3and R4form a benzene ring together with the carbon atoms to which they are linked, R2hydrogen or lower alkyl, R5and R6equal to or different hydrogen or lower alkyl or a group of f-crystals: -(CH2r-Pr with r=1-4, Pr-pyridyl, or its pharmacologically acceptable salt. 23 C.p. f-crystals, 3 tables.

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which functions are submitting is of Avani on leukotrienes and thromboxanes. Since it was found that these substances are related to a variety of inflammatory diseases, made active attempts to develop drugs capable of inhibiting thromboxane-a synthase or 5-lipoxygenase.

Steroid anti-inflammatory drugs such as prednisolone and non-steroidal anti-inflammatory drugs such as indomethacin and aspirin, are widely used at the present time. However, causing the fear of side effects of these steroid drugs makes them unsuitable for extended (long-term) applications. On the other hand, non-steroidal drugs (such as indomethacin and aspirin) do not inhibit the production of leukotrienes, which cause tissue damage, and inhibit the production of prostaglandin E2that, as expected, protects mucosa (mucous membrane). Thus, should apply more than adequate attention to the use of these drugs. Therefore, urgently requires the development of a drug which inhibits the production of leukotrienes and thromboxanes, officers, mediators of inflammation, but absolutely does not suppress the production of prostaglandin E2that protects mucosa.

Cnia diseases, which are effective in the inhibition of the production of leukotrienes, through the function of inhibiting 5-lipoxygenase, and the function of inhibiting the production of thromboxanes via inhibition of thromboxane synthetase, and pharmacologically acceptable salts. In addition, another objective of the invention is to develop a method of producing the aforementioned compound or pharmacologically acceptable salt, and development of medicines, which includes the aforementioned compound or pharmacologically acceptable salt as active ingredient. When the circumstances were started searching for a new medicinal product. In the result it was found that the above objectives can be achieved by use of the derivative of benzothiazole.

The proposed connection is a derivative of benzothiazole represented by the General formula (I) and pharmacologically acceptable salt thereof:

NR5R6(I) where R1and R3are either the same or different, and each represents a hydrogen atom, a lower alkyl group, lower alkoxy group, a group represented by the formula:

(CH where p is an integer from 1 to 4, or a group, predstavleniya group, the group represented by formula

_ where q is an integer from 1 to 4

or a group represented by the formula

where R7lower alkyl group;

or R3and R4may form a benzene ring together with the carbon atoms to which they are linked;

R2a hydrogen atom or a protective group for hydroxyl group;

R5and R6are either the same or different, and each represents a hydrogen atom, a lower alkyl group, a group represented by the formula

_ where r is an integer from 1 to 4

or acyl group.

Derivative of benzothiazole or pharmaceutically acceptable salt it includes the following derivatives of benzothiazole and their pharmacologically acceptable salt:

6-hydroxy-5,7-dimethyl-2(3-pyridylmethyl)-aminobenzothiazole;

6-hydroxy-4,5,7-trimethyl-2-(3-pyridine - Tyl)-aminobenzothiazole;

6-hydroxy-4,7-dimethyl-2-(3-pyridylmethyl)- aminobenzothiazole;

2 ethylamino-6-hydroxy-4,7-dimethyl-5-(3 - pyridylmethyl)-benzothiazole;

6-hydroxy-5,7-dimethyl-2-methylamino-4(3-pyridylmethyl)-benzothiazole;

2 ethylamino-6-hydroxy-4,5-dimethyl-7-(3 - pyridylmethyl)-benzothiazole.

In addition, the invention provides an inhibitor of 5-lipo, the food is described which includes benzothiazole derivative or a pharmacologically acceptable salt as active ingredient.

In addition, the invention provides prophylactic and therapeutic agent for the treatment of diseases for which effective is the function of inhibiting 5-lipoxygenase, an effective function is the inhibition of thromboxane synthetase, effective function is the inhibition of leukotriene synthesis or effective function is the inhibition of the synthesis of thromboxanes, and inflammatory intestinal diseases, which (means) includes the described benzothiazole derivative or its pharmacologically acceptable salt as an active ingredient.

The invention provides a pharmacological composition which comprises a therapeutically effective amount described benzothiazole derivative or a pharmacologically acceptable salt it and pharmacologically acceptable excipient.

In addition, the invention provides the use described benzothiazole derivative or a pharmacologically acceptable salt it to create medicines for the treatment of diseases in which the surface is new or increased synthesis of thromboxanes, and to create medicines for the treatment of inflammatory intestinal diseases.

In addition, the invention provides a method of treating diseases, which includes the use of pharmaceutically effective amounts described benzothiazole derivative or a pharmacologically acceptable salt his patient suffering from a disease in which increased activity of 5-lipoxygenase, increases the activity of thromboxane synthetase, increased leukotriene synthesis or increased synthesis of thromboxanes, or a patient suffering from inflammatory intestinal diseases.

In the presented description of the compounds of formula I, the term "lower alkyl group" represented in the definition of R1, R3, R4, R5, R6, R7means of linear-chain or branched alkyl group having from 1 to 6 carbon atoms, for example methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, second-boutelou, tert-boutelou, n-pentelow (amylou), isopentanol (isoamylene), neopentyl, tert-pentelow, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropylene, n-hexoloy, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyloxy group. Among these groups, preferred examples include methyl, ethyl, n-sawn and ISO-propyl group and a methyl group is particularly preferred.

The term "lower alkoxy group", this when determining R1and R3assume a linear-chain or branched alkoxy group having from 1 to 6 carbon atoms, for example methoxy-, ethoxy-, n-propoxy, isopropoxy, h-butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, n-pentyloxy, isopentylamine, neopentylene-, tert-pentyloxy-, 1 methylbutoxy-, 2-methylbutoxy-, 1,2-DIMETHYLPROPANE and hexyloxy group. Among these groups, preferred examples include methoxy and ethoxy group, and methoxy group is particularly preferred.

The term "acyl group", this when determining R5and R6may be any of aliphatic, aromatic and heterocyclic acyl groups without restriction. Among these acyl groups are preferred examples include lower alcoholnye groups, such as formyl, acetyl, propylaniline, Butyrina, Valerie is th group and heteroaryl group, such as frolina, nicotinoyl and isonicotinoyl group.

Deputy -(CH2)p- in the group of the formula _ when determining R1and R3preferably located in position 3 or 4, and p is preferably 1 or 2. Especially preferred when the Deputy is located at position 3, and p is 1.

Deputy -(CH2)q- in the group of the formula _ when determining R4preferably located in position 3, or -4, and q is preferably 1 or 2. Especially preferred when the Deputy is located at position 3, and q is 1.

Deputy -(CH2)rin the group of the formula _ when determining R5and R6located preferably in position 3 or 4, and r is preferably 1 or 2. Especially preferred when the Deputy is in position 3, and r is 1.

Examples of protective groups for hydroxyl group, represented by the definition of R2include lower alkyl groups such as methyl and ethyl groups, and acyl groups such as acetyl, propylaniline, butirosin, pivellina which may be decomposed and thus exempt from hydroxyl group in one way or another in vivo (in vivo).

Examples of pharmacologically acceptable salts used in the invention include the salts of inorganic acids such as hydrochloride, bromohydrin, sulfate and phosphate, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, bansilalpet and toluensulfonate, and salts of amino acids such as arginate, aspartate and glutamate.

In addition, some compounds form salts with metals such as sodium, potassium, calcium and magnesium. These metal salts are also included in pharmacologically acceptable salt, which is used in the invention.

Examples of the most desirable compounds are compounds represented by the General formula and pharmaceutically acceptable salts of them

R6(A), where R1, R2, R3, R5, R6and q are as defined above values;

R1and R3can be either the same or different and each preferably represents a hydrogen atom, a lower alkyl group or lower alkoxy group, more preferably methyl group, ethyl group, methoxy group or ethoxypropan;

R2preferably a hydrogen atom, a methyl group or acetyl group, and a hydrogen atom is n the tion is located in position 4 - or 3-pyridine cycle, and q is preferably an integer of 1 or 2. Namely, the group represented by formulas

are preferred. Among these groups, a group represented by the formula_CH is the most desirable.

R5and R6can be either the same or different and each preferably represents a hydrogen atom or a lower alkyl group. A hydrogen atom, methyl group, ethyl group and through the group are preferable. It is preferable that any one of them was a hydrogen atom.

Examples the following most desirable compounds are compounds represented by the following General formula(I) and pharmacologically acceptable salts of them

NCH) (B), where R1, R2, R3, R4, R5and r have the aforesaid meanings;

R1and R3can be either the same or different and preferably each represents a hydrogen atom, a lower alkyl group or lower alkoxy group, still preferably a hydrogen atom, methyl group, ethyl group, methoxy group or ethoxy-group;

R2preferably a hydrogen atom, a methyl group or acetyl group, and the atom waters of the methyl group and ethyl group are the most desirable for him;

R5preferably a hydrogen atom or a lower alkyl group and a hydrogen atom is most desirable for him.

In the group represented by the formula

_ linear-chain residue preferably is located in position 4 - or 3-pyridine cycle, and preferably r is an integer 1 or 2,

namely, the group represented by formulas

_ ,,andare preferred. Among these groups, a group represented by the formula

CH is the most desirable.

Examples of third most desirable compounds are compounds represented by the General formula (C), and pharmacologically acceptable salts of them:

NR5R6(C) where R1, R2, R4, R5, R6and p are as defined above values;

R1preferably a hydrogen atom, a lower alkyl group or lower alkoxy group, and preferably methyl group, ethyl group, methoxy group or ethoxy-group;

R2preferably a hydrogen atom, a methyl group or acetyl group, and a hydrogen atom is most desirable.

In the group represented by the formula

_ linear-chain remain the number 1 or 2.

Namely, the group represented by formulas

CH CH and are preferred. Among these groups, a group represented by the formula

CH is the most desirable;

R4preferably a lower alkyl group, and methyl group and ethyl group are the most desirable for him;

R5or R6can be either the same or different and each preferably represents a hydrogen atom or a lower alkyl group. A hydrogen atom, methyl group, ethyl group and through the group are preferable. It is preferable that any one of them was a hydrogen atom.

The method of obtaining

The proposed compound can be obtained in various ways.

The way I get

When R5and R6in the General formula I are hydrogen atoms, the proposed connection can be obtained, for example, in the following way.

The reaction scheme

< / BR>
The compound of formula II is subjected to cyclization conventional method, to thereby obtain a compound represented by the General formula III, which is one of the target compounds.

In this reaction, the compound II with minortiy, for example, with the known method (see Beilstein, 27 (2), 334). A mixture of acetic acid and water at a ratio of(1:1)-(95:5) can be considered as examples of the solvent for the reaction. The reaction temperature ranges from 0aboutWith up to room temperature.

The method of obtaining 2

When the target compound of General formula I is represented by the following formula

N (IV) of the target compound can be obtained by the method of cyclization, as it is represented by the following scheme:

where R1, R3, R4, R5, R6have the above specified values.

In the reaction of 1,4-benzoquinone (V) is condensed with a derivative of thiourea (VI) in the presence of concentrated hydrochloric acid in accordance with the known method (see I.Org. Chem. 35, 4103, 1970), to thereby obtain the compound of formula (IV).

Methanol or ethanol are suitable for use as a solvent in this reaction. The reaction temperature ranges from 0aboutC to the boiling point with reverse drains phlegmy the selected solvent.

The method of obtaining 3 ( via iminobiotin)

The reaction scheme:

) where R1, R2, R3, R4, R5, R6have the above specified values.aboutC to the boiling point of the solvent with reverse drains phlegmy.

Iminobiotin (VIII) interacts with the amine (IX) in the presence of a base and thus obtained compound (X). There can be used any basis and can be used any solvent, if he does not participate in the reaction. On the other hand, the reaction can be carried out without using any solvent. The reaction temperature ranges from room temperature to 180aboutC.

The method of obtaining 4

When the target compound of General formula I is a compound represented by the following formula XI:

NH (XI) target connection are as defined above values;

X halogen atom.

In this reaction, the compound III with an amino group is subjected to reaction with acid halide (halogenerator acid) (XII), preferably in the presence of a base, to thereby obtain an amide compound XIII. Then the obtained amide compound XIII is restored to thereby obtain the target compound XI.

As galodamadruga acid can be used the acid chloride acid or bromohydrin acid. Examples of bases suitable for use in this invention include carbonates or bicarbonates of alkali metals such as sodium bicarbonate, potassium carbonate and sodium carbonate, hydroxide of alkali metals such as sodium hydroxide and potassium hydroxide, organic bases such as triethylamine, pyridine and diethylaniline, and sodium hydride. As an example, the reductant may be called DIBORANE. Here may be appropriately selected any solvent, if he does not participate in the reaction. The reaction temperature usually ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy.

The method of obtaining 5

When the target compound of General formula the following way via Schiff base.

The reaction scheme

where R1, R2, R3and R4have the above specified values.

Compound III with an amino group is subjected to reaction with aldehyde XIV, removing the formed thus water, thereby obtaining the Schiff base (XV). In this stage can be used any solvent, if he does not participate in the reaction. Preferred examples of the solvent include benzene and toluene. The temperature varies in the range of room temperature to the boiling point of the solvent with reverse drains phlegmy. Adding small amounts of ammonium acetate is useful to accelerate the reaction.

Then thus obtained Schiff base (XV) is restored to the amine (XI); examples of the reductant include sociallyengaged, borohydride sodium and cyanoborohydride sodium. On the other hand, can be made catalytic reduction using palladium on charcoal, platinum oxide or Raney Nickel as catalyst. In this reaction may be used any solvent, if he does not participate in the reaction. The reaction temperature ranges from 0aboutC to the boiling temperature of the selected solvent with about when using sociallyengaged, methanol, ethanol and a mixture of water and alcohol, when used with borohydride sodium or cyanoborohydride sodium and ethyl acetate, methanol and ethanol, when catalytic reduction is carried out.

The method of obtaining 6

When the target compound of General formula I is a compound represented by the following formula XVI:

N (XVI) of the target compound can be obtained in the following way:

The reaction scheme

< / BR>
where R1, R3, R5, R6and R7have the above specified values;

IU methyl group.

First of 2,5-dimethoxybenzaldehyde (XVII) and bromopyridin subjected to the Grignard reaction in the presence of magnesium, thereby obtaining the secondary alcohol (XVIII). There may be used any solvent, if he does not participate in the reaction. As preferred examples of the solvent may be called tetrahydrofuran. The reaction temperature ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy. Then the above alcohol (XVIII) is subjected to reaction with the anhydride of the acid (XIX), thereby obtaining acylated dimethyl ether (XX). There may be used any solvent, if he does not accept Uch the action ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy. Then acylated dimethyl ether (XX) is oxidized to quinone (XXI). As examples of the solvent for the reaction may be named acetonitrile/water. As an example, the oxidant may be called ammonium nitrate and cerium (mixed nitric acid salt of ammonium and cerium). The reaction temperature ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy.

The resulting quinone (XXI) is subjected to reaction with thiourea (XXII) in the presence of concentrated hydrochloric acid and the thus obtained target compound (XVI). Preferred examples of the solvent used in this case include methanol and ethanol.

With the aim of obtaining alcohol (XVlII) of 2,5-dimethoxybenzaldehyde (XVII), aldehyde (XVII) is subjected to reaction with bromopyridine in the presence of n-utillity. In this reaction may be used any solvent, if he does not participate in the reaction such as tetrahydrofuran is suitable for use herewith. The reaction temperature ranges preferably from -60 to -10aboutC.

On the other hand, alcohol (XVIII) can be obtained after>/P>In the presence of n-utility peridically (XIV) is subjected to reaction with dimethyl ether (XXIII), thereby obtaining the alcohol (XVIII). As solvent for the reaction may be selected, for example, tetramethylethylenediamine/dry ether. The reaction temperature ranges from -65aboutWith up to room temperature.

The way to obtain 7 (diallylamine).

When the target compound of General formula I is a compound represented by the following formula XXIV:

N (XXIV) of the target compound can be obtained in the following way:

The reaction scheme

where R1, R2, R3, R5, R6, R7have the above specified values.

Acyl compound (XVI) decelerate, to thereby obtain diallylamine compound (XXIV). Examples dealerused tools include zinc/acetic acid and palladium/charcoal. This can be used any solvent, if he does not participate in the reaction. The reaction temperature ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy.

The method of obtaining 8 (demethylation)

When R2in the General formula I is a hydrogen atom, a target compound m is SUP> and R6have the above specified values.

Methyl compound (XXV) demetiliruetsa, to obtain thereby demetilirovanie compound (IV). Examples demetrious tools include trichromacy Bohr, trimethylsilane iodide and hydrogen bromide/acetic acid. This can be used any solvent, if he does not participate in the reaction. Examples of the solvent include, in particular, methylene chloride and chloroform. The reaction temperature ranges from 0aboutC to the boiling point of the solvent with reverse drains phlegmy.

P R I m e R 1 (experimental).

Suppression of the production of leukotriene4(FULLY4), thromboxane2(DV2) and prostaglandin E2(PRE2) from the cells of the peritoneal (abdominal) exudate of rats.

In each of the rats male Fischer Massey-200 g intraperitoneally injected with 10 ml of 6% (weight/volume) solution of glycogen (Type II from oyster Sigma) in saline. After 20-24 h, harvested cells of peritoneal exudate of rats, washed and suspended in buffered saline solution, Hank (NW) with a concentration of 5 x 106/ml. Then 100 μl of the cell derived cell corazza drugs diluted to a certain concentration. The Petri dish is incubated at 37aboutC for 5 min and add A (CALBIOCHEMRin order to obtain a final concentration of 2 μg/ml After incubation at 37aboutC for an additional 10 min in a Petri dish transferred on ice and add a solution of BW 755C, in order to obtain a final concentration of 100 μm. The contents of the Petri dishes centrifuged with a speed of 15,000 rpm for 10 min and the supernatant collected. Then fully4, DV2and PRE2contained in the supernatant liquid is determined using immunofermentative analysis using the set for immunofermentative analysis produced by the firm CAYMAN (CAYMAN).

Table. 1 shows the functions (actions) (designed in the form of the IC50each connection represented by the connection number given in the following examples for the suppression of the production of fully4, DV2and PRE2.

P R I m m e R 2 (experimental).

The function of suppressing the production and allocation is fully4and DV2of the colon (large intestine) rats with colitis, induced by tnbs (trinitrobenzenesulfonic acid)

Tnbs-colitis in rats is in F344 at the age of 9 weeks on hunger strike for 2 days, and then subjected to ether anesthesia. Probe (1.2 x 80 mm, manufactured by Fuchigami Kiki-ten), is introduced into the rectum of the animal to be injected with 0.25 ml of tnbs (production company Tokyo Casey K. K.) in 50% ethanol with a concentration of 120 mg/ml, the Effects of each compound on the production and allocation is fully4and DV2from the colon of rats with tnbs-colitis assessed through the use of rats after 7 days after tnbs injection, namely each connection (5% suspension in methylcellulose) orally administered to the rat at a dose of 0.5 ml/100 g body weight. After 6 h, the animal is exposed to deep ether anesthesia and autopsy. Thus is subjected to the removing (completely remove) the tissue of the colon. The colon incubated in a solution of Tyrode (CALBIOCHEM containing 5 μg/ml A-calcium ionophore) at 37aboutC for 20 min according to the method of Kalinga and others (Dreyling et al, Biochem. Biophys. Acta, 878, 184-193 (1986). Then by radioimmunoassay (RIA) fully define4, DV2and PRE2produced and gathering thus in the environment. Following this, the suppression ratio is calculated based on the difference in the quantities produced and allocated fully4, DV2and PRE2

Table.2. shows the results of typical connections.

P R I m e R 3 (experimental).

Therapeutic effects on tnbs-colitis.

Tnbs-colitis in rats induce by the method of Morris and others, namely, each of the rats male F344 at the age of 9 weeks is subjected to starvation for 2 days, and then give the ether anaesthesia. Probe (1.2 x 80 mm, manufactured by Fuchigami Kiki-ten) is injected into the rectum of the animal to be injected with 0.25 ml of tnbs (production company Tokyo Casey K. K.) in 50% ethanol at a concentration of 120 mg/ml in the cavity of the colon. Later, 3 days after tnbs injection, each connection (5% suspension in methylcellulose) orally administered once a day for 11 days. After 14 days from the time of tnbs injection, the animal is subjected to autopsy and the colon is removed completely (subject of removing). The degree of damage to the colon assessed by determination of MPO (myeloperoxidase) contained in it.

therapeutic index is calculated by the following equation:

therapeutic index (5% methylcellulose group ethanol group) (group with the compound of the invention, the ethanol group).

Table.3 shows the results of the test.

the t production is fully4and DV2and promotiom producing PRE2.

Therefore, compounds of the invention are effective as a drug that can inhibit the production of leukotrienes and thromboxanes. The compound of the present invention is suitable for the prevention and treatment of disease caused by leukotrienes, for example, skin diseases such as psoriasis and eczema, allergic rhinitis, asthma, cardiovascular diseases, hepatitis, nephritis, ulcerative colitis, temporal colitis, nonspecific colitis and Crohn's disease (granulomatosus disease).

In addition, various experiments have confirmed that the proposed compound inhibits the production of leukotrienes, based on its potent activity of inhibiting 5-lipoxygenase, and suppresses the production of thromboxanes, based on its activity inhibition of thromboxane synthetase.

P R I m e R 4 (experimental).

Test toxicity

6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)-benzothiazole obtained in example 10, is injected rats a dose of 200 mg/kg once daily for 28 days again. However, it does not detect an anomaly, in whom I am quite safe and therefore very useful from this point of view.

When the proposed connection of the present invention should be administered as a prophylactic or therapeutic agent for these diseases, it can be incorporated into tablets, granules, capsules, syrups or inhalations. The dose varies widely depending on the conditions, age and illness of the patient. In total, approximately 0.1-1000 mg/day, preferably 1-500 mg/day, more preferably 10-500 mg/day, connections can be made for adults from one to several times per day.

The proposed connection can be included in the formulations along with the media, usually used in the field of conventional ways. When must be received solid preparation for oral administration, for example, the active component is mixed with fillers, optionally together with a binder agents, disintegrators, lubricating agents, dyes or korrigentami (modifiers drugs), and then included in the composition, for example, tablets, coated tablets, granules, Farrukh Dustov or capsules in the usual way.

Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide llulose, gum Arabic, tragakant, gelatine, shellac, oxypropylation, oksipropilmetiltselljuloza, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polietilenglikol, silicon dioxide and zatverdevaya vegetable oil. As dyes can be used pharmaceutically permitted dyes. As corrigentov can be used powdered cocoa, menthol, aromatic powder, peppermint oil, borneol and powdered bark cinnamon (cinnamon). Needless to say, these tablets and granules may be coated with sugar or gelatinous, if necessary.

When should be prepared injection solution, active component neobyazatelno mixed with pH regulators, buffers, stabilizers or solubilizers substances (increasing the solubility of substances) and the resulting mixture is included in the subcutaneous, intramuscular or intravenous injection solutions in the usual way.

Conventions used in chemical and structural formulas, respectively, have the following meanings:

Me: methyl group,

Et: ethyl group,

Ac: acetyl group, and
< / BR>
Chetyrehosnuju flask containing 30 ml of dry tetrahydrofuran and 0.31 g of magnesium, heated to 60aboutWith in a stream of nitrogen. Then heating stopped and the flask is added a small amount of iodine, and then 0.18 g of dibromoethane. To the resulting suspension is added dropwise a solution of 0.50 g of bromopyridine and 1.78 g of dibromoethane in 5 ml of tetrahydrofuran, while maintaining a low boil the reaction mixture under reflux. After heating in boiling water with reverse drains phlegmy for 30 min, the reaction mixture was added dropwise a solution of 0.61 g of 2,4-dimethyl-3,6-dimethoxybenzaldehyde in 3 ml of tetrahydrofuran.

After that the reaction mixture is cooled with ice, add 30 ml of a saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer is washed with water and brine and dried over magnesium sulfate. After removal of the solvent get to 0.72 g of the crude reaction product specified connection.

1H-NMR (400 MHz, Dl3) (M. D.):

22,28 (singlet, 3H), 2,31 (singlet, 3H), of 3.65 (singlet, 3H), 3,68 (singlet, 3H), 4,30 (doublet, 1H, J 10.0 Hz), 6,05 (doublet, 1H, J 10.0 Hz), 6,61 (singlet, 1H), 7,21 (two doublet, 1H, J 4.5 and 7.5 Hz), to 7.61 (broadened doublet, 1H, J 7.5 Hz), 8,43 (two take the l)2,5-dimethoxy-4,6-dimethylbenzylamine alcohol

< / BR>
Chetyrehosnuju flask containing 100 mg of dry ether, cooled to -50aboutWith in a stream of nitrogen.

Then it was added 48 ml of a 1.6 M solution of n-utility in hexane. After cooling to -60aboutTo add to the mixture in portions of 7.4 ml 3-bromopyridine. The mixture is then stirred at -60aboutM for 30 minutes and to the mixture in portions add a solution of 9.9 g of 2,4-dimethyl-3,6-dimethoxybenzaldehyde in 100 ml of dry ether and 40 ml of dry tetrahydrofuran. After complete addition, remove the cooling bath. When the temperature of the reaction mixture reaches -10aboutWith water is added and the mixture extracted with ethyl acetate. After washing with salt solution and drying the solvent is distilled off. Then the residue purified by column chromatography through silica gel (ethyl acetate hexane(1: 5)-(5:1). Thus obtain 14.0 g of the specified connection.

P R I m e R 3 (obtaining the target product)

-(3-Pyridyl)2,5-dimethoxy-4,6-dimethylbenzylamine alcohol

< / BR>
B 30 ml of dry ether is dissolved 3,0 1,3-dimethyl-2,5-dimethoxybenzene and 3.1 g of tetramethylethylenediamine and to the solution is added dropwise 17 m l 1.6 M solution of n-utility in hexane in a nitrogen atmosphere at room temperature. After 1 h the mixture is cooled to -65 the reaction mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After distillation of the solvent to obtain 6.4 g of crude reaction product specified connection.

P R I m e R 4 (obtaining the target product)

-(3-Pyridyl)-2,5-dimethoxy-4,6-dimethylbenzyl-acetate

< / BR>
A mixture containing 3.2 g -(3-pyridyl)-2,5-dimethoxy-4,6-dimethylaniline alcohol obtained by the method described in the previous examples to obtain. 5 ml of pyridine and 5 ml of acetic anhydride is heated and stirred at 80aboutC for 1 h and Then distilled pyridine and acetic anhydride, and the residue purified by column chromatography through silica gel. Thus obtain 2.9 g of the specified connection.

1H-NMR (400 MHz, DCl3) (M. D.):

2,17 (singlet, 6N), 3,23 (singlet, 3H), 3,61 (singlet, 3H), of 3.75 (singlet, 3H), 6,61 (singlet, 1H), 7,22 (two doublet, 1H, J 4.5 and 7 5 Hz), 7,50 (doublet and triplet, 1H, J 1.5 and 7.5 Hz), to 7.59 (singlet, 1H), 8,45 (broadened singlet, 2H).

P R I m e R 5 (obtaining the target product)

[2-(3,5-Dimethyl-1,4-benzopinacol)]-(3-pyridyl)-methyl acetate

< / BR>
In a solvent mixture containing 35 ml of acetonitrile and 17 ml of water, dissolve 3.5 g -(3-pyridyl)-2,5-dimethoxy-4,6-dimethylphenylacetate obtained in example 4. Then to the mixture EXT is the atur for 1 h the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. To the mixture was added 100 ml of ethyl acetate and filtered through Celite. The aqueous layer was additionally extracted with ethyl acetate. The organic layers are combined, washed with saline and dried over magnesium sulfate. After distillation of the solvent to obtain 3.1 g of the specified compound as a yellow oily substance.

1H-NMR (400 MHz, DCl3) (M. D.):

2,07 (singlet, 3H), 2.13 and (singlet, 3H), 2,20 (singlet, 3H), 6,61 (singlet, 1H), 7,14 (singlet, 1H), 7,28 (two doublet, 1H, J 4.5 and 7.5 Hz), 7,66 (doublet and triplet, 1H, J 1.5 and 7.5 Hz), 8,45 (doublet, triplet, 1H, J 1.5 and 4.5 Hz), 88,59 (broadened singlet, 1H).

P R I m e R 6 (obtaining the target product).

Hydrochloride of 2-amino-6-hydroxy-4,7-dimethylbenzothiazole

NH2HCl

To 2.24 g of thiourea add 60 ml ethanol and 2.5 ml of concentrated hydrochloric acid, followed by stirring. Then to the mixture is added slowly dropwise a solution of 8.0 g of para-kelahiran in ethanol (120 ml). The reaction mixture was stirred at room temperature for 24 h, and then concentrated to approximately half volume. Fallen thus precipitated crystals are collected by filtration and washed with small amount of ethanol. So get to 6.80 g named , N), 2,34 (singlet, 3H), 3,71 (broadened singlet, 3H), 6.73 x (singlet, 1H).

P R I m e R 7 (obtaining the target product).

2-amino-6-methoxy-4,5-trimethylpent - thiazole

< / BR>
In 1000 ml of acetic acid and 50 ml of water was dissolved 100 g of 1-amino-4-methoxy-2,3,5-trimethylbenzene. Then to the solution at room temperature add 212 g of potassium thiocyanate. The reaction mixture is cooled with ice and 37.5 ml of bromine is added dropwise to the mixture, followed by stirring for 30 minutes the Reaction mixture is neutralized 1 N. aqueous solution of sodium hydroxide. So produced is insoluble substance separating by filtration and washed with water. After recrystallization from methanol/tetrahydrofuran get 123 N. the specified connection.

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,16 (singlet, 3H), 2,24 (singlet, 3H), 2,35 (singlet, 3H), 3,59 (singlet, 3H).

P R I m e R 8 (obtaining the target product)

6-methoxy-4,5,7-trimethyl-2-(3-pyridin - carboxamido)-benzothiazole

< / BR>
In 50 ml of tetrahydrofuran suspended 2.2 g of 2-amino-6-methoxy-4,5,7-trimethyl-benzothiazole obtained in the example of a 7, and 2.7 g of the hydrochloride of the acid chloride of nicotinic acid and added to the mixture at room temperature 3 ml per. Fallen thus precipitated crystals are separated by filtration, washed with water and dried. Thereby obtaining 2.7 g of the specified connection.

1H-NMR (90 MHz, Dl3) (M. D.):

2,35 (singlet, 3H), 2,50 (singlet, 3H), 2,60 (singlet, 3H), 3,76 (singlet, 3H), 7,41 (two doublet, J 7 and 5 Hz, 1H), 8,32-charged 8.52 (multiplet, 1H), total of 8.74 (doublet, J 5 Hz, 1H), to 9.32 (singlet, 1H).

P R I m e R 9 (obtaining the target product).

6-Benzyloxy-5,7-dimethoxy-2-(3-Piri - dimethyl)-aminobenzothiazole

< / BR>
A mixture of 0.38 g of 6-benzyloxy-2-bromo-5,7-dimethoxybenzoate and 0.32 g of 3-aminomethylpyridine heated and stirred at 120aboutC for 4 h After addition of water the mixture is extracted with ethyl acetate and the organic layer dried over magnesium sulfate. After removal of the solvent the crude reaction product is crystallized from ether. So get 0.36g the specified connection.

1H-NMR (400 MHz, Dl3) (M. D.):

3,86 (singlet, 3H)= 3,96 (singlet, 3H), 4,68 (singlet, 2H), 5,01 (singlet, 2H), 5,47 (broadened singlet, 1H), 6,94 (singlet, 4H), 7,26-7,40 (multiplet, 4H), 7,49 (doublet, J 7.0 Hz, 2H), 7,76 (doublet, J 7.5 Hz, 1H), 8,56 (two doublet, J 1.7 and 4.8 Hz, 1H), 8,66 (doublet, J 1.7 Hz, 1H).

P R I m e R 1. 6-Hydroxy-5,7-dimethoxy-2-(3-pyridinemethanol, received in the sample receiving 9, 10 ml ethanol and 5 ml of concentrated hydrochloric acid, heated to boiling with reverse drains phlegmy within 2 hours the mixture is Then neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After removal of the solvent the crude reaction product is crystallized from ethyl acetate. Thus obtain 0.18 g of the above compound.

1H-NMR (400 MHz, d6-DMSO) (M. D.):

of 3.77 (singlet, 3H), 3,81 (singlet, 3H), 4,56 (doublet, J 5.5 Hz, 2H), 6,86 (singlet, 1H), 7,37 (two doublet, J 4.8 and 7.5 Hz, 1H), to 7.77 (doublet, J 7.5 Hz, 1H), 8,31 (triplet, J 5.5 Hz, 1H), at 8.36 (singlet, 1H), of 8.47 (two doublet, J 1.7 and 4.8 Hz, 1H), 8,59 (doublet, J 1.7 Hz, 1H).

P R I m m e R 2. 6-Methoxy-4,5,7-trimethyl-2-(3-pyridylmethyl)-aminobenzothiazole

< / BR>
in 30 ml of tetrahydrofuran suspended 0.3 g of 6-methoxy-4,5,7-trimethyl-2-(3-pyridinecarboxamide)-benzothiazole obtained in example receipt 8. Then to the mixture is added 10 ml of a 1.0 M solution of the complex of borane/THF in tetrahydrofuran and the mixture is heated at the boiling reverse drains phlegmy within 30 minutes After adding 20 ml of 1 N. hydrochloric acid, the mixture is additionally heated and permisive and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After distillation of the solvent to obtain 0.3 g of the above compound.

1H-NMR (400 MHz, Dl3) (M. D.):

2,27 (singlet, 3H), 2,33 (singlet, 3H), 2,48 (singlet, 3H), 3,68 (singlet, 3H) and 4.65 (singlet, 2H), 5.40 to (broadened singlet, 1H), 7,29 (two doublet, J 4.8 and 7.5 Hz, 1H), to 7.77 (doublet, J7,5 Hz, 1H), 8,55 (two doublet, J 1.7 and 4.8 Hz, 1H), 8,67 (doublet, J 1.7 Hz, 1H).

P R I m e R 3 6-Methoxy-4,5,7-trimethyl-2-(3-pyridylmethyl)- aminobenzothiazole

< / BR>
From 17.1 g (0.06 mol) of 2-bromo-6-methoxy-4,5,7-trimethylbenzoyl and to 19.4 g of 3-aminomethylpyridine get 15,9 specified connection using the same method described in example receipt 9.

P R I m e R 4. 6-Hydroxy-4,5,7-trimethyl-2-(3-pyridylmethyl)-aminobenzothiazole

< / BR>
In 10 ml of methylene chloride was dissolved 0.3 g of 6-methoxy-4,5,7-trimethyl-2-(3-pyridylmethyl)-aminobenzothiazole obtained in example 2 or 3, and to the mixture is added 5 ml of a 1.0 M solution trichromate boron in methylene chloride. After stirring at room temperature for 20 min the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After removal of the solvent obtained tx2">

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,12 (singlet, 3H), 2,18 (singlet, 3H), 2,35 (single, 3H), 4,55 (doublet, J 5.7 Hz, 2H), was 7.36 (two doublet, J 4.8 and 7.5 Hz, 1H), 7,81 (doublet, J 7.5 Hz, 1H), of 7.90 (singlet, 1H), 8,16 (triplet, J 5.7 Hz, 1H), 8,46 (two doublet, J 1.7 and 4.8 Hz, 1H), 8,62 (doublet, J 1.7 Hz, 1H).

P R I m e R 5. 6-Hydroxy-4,7-dimethyl-2-(3-pyridylmethyl)-aminobenzothiazole

< / BR>
In 500 ml of toluene suspended 10.0 g of the hydrochloride of 2-amino-6-hydroxy-4,7-dimethylbenzothiazole obtained in the example of a 6, and to the mixture of 33.4 g of ammonium acetate. Then the reaction mixture is vigorously stirred and heated at the boiling reverse drains phlegmy for about 5 hours, removing the formed water trap Dean-stark. After cooling in an ice bath dropdown thus precipitated orange crystals are separated by filtration. The crystals are washed with water and dried, to thereby obtain 12.4 g of the crude imine. In 200 ml of ethanol is suspended 10.7 g of this imine and stirred in an ice bath. To the mixture in portions add to 1.33 g of sodium borohydride. The mixture is stirred at ice temperature for 3 h, and then neutralized by adding it in portions of 10% hydrochloric acid. After extraction with ethyl acetate the organic layer was washed with SOLEV the Noah chromatography through silica gel (solvent: ethyl acetate hexane(1:3)-(4:1), in order to obtain 5.2 g of the compounds in the form of a pale yellow substance.

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,10 (singlet, 3H), 2,43 (singlet, 3H), 4,51 (doublet, 2H, J 6.0 Hz), 6,55 (singlet, 1H), 7,34 (two doublet, 1H, J 4.5 and 7.5 Hz), 7,78 (broadened doublet, 1H, J 7.5 Hz), 8,17 (triplet, 1H= J 6 Hz), 8,43 (doublet, 1H, J 4.5 Hz), to 8.57 (singlet, 1H), 8,90 (singlet, 1H).

The following compounds receive according to the method described in example 5.

P R I m e R 6. 6-Hydroxy-4-phenyl-2-(3-pyridylmethyl)-aminobenzothiazole

N

1H-NMR (400 MHz, d6-DMSO) (M. D.):

4,49 (doublet, 1H, J 7.0 Hz), 7,00 (singlet, 1H), 7,30-7,46 (multiplet, 5H), 7,54 (singlet, 1H), 7,66 (singlet, 1H), 7,76 (broadened doublet, 1H, 1H, J 7 Hz), of 8.47 (doublet, 1H, J 5 Hz), 8,54 at 8.60 (multiplet, 2H).

P R I m e R 7. 6-Hydroxy-4,5,7-trimethyl-2-(4-pyridylmethyl)-aminobenzothiazole

< / BR>
1H-NMR (400 MHz, DCl3) (M. D.):

2,24 (singlet, 3H), 2,30 (singlet, 3H), 2,47 (singlet, 3H), 4.26 deaths (singlet, 2H), was 7.36 (2H doublet, J 6.0 Hz), 8,51 (doublet, 2H, J 6.0 Hz).

P R I m e R 8. 5-Hydroxy-4-methyl-2-(3-pyridylmethyl)-aminonaphthol- [1-2-d]-thiazole

NH

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,41 (singlet, 3H), 4,58 (doublet, 1H, J 4.5 Hz), 7,38 (two doublet, 1H, J 4.5 and 7.5 Hz), 7,39-of 7.48 (multiplet, 2H), 7,87 (extended Doubilet, 1H), 8,32 (broadened singlet, 1H).

P R I m e R 9. [4-(6-hydroxy-5,7-dimethyl-2-methylamino)-benzothiazolyl]-(3-pyridyl)- methyl acetate

NHMe

To 0,48 g of 1-methyl-2-thiourea are added 20 ml of ethanol and 1.4 ml of concentrated hydrochloric acid and stirred. Then a solution of 3.0 g of [2-(3,5-dimethyl-1,4-benzopyranyl)] -(3-pyridyl)-methyl - acetate obtained in example receiving 5, in ethanol (total volume 12 ml) is added dropwise to the mixture within 30 minutes After stirring at room temperature over night dropdown thus precipitated crystals are separated by filtration, dissolved in 10 ml of water and neutralized with a saturated aqueous solution of sodium bicarbonate. After xtractive with ethyl acetate the organic layer was washed with brine and dried over magnesium sulfate. After distillation of the solvent to obtain 1.0 g of the above compound in the form of white crystals.

1H-NMR (400 MHz, Dl3) (M. D.):

2,17 (singlet, 3H), 2,20 (singlet, 1H), 2,35 (singlet, 3H), 3,05 (singlet, 3H), 7,20 (two doublet, 1H, J 4.5 and 7.5 Hz), 7,54 (broadened doublet, 1H, J 7.5 Hz), 8,05 (singlet, 1H), 8,45 (doublet, 1H, J 4.5 Hz), charged 8.52 (doublet, 1H, J 1.5 Hz).

P R I m e R 10. 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)-benzothiazole

NHMe

In 5 ml of acetic KIS is the emer 9. To the mixture is added 0.75 g of zinc, and the mixture is heated at the boiling reverse drains phlegmy within 5 hours After addition of water the mixture is extracted with ethyl acetate and the organic layer dried over magnesium sulfate. After removal of the solvent the crude reaction product is recrystallized from ethanol. Thus obtain 0.26 g of the specified connection.

So pl. 236-238aboutC.

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,10 (singlet, 3H), 2,23 (singlet, 3H), 2,90 (doublet, 3H, J 4.5 Hz), 4,27 (singlet, 2H), 7,22 (two doublet, 1H, J 4.5 and 7.5 Hz), 7,50 (broadened doublet, 1H, J 7.5 Hz). 7,63 (broadened singlet, 1H), 7,89-7,94 (multiplet, 1H), 8.30 to (broadened doublet, 1H, J 5.0 Hz), 8,46 (broadened singlet, 1H).

The following connections receive according to the method described in examples 9 and 10.

P R I m e R 11. Dichlorhydrate 2 ethylamino-6-hydroxy-5,7-dimethyl-4-(3-pyridylmethyl)-benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

1,23 (triplet, 3H, J 7.0 Hz), 2,14 (singlet, 3H), 2,28 (singlet, 3H), 3,51 (doublet and triplet, 2H, J 7.0 and 5.0 Hz), 4,60 (singlet, 2H), 7,98 (triplet, 1H, J 7.0 Hz), 8,31 (doublet, 1H, J 7.0 Hz), 8,75 (singlet, 1H), 8,78 (doublet, 1H, J 7.0 Hz).

P R I m e R 12. Dichlorhydrate 6-hydroxy-5,7-dimethyl-2-propylamino - 4-(3-pyridylmethyl)-benzothiazole
t, 3H), 2,24 (singlet, 3H), 3,40 (broadened singlet, 2H), 4,56 (singlet, 2H), 7,94 (two doublet, 1H, J 5.5 and 8.0 Hz) compared to 8.26 (doublet, 1H, J 8.0 Hz), 8,72 (singlet, 1H), total of 8.74 (doublet, 1H, J 5.5 Hz).

P R I m e p 13. 6-Hydroxy-4,7-dimethyl-2-methylamino-5-(3-pyridylmethyl)-benzothiazole

NHMe

1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,13 (singlet, 3H), 2,29 (singlet, 3H), 2,90 (doublet, 3H, J 4.8 Hz), 4,25 (singlet, 2H), 7,95 (two doublet, 1H, J 8.0 and 4.8 Hz), 8,31 (doublet, 1H, J 8.0 Hz), 8,68 (singlet, 1H), 8,75 (doublet, 1H, J4,8 Hz), 8,93 (multiplet, 2H).

P R I m e R 14. 2 Ethylamino-6-hydroxy-4,7-dimethyl-5-(3-pyridylmethyl)-benzothiazole

NHEt

1H-NMR (400 MHz, d6-DMSO) (M. D.):

1,18 (triplet, 3H, J 7,1 Hz), 2,24 (singlet, 3H), 2,34 (singlet, 3H), 3,34 (multiplet, 2H), 4,06 (singlet, 2H), 7.23 percent (two doublet, 1H, J 7.8 and 4.8 Hz), 7,44 (doublet, 1H, J 7.8 Hz 7,63 (triplet, 1H, J 5.1 Hz), 8,15 (broadened singlet, 1H), 8,33 (two doublet, 1H, J 4.8 and 1.5 Hz), to 8.41 (doublet, 1H, J 2.2 Hz).

P R I m e R 15. (Dichlorhydrate 2-amino-6-hydroxy-,5-dimethyl-7- (3-pyridylmethyl)-benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,20 (singlet, 3H), 2,39 (singlet, 3H), 4,30 (singlet, 2H), 7,95 (two doublet, 1H, J 7.8 and 4.8 Hz), 8,28 (doublet, 1H, J 7.8 Hz), 8,75 (singlet, 1H), 8,78 (doublet, 1H, J 4.8 Hz).

P R I m e R 16. Dichlorhydrate 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)-beet, 3H), 2.26 and (singlet, 3H), 3.00 and (doublet, 3H, J 0.5 Hz), 4,53 (singlet, 2H), 7,95 (triplet, 1H, J 7.0 Hz), 8,32 (doublet, 1H, J 7 Hz), 8,77 (broadened singlet, 1H), 8,75 (broadened singlet, 1H).

P R I m e R 17. 2 Ethylamino-6-hydroxy-4,5-dimethyl-7-(3-pyridylmethyl)-benzothiazole

NHEt

1H-NMR (400 MHz, d6-DMSO) (M. D.):

1,13 (triplet, 3H, J 7 Hz), 2,14 (singlet, 3H), 2,35 (singlet, 3H), 3,30 (multiplet, 2H), 3,98 (singlet, 2H), 7.23 percent (two doublet, 1H, J 7.8 and 4.8 Hz), 7,53 (three doublet, 1H, J 7,8, of 4.8 and 2.4 Hz), 8,11 (singlet, 1H), 8,33 (doublet, 1H, J 4.8 Hz), 8,40 (doublet, 1H, J 2,4 (Hz).

P R I m e R 18. Dichlorhydrate 2-amino-6-hydroxy-5,7-dimethyl - 4-(3-pyridylmethyl)-benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,08 (singlet, 3H), 2,25 (singlet, 3H), 4,50 (singlet, 2H), 7,94 (two doublet, 1H, J 7.0 and 6.0 Hz), 8,20 (doublet, 1H, J 7.0 Hz), 8,71 (singlet, 1H), 8,75 (doublet, 1H, J 6.0 Hz).

P R I m e R 19. 6-Hydroxy-5,7-dimethoxy-2-methylamino-4(3-pyridylmethyl)-benzoate - azole

NHMe

1H-NMR (400 MHz, DCl3) (M. D.):

3,07 (singlet, 3H), 3,78 (singlet, 3H), 3,97 (singlet, 3H), 4.26 deaths (singlet, 2H), 7,13 (two doublet, 1H, J 8.0 and 4.8 Hz), 8,33 (three doublet, 1H, J 8,0, of 2.4 and 1.6 Hz), of 8.37 (two doublet, 1H, J 4.8 and 1.6 Hz), 8,64 (doublet, 1H, J 2.4 Hz).

Mass spectrum: Fast bombardment of atoms (put) m/z 322 (M+N)+< / BR>
P R I m e R 20. Dichloride is.d.):

2,21 (singlet, 3H), of 3.65 (singlet, 3H), 4,40 (singlet, 2H), 7,17 (singlet, 1H), 7,30 (singlet, 1H), 7,43 (singlet, 1H), 7,94 (two doublet, 1H, J 8.0 and 5.6 Hz), 8,35 (doublet, 1H, J 8.0 Hz), 8,75 (doublet, 1H, J 5.6 Hz), 8,80 (broadened singlet, 1H).

P R I m e R 21. Dichlorhydrate 6-hydroxy-5-methoxy-7-methyl-2-methyl - amino-4-(3-pyridylmethyl)-benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

2,18 (singlet, 3H), 2,94 (singlet, 3H), 3,66 (singlet, 3H), 4,39 (singlet, 2H), 7,94 (two doublet, 1H, J 8.0 and 5.6 Hz), of 8.37 (broadened doublet, 1H, J 8.0 Hz), 8,73 (doublet, 1H, J 5.6 Hz), 8,81 (broadened singlet, 1H).

Mass spectrum: Fast bombardment of atoms (position.) m/z 316 (M+N)+< / BR>
P R I m e R 22.

Dichlorhydrate 2-amino-7-ethyl-6-hydroxy-5-methoxy-4-(3-pyridylmethyl)- benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

1,11 (triplet, 3H, J and 7.6 Hz), 2,62 (Quartet, 2H, J and 7.6 Hz), 3,64 (singlet, 3H), 4,35 (singlet, 2H), 7,92 (two doublet, 1H, J 8.0 and 5.6 Hz), 8,31 (broadened doublet, 1H, J 8.0 Hz), 8,73 (doublet, 1H, J 5.6 Hz), 8,77 (broadened singlet, 1H).

P R I m e R 23. Dichlorhydrate 7-ethyl-6-hydroxy-5-methoxy-2 - methylamino-4-(3-pyridylmethyl)-benzothiazole

< / BR>
1H-NMR (400 MHz, d6-DMSO) (M. D.):

1,09 (triplet, 3H, J and 7.6 Hz), 2,60 (Quartet, 2H, J and 7.6 Hz), 2,94 (singlet, 3H), 3,66 (singlet, 3H), of 4.38 (singlet, 2H), 7,13 (single, J 5.6 Hz), 8,82 (broadened singlet, 1H).

Mass spectrum: Fast bombardment of atoms (position.) m/x 330 (M+N)+.

1. Derivative of benzothiazole General formula

< / BR>
where R1and R3the same or different and each is hydrogen, lower alkyl, lower alkoxy, or a group of the General formula

< / BR>
where p=1-4-integer;

R4hydrogen, lower alkyl, phenyl, a group of General formula

< / BR>
where q=1-4-integer,

or a group of the General formula

< / BR>
where R7lower alkyl,

or R3and R4may form a benzene ring together with the carbon atoms to which they are linked;

R2hydrogen or lower alkyl;

R5and R6the same or different and each is hydrogen, lower alkyl or a group of the General formula

< / BR>
where r=1-4-integer,

provided that when R1and R3identical or different and denote hydrogen, lower alkyl or lower alkoxy, or R3and R4form together with the carbon atoms to which they are linked, benzene ring, or R5and R6the same or different, hydrogen, lower alkyl or 2-pyridylmethyl, R2cannot be hydrogen,

or its pharmacologically acceptable salt.

4. Derived under item 1, wherein R4lower alkyl group.

5. Derived under item 1, wherein R1a group of General formula

< / BR>
where p=1-4 is an integer.

6. Derived under item 1, wherein R3a group of General formula

< / BR>
where p=1-4 is an integer.

7. Derived under item 1, wherein R4a group of General formula

< / BR>
where q=1-4 is an integer.

8. Derived under item 1, wherein R2the hydrogen.

9. Derived under item 1, characterized in that R5and R6one hydrogen and the other is lower alkyl.

10. Derived under item 1, characterized in that R5and R6one hydrogen and the other group of General formula

< / BR>
where r=1-4 is an integer.

11. Derived under item 1, wherein R3, R4and R5each lower alkyl, R1a group of General formula

< / BR>
where p=1-4-integer,

R2and R6each hydrogen.

12. Derived under item 1, wherein R1, R4and R5each lower alkyl, R3a group of General formula

< / BR>
where p=1-4-integer;
5
each lower alkyl, R4a group of General formula

< / BR>
where q=1-4-integer;

R2and R6each hydrogen.

14. Derived under item 1, wherein R1and R4each lower alkyl, R3hydrogen or lower alkyl, R5a group of General formula

< / BR>
where r=1-4-integer;

R2and R6each hydrogen.

15. Derived under item 11, wherein R1- 3-pyridylmethylene group.

16. Derived by p. 12, wherein R3- 3-pyridylmethylene group.

17. Derived by p. 13, wherein R4- 3-pyridylmethylene group.

18. Derived by p. 14, wherein R5- 3-pyridylmethylene group.

19. Derived by p. 14, wherein R1, R3and R4each methyl, R2and R6each hydrogen, R5- 3-pyridylmethylene group.

20. Derived by p. 14, wherein R1and R4each methyl, R2, R3and R6each hydrogen, R5- 3-pyridylmethylene group.

21. Derived by p. 12, wherein R1and R4each methyl, R2and R6each hydrogen, R33-feast and R5each methyl, R2and R6each hydrogen, and R4- 3-pyridylmethylene group.

23. Derived under item 1, wherein R1and R3each methoxy group, R2, R4and R6each hydrogen, R5- 3-pyridylmethylene group.

24. Derived under item 1, wherein the benzothiazole derivative is selected from the group consisting of the following derivatives of benzothiazole:

6-hydroxy-5,7-dimethyl-2-(3-pyridylmethyl)-aminobenzothiazole;

6-hydroxy-4,5,7-trimethyl-2-(3-pyridylmethyl)-aminobenzothiazole;

6-hydroxy-4,7-dimethyl-2-(3-pyridylmethyl)-aminobenzothiazole;

2 ethylamino-6-hydroxy-4,7-dimethyl-5-(3-pyridylmethyl)-benzothiazole;

6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)-benzothiazole;

2 ethylamino-6-hydroxy-4,5-dimethyl-7-(3-pyridylmethyl)-benzothiazole.

 

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