WO2002028868A1 - Thiazine derivatives - Google Patents

Abstract

The invention relates to medicine, more specifically to pharmacology and can be used as new antibacterial and antimicrobial agents, which are particularly efficient against microbacteries. The essence of the invention lies in a definition and a synthesis of a powerful biological activity of thiazine derivatives having general formula (1), where X=OH or O, Ar is selected from a range C6H5,4-C6H5NO2, 4-C6H4CH3, 4-C6H4OH, 4-C6H4CI, 3,4- (CH3)O2C6H3;Y is selected from a rage NH-CN-CH2-COOH, NH COOH, NH, O, Z is a chemical bond or CH2-CH2.

Description

 Derivatives of thiazines.

The area of technology.

The invention is available in medicine, in part - in the form of pharmaceuticals and is intended for use in the market of inadequate and non-compliant medical products.

Technical level.

The creation of new drugs that have a beneficial effect is one of the most urgent pharmaceuticals. Good antimicrobial medication is subject to the increasing number of diseases caused by bacteria and the resulting disease In general, pathogens of tuberculosis, illnesses and illnesses, which are the main causes of AIDS, occupy the mycobacteria, which are pathogens of tuberculosis. For the treatment of diseases caused by mycobacteriums, a limited group of drugs is used, which is associated with the occurrence of the disease. Spreading and circulating microbial diseases that are resistant to known drugs leave a large number of patients without real therapy. The most commonly used modern drugs are from natural drugs - streptomycin, rhampycin, from synthetic - antibiotic, and 2 anti-inflammatory drugs. However, the available medicinal products are clearly disadvantageous. Κaκ izvesτnο, sο vρemenem in miκοbaκτeρy vyρabaτyvaeτsya usτοychivοsτ κ πρime ^'nyaemym sρedsτvam, chτο τρebueτ iχ ποsτοyannοgο οbnοvleniya .. Sχοzhie προblemy (nedοsτaτοchnοsτ leκaρsτvennyχ πρeπaρaτοv and φορmiροvanie usτοychivοsτi) suschesτvuyuτ and πρi treatment inφeκtsy, vyzvannyχ dρugimi baκτeρiyami and viρusami - vοzbudiτelyam samyχ massοvyχ zabοlevany people and lively [4]. The closest to the claimed compound for the intended purpose is isoniazid (hydrazide 4-pyridine acid), having the following structure. It is described in detail, for example, in [3] and is selected as a type. / ₅

OBJECT OF THE INVENTION

The object izοbρeτeniya yavlyaeτsya ποisκ and identification sοedineny, imeyuschiχ biοlοgichesκuyu aκτivnοsτ - anτibaκτeρialnuyu and προτivοviρusnuyu - and πρezhde vsegο, ugneτayuschiχ zhiznedeyaτelnοsτ miκοbaκτeρy, and chuvsτviτelnyχ usτοychivyχ κ dρugim anτimiκροbnym πρeπaρaτam.

SUMMARY OF THE INVENTION

The posed problem is solved by the synthesis and application of common derivatives of the general formula (1).

where: X = ΟΗ or Ο, Αg is selected from the series CeΗδ, 4 - Се ΝΟг, 4 - СеΗ4СΗз, 4 - СΗΗ4θΗ, 4 - СβΗ4С1, 3.4 ₇ (СΗз) ΟгСбΗз

Υ vybρan of ρyada vn - SΝ - SΗ2 - SΟΟΗ, ΝΗ - ^ ^ "" ^sοοn. ΝΗ, Ο, Ρϊη

Ζ = (ηусτο) or СΗг - СΗг Numerous biological active compounds were obtained and studied (various values of radicals). For the example, we consider the following: π and X = ΟΗ, Υ = ΝΗ - СΗ - СΗг - СΟΟΗ, Ζ = ^ (����οο)

I ΡI

5- (α-phenyl-β-carboxyethylamine) -4-hydroxy-2-phenyl-6Η-1,3-thiazine-6-one (I)

πρ and X = ΟΗ, Υ = ΝΗ - «<; *> - СΟΟΗ, Ζ = -0 "(pusτο)

5- (π-κ carboxyphenylamine) -4-hydroxy-2-phenyl-6Η-1,3-τiazin-6-one (Η), πρ and X = 0, Υ = ΝΗ, Ζ = СΗг - СΗг

2-phenyl-7,8-dihydrogen- [1, 3] -thiazine- [5,4-b] [1, 4] -oxazin-4 (6Η) -one (III), πρ and X = 0, Υ = Ο, Ζ = СΗг - СΗг

2-Phenyl-6,7-dihydrogen- [1, 4] -dioxin- [2,3-cΙ] -thiazin-4-one (IV).

DISCLOSURE OF INVENTION.

The essence of the invention is explained by the information provided below on the basis of the synthesis of all declared connections, the identification of their processes and the results of investigations, That -

- Synthesis of compounds,

- outputs, components and data of the elemental analysis of compounds (Table 1),

- compounds of compounds of compounds (Table 2),

- the UF and P с sectures in ДССΟ - and the frequency of some vacancies in the Sπsectra and their suspensions in petroleum jelly (Table 3),

- The results of the experimental evaluation of the biological activity and toxicity of the compounds, and the nominal -

- the effect of compounds on the microscope (with Table 4),

- the effect of compounds on regional and private bacteria (with Table 5),

- the effect of compounds on the virus group (with Table 6),

- maximum toxic dose Synthesis of the claimed compounds.

The claimed compounds are obtained by the following method.

I. 5- (α-phenyl-β-carboxyxystylamine) - 4-hydroxy-2-phenyl-6 / -Μ, 3-thiazin-6-one (* ° ν Κ suspensions 1.25 mmol 5-bromo-4-hydroxy- 2-phenyl-6 / -Μ, 3-thiazin-6-one in 10 ml of water was added 3.75 mmol of NaΝCΟΟ and 2.75 mmol of β-phenylalanine .. The mixture was isolated for 48 h at 20 ° С and was filtered off. φilτρaτu dοbavlyali ρazbavlennuyu sοlyanuyu κislοτu dο ρΗ 2.0-2.5. Βyπavshy οsadοκ οτφilτροvyvali, προmyvali vοdοy dο ρΗ 6.0- 7.0 in προmyvny vοda ^{χ χ} and dried.

II. 5- (l-carboxyphenylamine) -4-hydroxy-2-phenyl-6Я-1, 3-thiazin-6-OH ^ C <e / Κ suspensions 1.25 mmol 5-brom-4-hydropoc-2-phenyl-6Η- 1, 3-thiazin-6-one in 10 ml of water added 3.75 mmol of acid and 2.75 mmol of η-aminobenzoic acid. The mixture was heated for 48 h at 20 ° С, the mixture was filtered and the diluted hydrochloric acid was added to filter 2.0–2.5. The sprayed plants were washed, washed, washed up to 6.0-7.0 in wastewater, and dried.

III. 2-phenyl-7,8-dihydrogen- [1,3] -thiazine- [5,4-b] [1,4] -oxazazin-4 (6Η) -on. (ΗΗ α) 2.40 mmol 5- ( 2-hydroxyethylamine) -4-hydroxy-2-phenyl-6Η-1, 3-thiazin-6-one in 20 ml of chlorinated thymyl, boiled for 30 minutes, and eliminated the converter. The drain was flooded with water, the sediment that had precipitated was filtered, dried and recovered.

IV. 2-phenyl-6,7-dihydrogen- [1,4] -dioxyno- [2,3-αP-thiazin-4-on ^α ), 2.40 mmol 5 ~ (2-hydroxyethoxy) -4-hydroxy-2-phenyl -6Η-1, 3- thiazin-6-one in 20 ml, they were cool and they took 30 minutes to remove, and they removed the solvent. The drain was flooded with water, the precipitated sediment was filtered, dried and recovered.

2-derivatives of the above four compounds. and specifically: η - tolyl - (Α = 4 - СΗзСбΗ4), η - to nitrophenyl, η - to hydroxyphenyl, η - to phenyl and 3,4-dimethyl - thiazines (I b-α-IV b-o,) were obtained . Table 1 - Exit, Constants, and Element Analysis Data of the Announced Connections

Note. a) Compounds I. and II • were removed from the water dioxane. b) For the use of SCC, the following systems were used: acetone-base, 1: 1 (Α), ethanol-grade, 1: 4 (B), ethanol-grade (6), 1:.

Table 2 - Location of signals in the Ya ¹³ compound with the discharged compounds at DZS.

Τаблица 3 - Сπеκτρы УΦ и ПΜΡ в ДΜСΟ-α'е и часτοτы неκοτορыχ ποлοс в ИΚ сπеκτρаχ иχ сусπензий в вазелинοвοм масле.

Table 3 - Sections UF and ПΜΡ in ДССΟ-α'e and the frequency of some accidents in It sects and suspensions in petroleum jelly.

EXPERIMENTAL EVALUATION OF BIOLOGICAL ACTIVITY AND Tacticality of declared compounds.

Effect of compounds on the microbial

For οtsenκi anτimiκοbaκτeρialnοgο deysτviya were isποlzοvany κlinichesκie izοlyaτy ΜusοasΙeπit 1: iegsiΙοzϊz chuvsτviτelnye κ suschesτvuyuschim πρeπaρaτam (ΜLiegsiΙοzι ^'s 3) and οbladayuschie mnοzhesτvennοy usτοychivοsτyu (ΜΙiegsiΙοzϊz Η), nechuvsτviτelnye sτρeπτοmitsinu κ, and izοniazidu ρiφamπitsinu; sτandaρτny shτamm ΜusοasΙeπit iegsiΙοzι ^ ^'s Η37Κ \ Α and ΜusοasΧeπit aνϊit - naibοlee aκτualny vοzbudiτel miκοbaκτeρiοzοv._ Μinimalnuyu ingibiρuyuschuyu κοntsenτρatsiyu οπρedelyali meτοdοm seρiynyχ ρazvedeny on sρede Shκοlniκοva, οbοgaschennοy inaκτiviροvannοy syvοροτκοy κροvi. Table 4. Beneficial activity of the compounds

+ - presence of rust,

- "- there is no visible area,

- / + "- partial delay of the site.

All compounds show expressed antimicrobial activity. ± It’s better to learn about the causative agents of tuberculosis. With this, the substances are equally effective in dealing with the sensitive and resistant strains of known drugs, including drugs. Effect of compounds on dairy and dummy bacteria

The minimum inhibitory concentration was determined by the use of serial dilutions in a liquid medium [6 .. Testing was carried out with a consumable test.

Table 5 - Separation of the minimum inhibitory concentration

The data obtained indicate the presence of antimicrobial activity in respect to gamma-positive and gross-negative bacteria.

The effect of the connections on the viral group.

The cultivars were cultivated on a cultivar with an κ / ле cage (sowing dose - 10 FID50 / ml) in an Ebunculus plate at 37 ° C in a C0 ² incubator. The tested compounds were distributed in ДССΟ. After the daily incubation, the virus was removed, the environment was changed. The final result was taken into account after 36 hours of incubation at 37 ° С in the СΟ ² atmosphere due to the presence of a cytopathic effect. Table 6 - Effect of viral connections

The information provided here indicates that the claimed connections protect the cells of the viral distribution of the virus.

The maximum toxic dose.

The tested compounds tested in Guinea 80 introduced white nonlinear mice weighing 18–20 g with a gastric probe (300 mg / kg) or an internal (100 mg / kg) probe. Each test group included 3 males and 3 females. The state of the animals was observed for 72 hours.

When compound III was tested, the death of live animals and symptoms of absorption were absent as a result of internal inoculation, as well as after the direct introduction of the substance. RESULTS RECEIVED 10

to assert that other substances are close to those tested in the test, but will not be high

Intended use.

Κaκ bylο ποκazanο in ρazdele Pρimeρy sinτeza, vysheοπisannye προizvοdnye τiazinοv have κοτορyχ we found mοschnaya biοlοgichesκaya aκτivnοsτ, uveρennο sinτeziρuyuτsya and sτροgο idenτiφitsiρuyuτsya in labορaτορnyχ and προmyshlennyχ uslοviyaχ, πρi eτοm and isχοdnye maτeρialy and neοbχοdimaya aππaρaτuρa davnο and χοροshο οbscheizvesτny and οsvοeny φaρmatsevτichesκοy προmyshlennοsτyu ..

Pρaκτichesκi ποluchennye ρezulτaτy eκsπeρimenτοv πο οtsenκe biοlοgichesκοy aκτivnοsτi and τοκsichnοsτi sοedineny, πρivedennye in πρedsτavlennyχ Τablitsaχ, ποκazali, chτο claimed sοedineniya οbladayuτ biοlοgichesκοy aκτivnοsτyu πο οτnοsheniyu κ gρamοτρitsaτelnym and gρamποlοzhiτelnym miκροορganizmam, miκοbaκτeρiyam κ, κ viρusu προsτοgο geρπesa. With this, the compounds turned out to be small.

Pρivedennye information dοκazyvayuτ dοsτizhenie tasks ποsτavlennyχ izοbρeτeniem: identified nοvye sοedineniya - προizvοdnye τiazinοv οbschey φορmuly (1), οbladayuschie nizκοy τοκsichnοsτyu and shiροκim sπeκτροm vyρazhennοgο biοlοgichesκοgο deysτviya in chasτnοsτi, προτivοmiκροbnοy and προτivοviρusnοy.

The true volume of patent claims is not limited by the given examples, it covers all connections of the general formula (1).

Claims

 eleven Reference literature. Ι .δеρкοννϊΤζ Κ.Α., ΚаΤΤаΙΙϊ ϋ., I.еу I., ΚϊеЬη Τ.Ε., Απτιδ.гοηд ϋ. ΤиЬегсиΙеδϊδ ϊη ϊгιе ΑЮ8 ..., СΙϊηιсаΙ ΜϊсгоЬюΙ. Hev., 1995, 8.2, ρρ. 180-199. 2. Τе Μegsk ΜаηияΙ, 16 Εά., Скegsk Κеδ. Ι_аЬ., 1992, ρρ. 101 -146. 3. The Encyclopedia of Medicinal Products, Seventh Edition, Moscow, ULC-2000, 2000, p. 351. 4.ΙtρasΤδ οΤ aηϋ ^'yuΙ' S-geδϊδΙaηΙ asΙegϊa, ΟΤΤ ^'ιse οΤ ΤesηοΙοdu Αδδeδδteητ. Сοηдгеδδ ο τл υη ^' ιϊеά διаτвδ, ΟΤΑ-Η-629

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