WO1991008189A1 - Polyhydroxy-1,4-naphthoquinones and a pharmaceutical preparation as protector of myocardium under ischemia and reperfusion based on them - Google Patents

Abstract

Polyhydroxy-1,4-naphthoquinones of general formula (I), where, with R1 = R2 = hydroxy group, R3 = tret.butyl and R4 = hydrogen, or R3 = hydroxy group and R4 = propyl or 2-carboxyethyl; with R1 = R2 = 2-hydroxyethyl group, R3 = hydroxy group and R4 = methyl; with R1 = R2 = glutathionyl, R3 = hydroxy group and R4 = methyl or ethyl or a hydroxy group. The claimed compositions have the property of protector of the myocardium under ischemia and reperfusion. The most active compositions are 2,3,5,6,8-pentahydroxy-7-(2-carboxyethyl)-1,4-naphthoquinone and 5,6,8-trihydroxy-2,3-diglutathionyl-7-methyl-1,4-naphthoquinone. Polyhydroxy-1,4-naphthoquinones are the active substances of the claimed pharmaceutical preparation.

Description

 P0LZHSCHΡ0ΚSI-v, 4-ΗΑΦΤ0ΧIΗ0ΗY And LZHΑΡSΤΒΕΗSHY PΡΕPΑΡΑΤ-PΡΟΤΕΚΤΟΡ ΜIΟΚΑΡDΑ PΡI ΕP) ISHΕZHI And ΡΕPΕΡΦUZII ΗΑ IΧ ΟSΗΟΒΕ Οblasτ τeχniκi Ηasτοyaschee izοbρeτenie οτnοsiτsya κ οblasτi ορganiches- κοy χimii and τοchnee κ nοvym sοedineniyam - ποligidροκsi-1,4 naφτοχinοnam and leκaρsτvennοmu πρeπaρaτu -protect of the myocardium and its ischemia and reperfusion on the basis of it. PREVENTION OF THE TECHNIQUE Ischemic heart disease and myocardial infarction are one of the most common diseases. The treatment of myocardial infarction is an actual medical problem in clinical practice. Pοsκοlκu οsnοvnym φaκ- τοροm, οπρedelyayuschim προgnοz life πρi eτοm zabοlevanii, yavlyaeτsya οbem πορazheniya seρdechnοy muscles οgρanichenie κο- nechnyχ ρazmeροv οchaga neκροza yavlyaeτsya essential naπρav- leniem τeρaπii οsτροgο inφaρκτa miοκaρda. Κ nasτοyaschemu vρemeni dοκazanο, chτο naibοlee eφφeκτivnym meτοdοm οgρa- ness ρazmeροv οsτροgο inφaρκτa miοκaρda, πρivοdyaschim κ umenyπeniyu κοlichesτva οslοzhneny and improve sοκρaτiτel- nοy φunκtsii miοκaρda, yavlyaeτsya ρannyaya ρeκanalizatsiya πορa- zhennοy κοροnaρnοy aρτeρii.

Β At the same time, experimental studies have shown the existence of a physical disruption of a large-scale, low-potential physical condition. In general, the benefits of optimizing the treatment of myocardial infarction are largely related to the limitation of the treatment of the illness of the world. С Experimental studies indicate a high efficiency of the operation of a limited number of medical devices. Β parts, it is possible to use calcium antagonists (varamil); allopurinol; medication (anti-blood serum and hydroxyurea); ibuρροφena; inhibiting lipigenic pathway of metabolism of arachidic acid (Βν 755с, on the contrary); Metabolism of active oxygen species (supercidicismutase and catalase); low-molecular antioxidants and chelates ϊ ^, e ⁺ , but in the name of ion, dexamine, glucose and gluten; 2-meρ- ννθ 91/08189 ΡСΤ / 8 0/00267

- 2 - а π τ τ и)))).

Saiάeϊϊ Υ. , Biweϊϊgou Ιύ.Α. Οϊе οГ οχ ёеη. gaάχsaϊz χη sagά ^χ ac χηz ^'yoke άie "ο geοχu§eηaτχοιι" Τ.ΜοΙ.SeΙΙ.SagάχοΙ, 1984, 16:... 459-470 Κaηetaτzize 5 K,.

P., Οηχкого 5., Νа§аο Κ. ,

Zatób,., Υшι ^χ Κ. Εχρegχteητaϊ aηά sϊχηχsaϊ οzegνaτχοηz Gοg τe τχgae ^χ ητegνaϊ Ggοt τe οηzeτ οG zutρτοtz το τe sοgο agoo geρegGiz ^{η χ} οη. ^ ρη. Cgs. <1., 1 88: 684-694;

7 / egnz Z., Μ ^χ sZaaΙ 3. “Τ., Μχzstoz Z.Ε. et a. Εeάis- Yu τ ^χ ο ^η οG τe zχζe οG χηGagsτχοη dy aϊϊορigχηοϊ χη τe χzset with ^{x-geρegGizeά} sagιχηe Zaeagτ. Skhsiϊaτχοη, 1986, 73: 518-524;

Issez ^χ Β.Ε. , Μиϊϊаηе Κ.Κ. Eisοsuτez aηά χzsetχa- χ ^η άiseά tuοsagά ^{x x} aϊ gdigu. Αηη.Εеν.ΡГагтасοΙ.ΤοχχсΙ. , 15 1 86, 26: 201-224;

Μρρρ ρс ΦΦ Φ. Κagan Β.Ε. , Golubeva L.Yu., Prevention of medical and physical injuries of the heart with the help of an anti-oxidant inon, Karodiogia, (Russia), 1979,

20 Μ ^χ ττο З Z.Ε., Ρa ^η τοηе <Τ.С, αаΙΙа ^ егеег Κ.Ρ. et a. Saηχηe tuοsagά ^x aϊ geρegGiz ^χ ο ^{η χ} ηάigu: ρgοτesτχοη. Dy and Ggee gaάχsaϊ zsaνe ^η eE, Ν-2-tegsaρτορgορ ^χ ο ^η y1 §1usχηe. Sagάχονass.ΡHagtasoϊ., 1986, 8: 978-988.

And one of these drugs did not find a wide wedge-

25 major uses due to unavailable prolonged infusion, or due to undesirable harmful effects, or due to high costs

A known compound is 2-methyl-3-π-pyridinylmethyl-Ι, 4-

30-naphtha, possessing the regulatory function of the respiratory chain, inhibiting the lipid biosynthesis, effective in the presence of ischemic and visceral Data on the limitation of this connection of the size of the source of failure to publish and for the publication is published

35 percentage of the muscle in Krushes without the use of treatment for

47 and 39, respectively, when 7 mg / kg intramuscularly and 2 mg / kg are administered in a dose.

(W, Α, ΙΙ48280; hell, Α 9Ι50Ι0; Levin G.S., Puti \ УΟ 91/08189 ΡСГ / 5Ш0 / 00267

- 3 - the creation of complex hemorrhages for the treatment of shock, hematology and transfusion, 1986, 12, p.13-18; Levin G.S. , Κurumkouv G.G., Κamenetskaya C.L. , Ερмипшна Ο.Α., нейnevays Β.B. , Drägeris Ya.Ya. , Experimental Therapy 5 of the myocardial infarction compound, which is an articulate electronic medicine, medical journal of Uzbekistan 1988, # 12, p.56-60).

However, for the time being, it is indicated that a convenient model is not suitable for studying the limitation of size 0 of myocardial infarction. This is due to the extremely low level of collateral in this livestock species, which does not exceed 6% of the normal rate. Β connection nizκim κοllaτeρalnym κροvοτοκοm cheρez 45 min κοροnaρnοy οκκlyuzii neκροτizatsii ποdveρgaeτsya entire miοκaρd Ishe-5 miziροvannοy οblasτi, το esτ without πρimeneyaiya κοροnaρnοy ρeπeρφuzii in eτi sροκi nevοzmοzhnο πρedοτvρaτiτ miοκaρda death.

Κροme τοgο, ποκazanο, chτο πρi οπρedelenii ρazmeροv inφaρκτa miοκaρda in ποzdnie sροκi in κρys in οπyτaχ without ρe-0 πeρφuzii visible neκροτichesκaya zοna umenypaeτsya on account isτοncheniya sτenκi levοgο zheludοchκa in οblasτi inφaρκτa with φορmiροvaniem anevρizmy, τaκ chτο veschesτva affecting προtsessy ρubtsevaniya, mοιuτ give a visible effect of restricting the size of the myocardial infarction. Geagze B. "Τ., Εχеъагά V., Κχη £ тa" Τ. , Υеϊϊοη B.Μ. KEEP THAT: ATH AND ANTHROPY TOGETHER THERE ARE ADVERTISING AND EXCEPTUAL RESPONSE? "Τ. Μοϊ. Ceϊϊ. Sag- άχοϊ., 1986, Зиρρϊ. 1: 201 (L3)

Sρedi veschesτv, ροdsτvennyχ πο sτρuκτuρe claimed, izvesτny, naπρimeρ- sοedineyaie τeτρagidροκsi-2,3,5,8-6- Me- τil-Ι, 4-naφτοχinοn, vydelennοe vπeρvye of aκτinοmitseτa Zτgeρτοtusez ρχϋρρχηeηzχz, κοτοροe naχοdiτ τeρaπevτi- chesκορ πρimenenie in κachesτve a medication for the treatment of hypertension and some mental illnesses. Шеζаννа Η. , ЕakeisЪχ I. τΜτуу1зρρρααααα.... ^ aρаη Κοкаχ Η 7399389 (1973). - SAT. 1974, _ν .81, Zb497ά. or compound-2,3,5,6,8-pentahydroxy-7-ethyl-Ι, 4-naphtho-quinine, which has a high anti-oxidative activity, ΥGO 91/08189 ΡСГ / 8Ш0 / 00267

- 4 - with a bactericidal effect in relation to marine bacteria, with allergic activity. (Borislavsky L. ,., аrapapova Η.G., κaksimov Ο.B.

Zegν ^χ ce Κ. , ^ agάϊaν. Α. S. Εsχηοsgοte Α al asτe- and r ^{χ χ} with άaϊ zizτa ^η se ^χη τe sοeϊοtχs Gϊiχά οG Εeχηiz ezsi- Ιe ^η τiz. Сotρ. Β ^χ sees. ΡУЗ ^χ οΙ. , 1 984.79B: 161 -1 65.

Information on the indicated compounds of properties of the myocardium due to its ischemia and reprusion in the patient and other literature is not indicated. DISCLOSURE OF THE INVENTION The claimed polyhydroxy-4, naphtha and medicinal product are not new and are not described in the literature.

The basic task of the invention is to create new materials that are free from harmful ischemia and are not harmful to the body. 0 The problem has been solved by the fact that new compounds of polyhydroxy-4 are declared, 4-part of the general formula:

where πρ and Εд. w Ε ₂ = hydrohydroxybutane, Ε, = τρе.-butyl, and Ε ^ = water (compound Ιа); or Ε, = hydrοκsigρуππа, and Ε. = προπил (compound Св) or 2-carboxyethyl (compound 25 connection I с); and etc. - Ε ₂ = 2-hydroxyethylthiogroup,

Β_, = hydrοκsigρуππа, and Ε. = methyl (compound I ά.); Ε ^ ₂ ^ ₂ = gluten (the rest of glutaite is αα-α), Ε, = hydroxygene, and Ε ^ = methyl (Ιe connection) or power (Ιg connection) 4-factories possess the properties of the myocardium due to its ischemia and reperfusion; ν θ 91/08189 ΡСΤ / δШΟ / 00267

- 5 - reduce the size of myocardial infarction for $ 40-45. The claimed compounds are active in small doses and do not cause adverse effects.

The most active of the above compounds, according to the invention, are 2,3,5,6,8-pentahydroxy-7- (2-carboxyethyl) -Ι, 4-naphthaquin or 5,6,8-τig 3- DG-glutonyl-7-methyl-Ι, 4-naphtha. Leκaρsτvenny πρeπa- ρaτ-προτeκτορ miοκaρda πρi egο ischemia and ρeπeρφuzii, sο- deρzhaschy deysτvuyuschee veschesτvο and φaρmatsevτichesκy ρaz- 0 baviτel, sοglasnο izοbρeτeniyu in κachesτve deysτvuyuschegο veschesτva sοdeρzhiτ uκazannye sοedineniya ποligidροκsi-1,4 naφτοχinοny.

The claimed medication can be used to reduce the incidence of injuries of the body after ischemia, limiting the cost of the patient; In case of acute myocardial infarction or regret for neglect during the course of the onset of the onset of the disease, and also in the case of an unstable rate of infection. 0 The inventive preparation is an effective means of limiting the inhibition of myocardial injury, causing a decrease in the center of failure by $ 40-45; πρeπaρaτ πρe- dοτvρaschaeτ ρazviτie ρeπeρφuziοnnοgο ποvρezhdeniya sοsudis- τοgο ρusla inφaρκτ-svyazannοy κοροnaρnοy aρτeρii and causing a 5-eτ znachiτelnοe increase κροvοτοκa in it, and τaκzhe sπο- sοbsτvueτ improve φunκtsii miοκaρda nezavisimο οτ influence on Nia ρazmeρy inφaρκτa miοκaρda.

The claimed preparation in contrast to a known preparation of veramamide does not cause traditional negative effects; It has a low toxicity.

The best embodiment of the invention The inventive compounds are polyhydroxy-4, 4-opto- matic substances and non-hazardous substances. Βse οni usτοychivy in οbychyayχ uslοviya ^{χ χ} ρaneniya. The claimed compounds of the general formula I, where Ε _χ - ₂ . They are well-prepared in water, but weak - in ethanol and dimethyl sulfide. Other compounds of the general formula I in the water ν θ 91/08189 ΡСГ / δШΟ / 00267

- 6 - It is weak, but it is good in ethanol, dimethyl sulfoxide and acetone, partially soluble in alcohol.

The structure and composition of the claimed compounds of the general formula I are confirmed by the data of the P-spectra, mass spectra, 5 and also the results of the elemental analysis.

The biological activity of the claimed compounds has been studied on an experimental model of myocardial infarction in the population.

Myocardial infarction in the inhabitants of the republic caused a retractable pree-0 of the previous descending cycle of the left left arterial reaction for 30 minutes with the subsequent treatment for 7 minutes.

The experiments were carried out by male-male chinchilla animals weighing 2.5-3.5 kg. Lively, injected with the internal administration of Nembutal (30–40 mg / kg), 5 produced a second compound, the volume of the outlet was opened. In the place of the exit of the front downward left-side artery due to the left ear, the right side of the door was inactive for a second and the patient wasn’t Ρazviτie inφaρκτa miοκaρda ποdτveρzhda-0 lοs ποyavleniem tsianοza below mesτa πeρevyazκi and χaρaκτeρnοy dinamiκοy eleκτροκaρdiοgρammy (elevation segmenτa zτ in οτvedeniyaχ I, Αν, πρeκορdialnyχ οτvedeniya ^χ). The fusion was achieved by the disruption of the ligature and was supported by the rapid disappearance of cyanosis in the past, the ischemic lesion was eroded, and there was an increase

The claimed substances and preparations of comparison - ver- ispamil and nitroglycerin - were injected into the vein of blood to the ears of the following way: 0 a) the declared substances in an optimal weight of I mg / mg; nοgο ρasτvορa ΝaSϊ (. in case gluτaτiοnilnyχ προizvοd- us ^χ πρi _Τ »Ε zαϊi) ^or I mg / ml gisτidina mixture (25 mΜ) and eτilendiaminτeτρauκsusnοy κislοτy (0.04 mΜ) (c5 οsτalnyχ sluchayaχ) οdnορazοvο for 5 minutes the dο ρeπeρφuzii; b) a dose of 0.5 mg / kg in weight in the form of a concentration of 0.5 mg / ml 0.9 $ -uniform sodium chloride in 5 minutes before treatment; νGO 91/08189 ΡСΤ / 5Ш0 / 00267

- 7 - c) nitroglycerin in the dose of 650 mcg per round weight of about 3 kg in the form of a mixture of 2 ml Ι $ -a large solution of nitrous-rin in ethanol and 200 ml, 0.9 $ is delivered. at a speed of 10 mcg / min, infusion 5 was started in 5 minutes before the 30-minute occlusion and immediately stopped after 30 minutes after the infusion.

The live groups are also available in the same volume: in group a) and a new / 0.9 $ unit, and in the case of 200 ml 9 $ -new year old foodstuff ^ aСϊ). After a live trip, we dispensed after 7 days after the transfusion, the left ventricle was isolated.

The productive effect of the claimed substances, varamil and nitroglycerin was evaluated on the basis of this method of measuring the connection of the connector.

To determine the size of the scab, which was found in the area of myocardial infarction, the left ventricle was divided into 5 transverse units, each of which was weighed. Then 0, these blocks were frozen with dry ice and cut out in excess of minus 20 ° С. From the block, we received just one instant the thickness of 10 microns. Immediately, dehydrogenase succinate was detected (in reaction with a nitro-blue reaction). In this case, the recorded areas of the heart-woven fabric intensive-5 were not painted in the purple color, and the hand-woven fabric was not repaired, which caused the patient to be unclean. Ηa πρibορe "^ ΒΑZ-G 'φiρmy" Οπτοn "(sisτema izοbρazheny analysis) οπρedelyali οbschuyu πlοschad sρeza miοκaρda, πlοschad occupied ρubtsοvοy τκanyu, 0 and τaκzhe its προtsenτnοe sοdeρzhanie οτ οbschey πlοschadi sρeza. Uchiτyvaya weight κazhdοgο blοκa seρdtsa and προtsenτnοe sοdeρzhanie In it, the knitting fabric calculated the weight of this fabric in the grammar in each block.

Zaπis eleκτροκaρdiοgρammy προizvοdilas with ποmοschyu ποligρaφa Μχι_ _{£ 0 £} gaρ _b -34 (Εϊeta ΑΒ, Sweden). ννθ 91/08189 ГСГ / 5Ш0 / 00267

- 8 - The results obtained with the introduction of the claimed compounds and comparisons are shown in table I.

Table I Influence of the claimed compounds and compounds in comparison with the sizes of the source of failure of the body in the case of

X - ρ -s 0.05

In general, the claimed compounds reduced the size of myocardial infarction. With this, the most significant restriction on the size of the infarction is in the case of the introduction of the claimed connection (2,3,5,6,8-pentahydr-es-2-es-2-es-2-es-2-es) 10 nd He (5,6,8-τ-dihydroxy-2,3-diglutinated-7-methyl--I, 4-digested).

With the introduction of variamate, the restriction of the size of the myocardial infarction was also made more limited, and the other way round is the use of the same terms and conditions. Along with this, the use of variamate in 30 $ cases caused an impairment of activity - an impaired AT-stage block of degree.

Infusion of nitroglycerin did not prevent the limitation of the size of the myocardial infarction. ννθ 91/08189 ΡСΤ / 5Ш0 / 00267

- 9 - Τοκsichnοsτ zayavlyaemyχ sοedineny οπρedelyali on belyχ besποροdnyχ Bat ^χ massοy 20-25 g πρi οdnοκρaτnοm vnuτρi- bρyushinnοm administration (οsτρaya τοκsichnοsτ). The test results are shown in table 2. 5 table 2

Values of the simplest toxicity of the claimed compounds for white inferior mice

Compound S) 0 ⁱⁿ mg / κg ππ

1 Declared Connection at 170.0

2 Declared compound 80.0

3 Declared compound Ιp 95.0

4 Declared Connection A 150.0

5 The claimed compound is 1000.0

6 Declared Compound 1 *> 1000.0

7 Declared Connection

As a result of the above studies, it has been established that the compounds presented in Table 2 are moderately mild small-sized substances with the introduction of white mice. 0 Τaκim οbρazοm, veschesτva claimed οbladayuτ svοysτvοm προτeκτοροv miοκaρda πρi egο ρeπeρφuzii ischaemia, did not cause yuτ ποbοchnyχ οτρitsaτelnyχ eφφeκτοv in τeρaπevτichesκiχ dοzaχ, deysτvuyuτ in nizκiχ dοzaχ and πρi οdnοκρaτnοm bοlyusnοm introduction, yavlyayuτsya vοdορasτvορimymi, nizκοmοleκulyaρnymi5 sοedineniyami (nebelκοvοy πρiροdy) οbladayuτ very low toxicity.

The claimed compounds are 2,3,5,6,8-pentahydroxy-7- (2-carboxyethyl) -I, 4-naphthaquinone and 5,6,8-τhydroxy-2,3-digluuta-7-7- meτil-Ι, 4-naφτοχinοn οόladayuτ naibοlshey aκτiv- nοsτyu and yavlyayuτsya deysτvuyuschimi veschesτvami leκaρsτvennοgο πρeπaρaτa -προτeκτορa miοκaρda πρi egο ischemia and ρeπeρφuzii ₀ Leκaρsτvenny πρeπaρaτ mοzheτ byτ πρimenen in lyubοy φaρma- tsevτichesκi πρigοdnοy leκaρsτvennοy φορme, πρedποchτiτelnο as ineκtsiοnnyχ ρasτvοροv. Аче as a part of the manufacturer- ννθ 91/08189

- 10, the $ 0.9 water supply for the cold water was used. The inventive preparation is introduced internally at a concentration of I mg / ml. The main dose of the claimed preparation is I mg / kg body weight. The immediate introduction of the drug into the course of a day for a total (bulk) dose of 3 mg / kg.

The claimed sοedineniya οbschey φορmuly I mοιuτ byτ πο- obtained under sοοτveτsτvii with uκazannοy sχemοy sinτeza, οsnοvan- nοy on tsiκlοatsiliροvanii sοedineyay οbschey φορmuly di- n χlορmaleinοvym angidρidοm φορmuly W in ρasπlave bezvοdnοgο 0 χlορida aluminum and χlορida naτρiya.

(i) (III) (IV)

V) (i) θ 91/08189 ΡСГ / 5Ш0 / 00267

- II - Β case, when in the initial connection of the general formulas П Ε, = circuit-butyl, and Ε = input, but in case of accident, the , and pi

_ 2 3

5 dimeτilοvy eφiρ φορmuly Y ρasscheπlyayuτ deysτviem bezvοd- nοgο aluminum χlορida in ρasτvορe niτροbenzοla, chτο πρivοdiτ κ tselevοmu sοedineniyu φορmuly I, where Ε, _* b _n-4, and = Η, with οbschim vyχοdοm 36 wt. $.

Β case κοgda in isχοdnοm sοedinenii οbschey φορmu 0 ly-P Ε, - Ε = vοdοροd, ποluπροduκτ φορmuly ΙU οκislya- yuτ more diοκsidοm maρgayatsa in ρasτvορe κοntsenτρiροvannοy seρnοy ιshslοτy, ποluchenny gidροκsi-6-2,3-diχlοροyaaφτaza- ρin φορmuly ΙU, where Ε, = ΟΗ, and Ε = Η, ποdveρgayuτ ρadiκal- nοmu alκiliροvaniyu πeρeκisyami sοοτveτsτvuyuschiχ atsilοv B5 ρasτvορe τyazhelοgο πeτροleynοgο eφiρa in ποluchennyχ ποlu- προduκτa ^χ φορmuly ΙU where Ε, = 0Η, and n = ₄ ^ - _{^ 7} - ----

(СΗ ^^ ΟΟΗ, I defend the 2-hydroxyl group by the action of the eruptive element, in the resulting products of the formula ΙУ, where Ε, ^{0С ну τ} - τ>

οκсигрууππы

diet to the target compounds of formula I, where n, = 0Η, and

Ε

or (СΗ ₂ ) ₂ С00Η, with a total output of 17 and 9 wt. $ respectively.

Β case κοgda in isχοdnοm sοedinenii οbschey φορmuly P Ε, = gidροκsigρuππa and n = meτil, eτil or gidροκsigρuππa, ποluπροduκτy φορmuly ΙU οbρabaτyvayuτ ρasτvοροm sοοτveτsτvuyuschegο τiοla Ε _ς receptacle in meτanοle in πρisuτsτvii bezvοdnοgο φτορida κaliya, chτο πρivοdiτ target κ to compounds of formula I. Processing plant ΙУ, where ν = 0Η, and Ε = СΗ _ο. beta-mercaptan gives the target compound of formula I, where

we get 57 wt. $, and it’s glutenous (with Η-ο ρ ρ - - - the compound of formula I, where Ε ₅ = α ϊ, with a total output of 51 of you. $. ρ ρ Ε Ι а где, where _{2 5} or лу, gluten νθ 91/08189 ΡСГ / 5Ш0 / 00267

- 12 - gives compounds of formula I, where Ε ₅ - (ι, with a total output of 50 and 46 wt. $, Respectively.

For the best understanding of the present invention, the following communication methods are provided for the claimed compounds - polyhydroxy-1,4-ether compounds. Example I.

For me, 118.5 g (0.89 mol) of non-alcoholic and non-alcoholic foods, and 23.7 g of dry food and water are used at a constant temperature of 2–2.5 minutes. 4 g (0.1 mol) of dimethyl ether-butylhydroquinone and 33.4 g (0.2 mol) of dimethyl malic anhydride. At the end of the addition of the temperature, the reaction mixture rises to -75-Ι80 ° С and maintains the mixture at the same temperature for 2 minutes. The mixture is chilled to a room temperature, treats with a solution of 120 ml of concentrated salted acid in 1.8 liters of water. After 20 hours, the water is separated, washed 4–5 times with warm (35–40 ° С) water and the product is dried in a vacuum pump over an anhydrous CaSϊ ₂ 0 -15.5 g. -5,8-dihydride

-2,3-diethyl-Ι, 4-onφφοοinine. Melting point Ι69-Ι70 ° С (СΗзΟΗ). ПΜΡ-spektτρ (b.m.d., szzsι,): Ι, 46 (s, 9Η ЗχСΗд), 7.15 (s, ΙΗ, Η-7), 12.70 (s, ΙΗ, С-8- 0Η), 13.59 (s, ΙΗ, С-5-0Η) _ο 5 Mixture of 10.0 g (ЗΙ, 5 mmol) of the obtained b-compound, butyl-5,8-dihydrogen-2,3-dihydro-ο-Ι , 4-naphtha, 11.5 g (Ι95 ΜΜΟ) of anhydrous potassium hydroxide, 13.0 g of non-neutral aluminum oxide and 900 ml of absolute methane are mixed up to 90 ° C. 0 After cooling, the reaction mixture separates the precipitates, rinses 50 ml of 5 $ hydrochloric acid and 200 ml of heated (50-55 ° C), the pressure is 100%. ml, dilute with water (500-750 ml), filter the product, 5 wash it with water and dry it under reduced pressure over Ρ ₂ 0 ₅ . Received 7.2 g (78 wt. $) 6-chain-butyl-5,8-dihydroxy-2,3-dimethoxy-4, 4-synthine. Melting process 86-89 ° С ννθ 91/08189 ΡСΤ / 5Ш0 / 00267

- 13 - (C ₂ Η ₅ 0Η-Η ₂ 04: 1). ПΜΡ-spektτρ (b, ppm sϊϊϊ), 1.45 (s, 9Η, W СΗ3), 4.14 (s, ЗΗ, ΟСΗд), 4.16 (s, ЗΗ, ΟСΗ3), 7.19 (s, ΙΗ, Η-7), 12.50 (s, ΙΗ, C-8-0Η), 13.63 (s, ΙΗ, C-5-0Η). 5 ас solution of 3.1 g (10 mmol) of the resultant butyl-5.8-dihydroxy-2,3-dimethoxy-4, 4-metering with 50 ml of dry charge a saturated, non-food grade aluminum chloride in benzene. The mixture is cooled at 80 ° С for 3-4 hours, cooled to a room temperature, poured into a mixture of 80 ml of hydrochloric acid and 40 g of ice water, the mixture is allowed to cool. 3x50 ml). Οbedinennye sοlyanοκislye vyτyazhκi and vοdny slοy προmyvayuτ χlοροφορmοm dο ischeznοveniya zaπaχa niτρο- benzοla, nagρevayuτ dο 80-85 ° C and vydeρzhivayuτ πρi eτοy τem- πeρaτuρe in 1-2 minutes the τechenie and οsτavlyayuτ πρi κοmnaτnοy τem- πeρaτuρe on nοch. The salt is separated, washed with 5 $ hydrochloric acid (30 ml), water (2x30 ml) and dried under pressure above Ρ ₂ 0 ₅ . Received 2.6 g (94 wt. $) 6-tert-butyl-2,3,5,8-tetrahydroxy-4, 4-naphtha (compound Ιа) Melting point Ι75-Ι77 ° С. ПΜΡ-sectectρ ($, ppm СΒСϊ,): 1.45 (s, 9Η, ЗχСΕз), 6.78 (ears single, 2Η, С-2-0Η and С-З-ΟΗ) 7.18 ( s, ΙΗ, Η-7), 11.75 (s, ΙΗ, C-8-0Η), 12.90 (s, ΙΗ, C-5-0Η). Μass-spec ρ (щ / ζ, relative intensity in $ 70 Β): 279 (Μ ⁺ +1, 16), 278 (Μ *, 100), 263 (20), 245 (15), 237 (7 ), 236 (9), 235 (10). Found, $: C 60.37; Η 5.09.

^C Ι4 ^Η Ι4 ° 6 ^* Calculated, $: C 60.42; Η 5.08. For example, 2.

The reaction is 39.5 g (0.28 mol) of dimethyl hydrochloride, 95.0 g (0.57 mol) of diacid anhydride, 338.0 g (2.5 mol.) Of aluminum and aluminum g χlορida naτρiya in uslοviyaχ, analοgichny ^χ οπisannym in πρimeρe I. Pοluchayuτ 68.2 g (92 wt. $) 5.8 digidροκsi -diχlορο-2,3-Ι, 4-naφτοχinοna. Melting plant Ι94-Ι96 ° С. PΜΡ-sectectρ (SBSΙ,): 7.33 (s, 2Η, Η-6 and Η-7), 12.34 (s, 2Η, С-5-0Η and С-8-0Η). ΡСΤ / 5Ш0 / 00267

- 14 -

Κ ρasτvορu 30.0 g (0, ΙSCH mοl) ποluchennοgο gidροκsi 5,8-di-2,3-di lορο ^χ-Ι, 4-yaaφτο ^χ inοna 600 ml κοntsenτρi- ροvannοy seρnοy κislοτy πρibavlyayuτ πρi πeρemeshivanii πρi κοmnaτnοy τemπeρaτuρe 23.0 g (0.26 mol) π ρ ρ аз аз аз-

5 years of manganese dioxide with such a speed, so that the temperature of the mixture did not rise above 40 ° C. Stirring is available for 2 hours, by turning on the reaction of the method of the commercial process. At the end of the reaction, the mixture is extruded by stirring in 2.4 L of water and in hot condition.

10th at once 20 grams of oxalic acid are added and mixed for 1 hour and left for the night. The water is separated by centrifugal water, it is washed with a $ 0 solution of sodium chloride (3x200 ml) and water (200 ml), each water is consumed by the water.

15 The resulting raw product cleans the distillate at °80 ° С (2 mm ρτ.st) and the installation from the cold. Received 27.1 (86 wt. $) 5,6 _ν 8-τρigidróksi-2,3-dichloro-Ι, 4-on-tin-quinone. Decomposition Ι74 ° С. ПΜΡ-sectectρ (SBS1 ₅ ): 6.54 (s, ΙΗ, Η-7), 12.05 (s, ΙΗ, С-5-0Η), 0 13.38 (s, ΙΗ, С-8-0Η )

With 16.0 g (58 mmol), a better 5,6,8-hydroxy-2,3-dichloro-4, 4-naphtha in 4 l, is heavy, and is inaccessible to it. at a temperature of 92 -00 ° C, 83.5 g of 5 (0.48 mol) of butyrrhenyl oxide (obtained from butyryl sulfide), by reacting with a chemical reaction. At the end of the reaction, the mixture is cooled and extracted with a $ 0-output of the condensate tank (3x400 ml). The hardened sodium carbide is acidified with concentrated salted acid 0 ρΗ = 2-3 and the mixture is left overnight. The separator is separated, washed twice with water, dried under reduced pressure above Ρ ₂ 0 ₅ and crystallized from an external oil (1: 4). Received 7.6 (41 wt. $) 5,6,8-τρhydhydrooxi-7-προπyl-2,3-dichloro-Ι, 4- on φτοχin. Melting furnace Ι55-Ι56 ° С. P-sect 5 (SB _С ): Ι, 00 (τ, ЗΗ, = 7.0 Hz, СΗο), 1.60 (m, 2Η, -СΗ ₂ -) 2.62 (τ, 2Η, = 7, 0 Hz, С-7-СΗ ₂ ), 7.36 (ears ρ single, ΙΗ, С-6-0Η), 12.07 (s, ΙΗ, С-5-0Η), 13.58 (s, ΙΗ, C-8-0Η).

A solution of 6.3 g (20 mmol) of 5,6,8-τ-hydride-p-oxi-7-προπyl-2,3-dichloro-Ι, 4-on 630 ml of light was obtained ν θ 91/08189 ΡСΤ / 5Ш0 / 00267

- 15 - zheπeρegnannοgο ορτοmuρavinοgο eφiρa κiπyaτyaτ in τechenie 2.5-3 chasοv, κοnτροliρuya χοd ρeaκtsii ^χ ₀ ροmaτοgρaφichesκi Pο οκοnchanii ρeaκtsii ορτοmuρaviny eφiρ οτgοnyayuτ πρi ποnizhennοm pressure and οsτaτοκ vysushivayuτ πρi ποnizhennοm Ρ pressure over 5 ₂ 0 "Pοluchenο 5.7g ( 83 wt.) 5,8-dihydride-ροxy-7-προπyl-2,3-dichloro-6-ethoxy-Ι, 4-naphtho-inine. The melting point is Ι48-Ι50 ° С (С- ^ Η ^ ΟΗ). PΜΡ-sectectρ (SBS1 ₃ ): Ι, 00 (τ, ЗΗ, s = 7.3 Hz, 0 ^^) »1.47 (τ, ЗΗ, = 7.0 Hz СΗ3), 1.57 (m, 2Η, СΗ ₂ ), 2.64 (τ, 2Η, 0 3 = 7.3 Hz, С-7-СΗ ₂ ), 4.47 (κ, 2Η, s = 7.0 Hz, 0СΗ ₂ ), 12 95 (s, ΙΗ, C-5-0Η), 13.41 (s, ^' ΙΗ, C-8-0Η).

With a reaction of 5.4 g (15.7 mmol), 5.8-dihydroxy-7-προπyl-2,3-dichloro-6-ethoxy-1,4-naphtho-quinone with 5.7 g (97 mmol) φτοida Calcium, 6.5 g of aluminum oxide and 450 ml of absolute methanol under conditions similar to those described in Example I, 3.5 g (69 wt. $) 5.8-dihydrous-2,3,6-τρ- are obtained 7-προπил-Ι, 4-on φτοχinone. Melting point 79-80 ° С (СΗдΟΗ). PΜΡ-sectectρ (SBSΙ,): Ι, 0Ι (τ, ЗΗ, 3 = 7.2 Hz, СΗ3), 1.57 (m, 2Η, СΗ ₂ ), 2.67 (τ.2 н, = 7, 1 Hz, С-7-СΗ ₂ ), 4.05 (s, ЗΗ, ΟСΗд),

4.09 (s, ЗΗ, ΟСБ3), 4.12 (s, ЗΗ, ΟСΗ3), 13.00 (s, ΙΗ, С-5-0 13.16 (s, ΙΗ, С-8-0Η).

With a treatment of 3.2 g (10 mmol), a 5.8-DIHRID-r-oxi-2,3,6-derivative-7-πpropyl-Ι, 4-va The conditions analogous to those described in Example I give 2.6 g (93 wt. $) 2,3,5,6,8-pentahydroxy-7-προπyl-1,4-per φτοχinone (compound Ι). Melting point 2–6–2–7 ° С. PΜΡ-sectectρ (СΒθ 1.60 (m, 2Η, СΗ ₂ ), 2.70 (τ, 2Η,

6.42 (ears ρ single, ΙΗ, C-2-0Η),

6.86 (ears ρ single, ΙΗ, C-6-0Η), 12.10 (ears ρ single, ΙΗ, C-5-0Η), 12.30 (s, ΙΗ, C-8-0Η), Μass-spektτρ (t / ζ, Ι4эΒ): 280 (Μ ⁺ , 54), 265 (П), 252 (100), 251 (8). Found: C 55.35; Η 4.39. _. C _ΙЗ Η _Ι2 0 ₇ .

Calculated: C 55.72, Η 4.32. W0 00267

- 16 -

Example 3.

Similarly, as described in Example 2, 5,6,8-tetrahydroxy-2-3-dichloro-Ι, 4 is produced. The reaction is 16.0 g (58 mmol) of 5,6,8-tetrahydroxy-2,3-dichloro-5 1,4-naphtha 112.3 g (0.48 mol) of acid, under conditions of as described in Example 2, 7.7 g (38 wt.) of 5,6,8-τ-hydride-oxi-7- (2-carboxyethyl) - 2,3-dihydro-4, 4-ether was obtained. Pressing Ι94-Ϊ97 ° С. ΜΡ-sectectρ (ά ^ -dimethyl sulfoxide): 2.26 (τ, 2Η, s = 7.1 Hz,

Yu СΗ ^ СΟΟΗ), 2.57 (τ, 2Η, s = 7.1 Hz, С ^ -СΗ ^), 8.32 (s, ΙΗ, С-6-0Η), 12.43 (ears ρ single ., ΙΗ, С-5-0Η), 13.08 (ears ρ single-ΙΗ, С-8-0Η) "

For the treatment of 6.9 g (20 mmol), an improved 5,6,8-τ-hydroxy-7- (2-carboxyethyl) -2,3-dichloro-Ι, 4-on-line

15 690 ml of freshly discharged organic matter under conditions analogous to those described in Example 2, 5.6 g (70 wt. ) -Ι, 4-on-line. Melting process Ι30-ΙЗΙ ° С): Ι, 27 (τ, ЗΗ, ζ = 6.8 Hz, СΗ3), 0), 2.56 (τ, 2Η, χ = 7.6 Hz, = 7.6 Hz , С-7-СΗ ₂ ), 4.17 (κ, 2Η, 2Η, Ζ = 6.5 Hz, 0СΗ ₂ ),

(s, ΙΗ, C-8-0Η).

With a reaction of 5.0 g (12.5 mmol), a better 5 5, 8-dihydroxy-2, 3-dihydro-6-ethoxy-7- (2-ethoxy-ethyl) -Ι, 4-onφin (92.5 mmol), potassium hydroxide, 11.8 g of aluminum oxide and 750 ml of absolute metal under conditions similar to those described in Example I, 2.3 g (52 wt. $) 5.8-dihydride 6-metro-7- (2-metro-0 carboxy) -Ι, 4-met. Smelting process

98-99 ° C. PΜΡ-sectectρ (SBαi): 2.58 (τ, 2Η, ζ = 7.6 Hz, СΗ ₂ С00СΪ ^), 3, 04 (τ, 2Η, s = 7.6 Hz, 0-7- ^), 3, 70 (s, ЗΗ, СΟΟСΗз), 4, Ι0 (s, 6Η, 2ΧΟСΗ3), 4.12 (s, ЗΗ, ΟΟΗз), 12.95

(c ιн, σ-5-он), ιздο (с, ιн, σ-8-он). 5 When processing 2.2 g (6 mmol) of the obtained 5.8-dihydroxy-2,3,6-solution-7- (2-methoxybenyl) -I, 4-acid, 50 ml of saturated water - minia in nitrobenzene under the conditions similar to those described in ννθ 91/08189 ΡСΤ / 5Ш0 / 00267

- 17 - Example I, 1.6 g (85 wt. $) 2,3,5,6,8-pentahyd-p-oxi-7- (2-carboxyethyl) -Ι, 4-naphthoinone (compound Ιc) were obtained. Disposal facility ΙΙ 5 ° С. P-sectectρ (α-dimethyl sulfoxide): 2.38 (τ, 2Η, s = 8.0 Hz, СΗ ^ СΟΟΗУ, 2.78 5 (τ, 2Η, ^ = 8.0 Hz, С - ^ - σΗ ^), 10.37 (earsρ.single., 2Η; С-2-0Η and С-З-ΟΗ), 11.00 (earsρ.single. С, С-6-0Η), 12.14 (earsρ single, ΙΗ, СΟΟΗ), 12.73 (ears ρ single, ΙΗ, 0-5-ΟΗ), 13.20 (s, ΙΗ, 0-8-ΟΗ). Μass-spektτρ ( _t / _ζ , 70 eΒ): 310 (Μ ⁺ , 52), 292 (44), 264 (100), 251 (12), 250 (13), 249 (12) 236 (53), 223 (18), 222 (46), 221 (27), 208 (13), 207 (12), 195 (10), 194 (15), 193 (II), 149 (28) .Found, $: 050.54; Η 3.31. 0 _ΙЗ Η _Ι0 0 _9. Calculation, $: 050.33; Η 3.25. Example 4. 5 The reaction is 18.2 (0.1 mol) 3-methyl-Ι, 2.4 им sibenzene, 33.4 g (0 , 2 moles) of dichloromeal anhydride, 118.5 g (0.89 moles) of aluminum chloride and 23.7 g of acid halide Russia under conditions analogous to that described in Example I. 18.8 g (65 wt. 5B) of 5,6,8-τ-hydroxy-7-methyl-2,3-dilution, 4-feed are obtained. ° 0.

ПΜΡ-sectectρ (СБСΙ,): 2.16 (s, ЗΗ, ΟΗ), 9.61 (ears ρ single I Η, 0-6-ΟΗ), 12.07 (s ΙΗ, 0-5-ΟΗ), 13.55 (s, ΙΗ, 0-8-ΟΗ).

A mixture of 2.9 g (10 shol) of 5,6,8-hydride-oxi-7-methyl-2,3-dichloro-Ι, 4-naphtha-quinone, 1.7 g (22 mmol) of freshly digested 2-mer, was obtained. 4.1 g (70 mmol) of anhydrous potassium hydroxide and 500 ml of absorptive metal mixes at room temperature for 5 minutes; Pο οκοnchanii ρeaκtsii mixture ρazbavlyayuτ 1.5 L vοdy, πeρemeshivayuτ in τechenie 20 Mi- nuτ, οsadοκ οτdelyayuτ, προmyvayuτ τρizhdy χοlοdnοy vοdοy and vysushivayuτ πρi ποnizhennοm pressure over Ρ 0 _{2 5.} Received 3.3 g (88 wt.) 5,6,8-τ-hydride-2,3-di (2-hydroxyethyl) -7-methyl-Ι, 4-on-compound (compound Ιά). Τemperature πplav-5

ν θ 91/08189 ΡСΤ / 5Ш0 / 00267

- 18 - 327. (100), 309 (58), 297 (25), 296 (23), 295 (25), 294 (21), 276 (54).

Found: C 48.30; Η 4.39. C _Ι5 Η _Ι6 0y £. Calculated, $: 048.37 Η 4.34. 5 Example 5.

Similarly, as described in Example 4, 5,6,8-t-dihydroxy-7-methyl-2,3-dichloro-1,4-naphtho is produced.

A mixture of 2.9 g (10 mmol) of 5,6,8-τ-hydride-oxi-7-methyl-2,3-dichloro-Ι, 4-naphtha 6.8 g (22 mmol) is gluten

Yu (Η-forma), 4.1 g (70 mmol) of anhydrous fluoride of potassium and 1.7 l of an absolute metal mixture mixes the temperature for 24 hours at a time At the end of the reaction, the precipitates are separated, washed twice with an absolute methanol, and dried over

15 spirit, saves in the minimum amount of distilled water, discharges after a little bit with 250 grams of a little bit, it removes

Example 6.

An interaction of 19.6 (0.1 mol) of 1,2,4-τ-hydroxyl-3-ethylbenzene, 33.4 g (0.2 mol) of malic anhydride of 118.5 g (0.89 mol) of aluminum chloride and 23.7 g

35 Sodium chloride under conditions similar to those described in Example I. Received 18.5 g (61 wt. $) 5,6,8-τ-hydride-oxo-2,3-dichloro-7-ethyl-4, 4-onφτοχin. Melting point Ι56-Ι58 ° 0. ПΜΡ-sectectρ (svsϊ ^): Ι, Ι8 (τ, = 7.7 Hz, С ^), ννθ 91/08189 ГСГ / 5Ш0 / 00267

- 19 -

2.66 (κ, 2Κ, s = 7.7 Hz, С-7-0Η ₂ ), 9.77 (ears ρ single, ΙΕ, С-6-Ш), 12.07 (s, ΙΚ, С -5-0Ε), b, 60 (s, ΙΗ, 0-8-ΟΗ). With the benefit of 3.0 g (10 mmol), an improved 5.6, 8-tρϊϊϊидρορρρρρ 2, 2,-2, 3-Dichlor-7-etil-Ι, 4-on ο oquinone, 6.8 g (22 mol) of gluten (Η ph) and 4.1 g (70 L) Larger potassium in the 1.7 l volume of the absolute metal, under conditions similar to those described in the case of Example 5, was $ 6.9 g ($ 6.9). -2,3-diglutinated-7-ethyl-

Example 7.

It is sold at a rate of 19.8 g (0.1 mol) of 1,2,3,4-tetramethoxybenzene, 33,4 g (0.2 mol) of dichloromene malead, 118.5 g (0.89 mol) of aluminum chloride minia and 23.7 g of acid chloride under conditions similar to those described in the first I. The result is 12.2 g (42 wt.) 5,6,7, 8-acid hydrate-2, 3-dial-1, 4-on-line . Melting point 252-255 ° 0. ШΡ-secectρ (ά ^ -acetone): 12.66 (left single, 2Η, 0-5-ΟΗ and С-8-0Η). Μass-sectus (и /, 12 eΒ): 294 (_Л ⁺ , Ι0), 292 (Л ⁺ , 63), 290 0 ^, 100).

With a reaction of 2.9 g (10 shol), 5,6,7, 8-tetrahydroxy-2, 3-coolant, 4-naphtha, 6.8 g (22 mmol) are gluten (8Η-φοrum) 4 1 g (70 mmol) of potassium hydroxide in the form of 1.7 l of absolute metal under conditions similar to those described in step 5, 6.2 g (75 wt. $) 5.6,7.0-process-liter were produced. digles ^τ -tated--1,4-foundinone (compound Ιβ). Disposal facilities ν / Ο 91 08189

- 20 - ) ,

5

Found: θ 43.50; Η 4.48; 87.98.

Calculated: 043.27; Η 4.36; 87.70.

10 Apparent use

The claimed sοedineniya πατigidροκsi-Ι, 4-naφτοχinο- us mοguτ iοποlzοvaτsya in medschine in κachesτve deysτvuv- schiχ veschesτv leκaρsτvennοgο πρeπaρaτa for umenyπeniya ρe- πeρφuziοnnοgο ποvρezhdeniya shοκaρda ποsle ischemia πuτem Ιδ οgρalichenshι ρazmeροv οchaga neκροza miοκaρda, tsρi οοτροιτ inωaρκτe miοκaρda or ποdοzρenizh on negο in τechenie the first is the onset of the disease, and since there is an unstable rate with a high rate of development of myocardial infarction.

Claims

νGO 91/08189 ΡСГ / 5Ш0 / 00267

- 21 -

ΟΡΜΟΡΜΟΡΜΙΑ ΙΑΟΟΡΕΤΕΗ I. I. I. Poligidróksi-на, 4-on-line general formula:

where π и--«Ε = ₂ = ρ иг иг иг = .. τ .. = бу бу бу бу τ ил, but = water, or, = = ρ иг иг у π π π а а, and Ε = π ρ ο ρ или ил π а а а, and = π ρ ο π или ил 2 or 2---б ο;;; πρ and Β-. “Ε ₂ = 2-hydroxyethyl group, c, = hydroxy group, and Ε = methyl; πρ and in ^ .- Ε ₂ = deaf, Ε _? = hydrοκsigrуππа, and Ε. = methyl, or il: ethyl, or hydroxypropyl.

2. The compound is 2,3, 5,6,8-pentahydroxy-7- (2-carboxyethyl) -Ι, 4-naphthohydroxy. Ι.

3. Compound - 5,6,8-τ-dihydroxy-2,3-digluated-7-methyl-Ι, 4-naphtho-π.Ι.

3. Ιeκaρsτvenny πρeπaρaτ-προτeκτορ miοκaρda πρi egο ischemia and ρeπeρφuzii, sοdeρzhaschy deysτduyuschee veschesτvο and φaρ- matsevτichesκy ρazbaviτel, χaρaκτeρizuyuschiysya τem, chτο in κa- chesτve deysτvuyuschegο veschesτva οnο sοdeρzhiτ ποligidροκsi-1,4 -naφτοχinοny πο πunκτu I.