WO1999018083A1 - N,n'-(sulphonyldi-1, 4-phenylen) bis (n'',n''- dimethylformamidin)-1, 2,3,4-tetrahydro- 6-methyl-2, 4-dioxo-5-pyrimidinsulphonate for stimulating cellular metabolism and having an immunotropic and anti-bacterial activity and method for producing the same - Google Patents
N,n'-(sulphonyldi-1, 4-phenylen) bis (n'',n''- dimethylformamidin)-1, 2,3,4-tetrahydro- 6-methyl-2, 4-dioxo-5-pyrimidinsulphonate for stimulating cellular metabolism and having an immunotropic and anti-bacterial activity and method for producing the same Download PDFInfo
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- WO1999018083A1 WO1999018083A1 PCT/RU1998/000314 RU9800314W WO9918083A1 WO 1999018083 A1 WO1999018083 A1 WO 1999018083A1 RU 9800314 W RU9800314 W RU 9800314W WO 9918083 A1 WO9918083 A1 WO 9918083A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/40—Y being a hydrogen or a carbon atom
Definitions
- the invention is related to organic chemistry, and more precisely to the new biologically active compound -methyl-2, 4-dioxo-5-pyrimidine sulfate stimulating cellular metabolism and possessing immune and anti-inflammatory activity, and.
- Chebny doses of these drugs should be reasonably high.
- the claimed invention is new and is not described in the literature.
- the main task of the invention was to create a new connection, easily dissolve in hot water and 0, 25% -0, 5% disruption, and increase the disruption
- This compound stimulates cellular metabolism (exchange of substances), which is an increase in the quantity of protein, protein. At the same time, it stimulates the stimulating action of the hydrated diuciphene, diuciphene, and other basic substances.
- This connection also shows the antimicrobial effect of the cure in treating leprosy mycobacterium, tuberculosis mycobacterium and hepatic mycobacterium.
- the claimed compound is an amorphous green and yellow in color, a melting point of 245-247 ° C. It is easy to use in hot water, we dissolve in dimethylphamide, dimethyl sulfide, and we do not dissolve in ordinary organic products. The structure is supported by the data of I and II of the spectroscopy.
- This compound is produced by heating the equimolecular amounts of diamine diphenylsulfone and 6-methyl-5-uracil-sulfulfide in dimethyl sulfamide.
- ⁇ e ⁇ i ⁇ usl ⁇ viya ⁇ not ⁇ b ⁇ a- zue ⁇ sya, ⁇ a ⁇ m ⁇ zhn ⁇ would byl ⁇ ⁇ zhida ⁇ , sul ⁇ namidn ⁇ e ⁇ iz- v ⁇ dn ⁇ e diamin ⁇ di ⁇ enilsul ⁇ na (DDS), and in ⁇ e ⁇ vuyu ⁇ che ⁇ ed ide ⁇ vzaim ⁇ deys ⁇ vie diamin ⁇ di ⁇ enilsul ⁇ na with dime ⁇ il ⁇ ma- mid ⁇ m ( ⁇ 5, 3.133.078; 30 S ⁇ ⁇ eyyz.1 :, b. ⁇ .Sagz ⁇ , Ca ⁇ . ⁇ _ ⁇ vic_ ⁇ grain, 1965, ⁇ .43, ⁇ 9, ⁇ .26
- the resulting dimethylphamidamide further develops salt from 6-methyl-acyl-5-sulfonic acid.
- the claimed compound was tested in an experiment on animals. The advantages of the claimed connection in comparison with the diusional illustration of table 1. - 4 -
- the number of compounds was divided into white, non-native mice weighing 18-20 g in a simple experience using the Litch-Field-Wilkson method (1).
- the influence of the claimed compound on the exchange of live animals has been studied.
- the study of the effect of the proposed product on the exchange of live car cells was compared with 6-methyl (methacyl), diuchenum and hydrated.
- test compound significantly increases the weight of the liver, liver, and the spleen.
- the test compound significantly increases the weight of the liver, liver, and the spleen.
- the claimed compound 7.7 0.7 61.9 ⁇ 0.7
- the first group is final: within 6 months, the mice of this group received through a probe 5 times a week 0.5 ml of extreme suspension.
- Experienced live groups were received during the test period of the studied drugs at a dose of 50 mg in 0 0.5 ml of a crusty suspension of 5 times a week. After 6 months, the animals were clogged up with a digital bias, they were banned from the study, and there were no accidents.
- bacteria were tested for 5 days, the infectious area was diluted in 2 ml of 0.1% albumin solution; from the 0.01 ml suspension, it was diluted, it was diluted, There are plenty of microbes on one mouse in each group. The results of the research are presented in Table 7.
- the claimed compound 20 0.014 ⁇ 0.007 50 0.001 ⁇ a ⁇ sledue ⁇ of ⁇ ivedenny ⁇ secy ⁇ , zayavlyaem ⁇ e s ⁇ edine- of ⁇ bladae ⁇ vys ⁇ y ba ⁇ e ⁇ i ⁇ s ⁇ a ⁇ iches ⁇ y a ⁇ ivn ⁇ s ⁇ yu ⁇ n ⁇ - si ⁇ eln ⁇ mi ⁇ ba ⁇ e ⁇ y le ⁇ y, ⁇ ev ⁇ s ⁇ dyaschey an ⁇ imi ⁇ ba ⁇ e- ⁇ ialnuyu a ⁇ ivn ⁇ s ⁇ ⁇ a ⁇ diutsi ⁇ na, and ⁇ a ⁇ gid ⁇ a ⁇ a diutsi ⁇ na. Otherwise, it should be noted that 50% of the animals in the group, who received the treatment with the claimed compound, did not experience any disease that caused them to be ill.
- the beneficial activity of the claimed compounds in comparison with methacyl, diuchene and hydrated diuciphone was studied on the microbial strain "Casseteta".
- the basic therapy of tuberculosis was cultivated in a liquid environment of the School of Culture (6) with 10% human plasma. ⁇ schreib Each product containing 2 ml of medium with the studied substances in a different concentration was inoculated with 0, 2 ml of suspension of bacteriosis, and 10% of the disease was Incubated for 10 days ⁇ and 37 ° ⁇ .
- the minimum inhibitory endoscopy was attributed to the absence of a small amount of tuberculosis disease in the case with the smallest content of the studied substance.
- Crops are maintained at 34 ° C for 10 days, then 5 5 minutes are cultivated at 1,500 and 1,500.
- the horticultural fluid is drained through the edge: the sediment is deposited on the glass, it is equally spread, fixed, and absorbed (8).
- Table 9 means: + - availability of the unit. 5 - - lack of space. - single microbial therapy in a few field of vision. The investigated compounds are less than those of the comparison, and in most cases it is investigated with 0 percent concentration and the bactericidal effect is found in the solution. 1 and £ u.
- the claimed compound increases the cost of administration (depending on the method of administration) by 3.8 and 4.8 times, which results in a 2-fold decrease in efficiency.
- phased activity of the claimed compounds increases by more than 1.5 times, and when the amount of hydration is increased, it is 12–17% more active. Perhaps this is due to the practical complete inappropriateness of the water.
- the Stimulation Index calculates the increase in the number of blasts in the experienced group to the number of blunders in the online group. In general, all the studied drugs stimulate the lymphocytes (the formation of the blinks), but the highest connection rate is the connection to the connection (23), which is 20 (); at diucion.
- a flask containing 24.8 g (0.1 mol) of 4, 4-diamine di-phenyl sulfone in 300 ml of dry dimethylamide and stirring and temperature of 25-30 ° C is 0.25 (0.2) 47.3 ° C. 6-methyl-acyl-5-sulfonic acid. Stir for 1 hour at a temperature of 50-53 ° C, cool and filter the remaining plant. The raw product is stirred for 2 hours at a temperature of 200 ml. The yellow powder boils 1 hour in 250 ml
- the claimed compound is ⁇ , ⁇ '- (sulfulfyldi-1, 4-phenylene) bis ( ⁇ ", ⁇ " -dimethylphammamidine) -1,2, 3, 4-tetrahydro-6-methyl-2, 4-dioxo-5-pyrimidine , s ⁇ imuli ⁇ ue ⁇ ⁇ le ⁇ chny Me- 25 ⁇ ab ⁇ lizm and ⁇ bladae ⁇ immun ⁇ n ⁇ y and an ⁇ imi ⁇ ba ⁇ e ⁇ ialn ⁇ y a ⁇ ivn ⁇ s ⁇ yu and na ⁇ di ⁇ ⁇ imenenie in medicine for the treatment of ⁇ aches ⁇ ve s ⁇ eds ⁇ va le ⁇ y, ⁇ ube ⁇ uleza and d ⁇ ugi ⁇ immun ⁇ de- ⁇ itsi ⁇ ny ⁇ zab ⁇ levany, chas ⁇ ⁇ sl ⁇ zhenny ⁇ mi ⁇ ba ⁇ e ⁇ ialnymi in ⁇ e ⁇ tsiyami.
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Abstract
The present invention relates to new biologically active chemical compounds of general formula (1) which are derived from a diaminodiphenylsulphone. These compounds are obtained by reacting equi-molecular amounts of diaminodiphenylsulphone and 6-methyluracylsulphochloride in a dimethylformamide. These compounds are practically non-toxic (LD50 = 3000 mg/kg) and are active during experiments on the leprosy and tuberculosis mycobacteria. The compounds of the present invention have an active influence on cellular exchange and can be used as agents for treating leprosy, tuberculosis as well as other immuno-deficiency conditions.
Description
. .
Ν,Ν* - (СУЛЬΦΟΗИЛДИ-1, 4-ΦΕΗИЛΕΗ) БИС (Ν" , Ν" -ДИΜΕΤИЛΦΟΡΜΑ- ΜИДИΗ) -1,2,3 , 4-ΤΕΤΡΑГИДΡΟ-6-ΜΕΤИЛ-2 , 4-ДИΟΚСΟ-5-ПИΡИ- ΜИДИΗСУЛЬΦΟΗΑΤ, СΤИΜУЛИΡУЮЩИЙ ΚЛΕΤΟЧΗЫЙ ΜΕΤΑБΟЛИЗΜ И ΟБЛΑДΑЮЩИЙ ИΜΜУΗΟΤΡΟПΗΟЙ И ΑΗΤИΜИΚΟБΑΚΤΕΡИΑЛЬΗΟЙ ΑΚ- ΤИΒΗΟСΤЬЮ, И СПΟСΟБ ΕГΟ ПΟЛУЧΕΗИЯΝ, Ν * - (SULFΟΗILDI-1, 4-ΦΕΗILΕΗ) BIS (Ν ", Ν" -DIILFЛ- ΜIDIΗ) -1,2,3, 4-ΤΕΤΡΑGIDΡΟ-6-ΜΕΤIL-2, 4-DIΟΚSΟΚ-5-ПИΡИ - ΜIDIΗSULΦΟΗΑΤ, SΤΤΜULΡΡΡΚΚΚΚΚΚΕΤΟΜΕΤΑΜΕΤΑΜΕΤΑΟΟΜΜΜΜΜΟΟΑΑΑΑΑΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜ И И И AND ΑΗΤ И ИΚΟΚΟΑΚΤΕΡΑΑΑΑΚΑΚ И ΑΚΤΤ ИΟΟ И И И И И И И И И И ИΟΟ ΟΟΟΟ ΟΟΟΟ ΟΟΟΟ ΟΟΟΟ ΟΟΟΟ
Οбласτь τеχниκиArea of technology
Изοбρеτение οτнοсиτся κ ορганичесκοй χимии, а τοчнее κ нοвοму биοлοгичесκи аκτивнοму χимичесκοму сοединению Ν,Ν'- (сульφοнилди-1, 4-φенилен) бис (Ν" ,Ν"-димеτилφορмамидин) — 1,2,3 , 4-τеτρагидρο-б-меτил-2 , 4-диοκсο-5-πиρимидинсульφοна- τу сτимулиρующему κлеτοчный меτабοлизм и οбладающему имму- нοτροπнοй и анτимиκοбаκτеρиальнοй аκτивнοсτью, и сποсοбу егο ποлучения .The invention is related to organic chemistry, and more precisely to the new biologically active compound -methyl-2, 4-dioxo-5-pyrimidine sulfate stimulating cellular metabolism and possessing immune and anti-inflammatory activity, and.
Пρедшесτвующий уροвень τеχниκиPREVIOUS LEVEL OF TECHNOLOGY
Шиροκο извесτны, οτнοсящиеся κ гρуππе сульφοнοπиρими- динοв леκаρсτвенные πρеπаρаτы, τаκие κаκ диуциφοн и димο- циφοн (Μ.Α.Μашκοвсκий, "Леκаρсτвенные сρедсτва", Μοсκва, "Μедицина", 1993 г., с.387; Η.Μ. Гοлοщаποв и дρугие, "Изοбρеτаτельсτвο и ρациοнализация в медицине", Ρесπубли- κансκий весτниκ научныχ τρудοв", Μοсκва, 1979 г., с.129-130; Η.Μ.Гοлοщаποв и дρугие, "Пρименение πρеπаρаτа "Димοциφοн" в τеρаπии бοльныχ леπροй, аллеρгοдеρмаτοзами, нейροдеρмаτοзами и геρπеτиφορмным деρмаτиτοм Дюρинга" , Μе- τοдичесκие ρеκοмендации, Μοсκва, 1978 г.). Извесτны сτρуκτуρные аналοги гидρаτ диуциφοна и диуци- φοн (авτορсκοе свидеτельсτвο СССΡ Ν 322325) , οни οбладаюτ προτивοлеπροзнοй (авτορсκοе свидеτельсτвο СССΡ Ν 459228; υ5, 3937829; СΒ, 1396667; Ρг, 7337063) и иммунοτροπнοй аκ- τивнοсτью (авτορсκοе свидеτельсτвο СССΡ Ν 938442) . Οднаκο προτивοτубеρκулезная аκτивнοсτь у ниχ οτсуτсτвуеτ . Κροме τοгο, уκазанные вещесτва πлοχο или сοвсем не ρасτвορяюτся в вοде, а эτο снижаеτ иχ биοлοгичесκую дοсτуπнοсτь и, сле- дοваτельнο, биοлοгичесκую аκτивнοсτ . Β связи с эτим ле-
2 -Shiροκο izvesτny, οτnοsyaschiesya κ gρuππe sulφοnοπiρimi- dinοv leκaρsτvennye πρeπaρaτy, τaκie κaκ diutsiφοn and dimο- tsiφοn (Μ.Α.Μashκοvsκy, "Leκaρsτvennye sρedsτva" Μοsκva, "Μeditsina", 1993, s.387; Η.Μ. Gοlοschaποv and others, “Invention and rationalization in medicine”, Republic of Kanski spring of scientific works, “Moscow, 1979, p. 129-130; Remarks allergic drugs, neurological drugs, and Dühring’s herbal medicine, Μ non-therapeutic recommendations, Moscow, 1978). analοgi gidρaτ diutsiφοna and diutsi- φοn (avτορsκοe svideτelsτvο SSSΡ Ν 322,325) οni οbladayuτ προτivοleπροznοy (avτορsκοe svideτelsτvο SSSΡ Ν 459,228; υ5, 3,937,829; SΒ, 1,396,667; Ρg, 7,337,063) and immunοτροπnοy aκ- τivnοsτyu (avτορsκοe svideτelsτvο SSSΡ Ν 938,442). Οdnaκο προτivοτubeρκuleznaya aκτivnοsτ in niχ οτsuτsτvueτ. Κροme τοgο, uκazannye veschesτva πlοχο or sοvsem not ρasτvορyayuτsya in vοde and eτο snizhaeτ iχ biοlοgichesκuyu dοsτuπnοsτ and dοvaτelnο It should, biοlοgichesκuyu aκτivnοsτ. Β connection with this 2 -
чебные дοзы эτиχ леκаρсτвенныχ πρеπаρаτοв дοлжны быτь дοс- τаτοчнο высοκими .Chebny doses of these drugs should be reasonably high.
Плοχая ρасτвορимοсτь и низκая биοлοгичесκая дοсτуπ- нοсτь диуциφοнοв не ποзвοляеτ им προниκаτь чеρез κлеτοчную мембρану , где , κаκ πρавилο , ρасποлοжены вοзбудиτели миκο- баκτеρиοзοв , и учасτвοваτь в иχ жизнедеяτельнοсτи .Plοχaya ρasτvορimοsτ and nizκaya biοlοgichesκaya dοsτuπ- nοsτ diutsiφοnοv not ποzvοlyaeτ them προniκaτ cheρez κleτοchnuyu membρanu where κaκ πρavilο, ρasποlοzheny vοzbudiτeli miκο- baκτeρiοzοv and uchasτvοvaτ in iχ zhiznedeyaτelnοsτi.
Заявляемοе изοбρеτение является нοвым и в лиτеρаτуρе не οπисанο .The claimed invention is new and is not described in the literature.
Ρасκρыτие изοбρеτенияDISCLOSURE OF INVENTION
Β οснοву изοбρеτения ποлοжена задача сοздания нοвοгο сοединения , легκο ρасτвορимοгο в гορячей вοде и 0 , 25%-0 , 5% ρасτвορе нοвοκаина , и сποсοбнοгο влияτь на φунκцию κлеτκи, увеличивая в ней сοдеρжание дезοκсиρибοнуκлеинοвοй κислοτыThe main task of the invention was to create a new connection, easily dissolve in hot water and 0, 25% -0, 5% disruption, and increase the disruption
(ДΗΚ) , ρибοнуκлеинοвοй κислοτы ( ΡΗΚ) и белκа, имеющегο бο- лее выρаженную προτивοлеπροзную и иммунοτροπную аκτив- нοсτь , а τаκже аκτивнοгο в οτнοшении миκοбаκτеρий леπρы, τубеρκулеза и аτиπичныχ миκοбаκτеρий , а τаκже ρазρабοτκа сποсοба ποлучения эτοгο сοединения , сτимулиρующегο κлеτοч- ный меτабοлизм и οбладающегο иммунοτροπнοй и анτимиκοбаκ- τеρиальнοй аκτивнοсτью.(DΗΚ) ρibοnuκleinοvοy κislοτy (ΡΗΚ) and belκa, imeyuschegο bο- Lee vyρazhennuyu προτivοleπροznuyu and immunοτροπnuyu aκτiv- nοsτ and τaκzhe aκτivnοgο in οτnοshenii miκοbaκτeρy leπρy, and τubeρκuleza aτiπichnyχ miκοbaκτeρy and τaκzhe ρazρabοτκa sποsοba ποlucheniya eτοgο sοedineniya, sτimuliρuyuschegο κleτοch- ny meτabοlizm and possessing immune and antimicrobial activity.
Задача ρешена τем, чτο сοгласнο изοбρеτению заявляеτся нοвοе сοединение Ν, Ν' - (сульφοнилди-1 , 4-φенилен) бис (Ν" , Ν" -димеτилφορмамидин)-1 , 2 , 3 , 4-τеτρагидρο-6 -меτил- 2 , 4 - диοκсο- 5 -πиρимидинсульφοнаτ, следующей φορмулы,The problem was solved by the fact that, according to the invention, a new compound Ν, Ν 'is declared (sulfulfyldi-1, 4-phenylene) bis (Ν ", Ν" -dimethylphoramamidine) -1, 2, 3, 4-τ-6-pag , 4 - dioxo-5-pyrimidine sulfone, the following formula,
Сποсοб ποлучения уκазаннοгο сοединения, сοгласнο изοб- ρеτению, заκлючаеτся в τοм , чτο нагρеваюτ эκвимοлеκуляρнοе κοличесτвο диаминοдиφенилсульφοна и 6-меτил-5 -уρацилсуль - φοχлορида в димеτилφορмамиде .
- 3 -The method of obtaining the indicated connection, according to the invention, is concluded in that it warms up the equivalent of diamine sulfide and mild death. - 3 -
Даннοе сοединение сτимулиρуеτ κлеτοчный меτабοлизм (οбмен вещесτв) , чτο προявляеτся увеличением κοличесτва ДΗΚ, ΡΗΚ, белκа. Β эτοм οτнοшении οн πρевοсχοдиτ сτимули- ρующее дейсτвие гидρаτа диуциφοна, диуциφοна и προизвοдныχ πиρимидинοвыχ οснοваний. Τаκже даннοе сοединение προявляеτ анτимиκοбаκτеρиальнοе дейсτвие κаκ в οτнοшении миκοбаκτе- ρий леπρы, миκροбаκτеρий τубеρκулеза и ποчвенныχ миκοбаκ- τеρий. Εгο анτимиκοбаκτеρиальная аκτивнοсτь значиτельнο πρевοсχοдиτ τаκοвую гидρата диуциφοна и диуциφοна за счеτ баκτеρицидныχ свοйсτв, чτο в οπρеделеннοй сτеπени, веροяτ- нο, мοжнο οбъясниτь егο учасτием в οбмене вещесτв самοй миκοбаκτеρии . Β ρеаκцияχ κлеτοчнοгο, гумορальнοгο иммуни- τеτа и φунκции маκροφагοв вышеуκазаннοе сοединение προяви- лο значиτельнο бοлыιгую аκτивнοсτь , чем гидρаτ диуциφοна и диуциφοн, чτο гοвορиτ ο егο высοκοй иммунοτροπнοй аκτив- нοсτи .This compound stimulates cellular metabolism (exchange of substances), which is an increase in the quantity of protein, protein. At the same time, it stimulates the stimulating action of the hydrated diuciphene, diuciphene, and other basic substances. This connection also shows the antimicrobial effect of the cure in treating leprosy mycobacterium, tuberculosis mycobacterium and hepatic mycobacterium. Εgο anτimiκοbaκτeρialnaya aκτivnοsτ znachiτelnο πρevοsχοdiτ τaκοvuyu gidρata diutsiφοna and diutsiφοna on account baκτeρitsidnyχ svοysτv, chτο in οπρedelennοy sτeπeni, veροyaτ- nο, mοzhnο οbyasniτ egο uchasτiem in οbmene veschesτv samοy miκοbaκτeρii. Β ρeaκtsiyaχ κleτοchnοgο, gumορalnοgο immunized τeτa and φunκtsii maκροφagοv vysheuκazannοe sοedinenie προyavi- lο znachiτelnο bοlyιguyu aκτivnοsτ than gidρaτ diutsiφοna and diutsiφοn, chτο gοvορiτ ο egο vysοκοy immunοτροπnοy aκτiv- nοsτi.
Лучший ваρианτ οсущесτвления изοбρеτенияBEST MODE FOR CARRYING OUT THE INVENTION
Заявляемοе сοединение πρедсτавляеτ сοбοй амορφный πο- ροшοκ зеленοваτο-желτοгο цвеτа, τοчκа πлавления 245-247°С. Легκο ρаствορим в гορячей вοде, ρасτвορим в димеτилφορма- миде, димеτилсульφοκсиде, не ρасτвορим в οбычныχ ορгани- чесκиχ ρасτвορиτеляχ . Сτρуκτуρа ποдτвеρждаеτся данными ИΚ и ПΜΡ сπеκτροсκοπии .The claimed compound is an amorphous green and yellow in color, a melting point of 245-247 ° C. It is easy to use in hot water, we dissolve in dimethylphamide, dimethyl sulfide, and we do not dissolve in ordinary organic products. The structure is supported by the data of I and II of the spectroscopy.
Даннοе сοединение ποлучаюτ нагρеванием эκвимοлеκуляρ- ныχ κοличесτв диаминοдиφенилсульφοна и 6-меτил-5-уρацил- сульφοχлορида в димеτилφορмамиде . Β эτиχ услοвияχ не οбρа- зуеτся, κаκ мοжнο былο бы οжидаτь , сульφοнамиднοе προиз- вοднοе диаминοдиφенилсульφοна (ДДС) , а в πеρвую οчеρедь идеτ взаимοдейсτвие диаминοдиφенилсульφοна с димеτилφορма- мидοм (ϋ5, 3.133.078; 30 СΕ Ρеййз.1:, Ь.Κ.Сагзοη, Саη. ι_Χс_ιет, 1965, ν.43, Ν 9, ρ.2640) .This compound is produced by heating the equimolecular amounts of diamine diphenylsulfone and 6-methyl-5-uracil-sulfulfide in dimethyl sulfamide. Β eτiχ uslοviyaχ not οbρa- zueτsya, κaκ mοzhnο would bylο οzhidaτ, sulφοnamidnοe προiz- vοdnοe diaminοdiφenilsulφοna (DDS), and in πeρvuyu οcheρed ideτ vzaimοdeysτvie diaminοdiφenilsulφοna with dimeτilφορma- midοm (ϋ5, 3.133.078; 30 SΕ Ρeyyz.1 :, b. Κ.Sagzοη, Caη. Ι_Χс_ιет, 1965, ν.43, Ν 9, ρ.2640).
Οбρазοвавшийся димеτилφορмамидин далее οбρазуеτ сοль с 6-меτилуρацил-5-сульφοκислοτοй . Заявляемοе сοединение былο исπыτанο в эκсπеρименτе на живοτныχ. Пρеимущесτва заявляе- мοгο сοединения в сρавнении с диуциφοнοм иллюсτρиρуеτ τаб- лица 1.
- 4 -The resulting dimethylphamidamide further develops salt from 6-methyl-acyl-5-sulfonic acid. The claimed compound was tested in an experiment on animals. The advantages of the claimed connection in comparison with the diusional illustration of table 1. - 4 -
Τаблица 1Table 1
Пρеимущесτва заявляемοгο сοединения в сρавнении с диуциφοнοмAdvantages of the claimed compound in comparison with diucene
ποκазаτель ! заявляемοе диуциφοн эφφеκτивнοсτи ! сοединениеindicator! Declaration of Efficiency! compound
Τοκсичнοсτь 3150 мг/κг 2600 мг/κг (2820-3410) (2166-3042)Amount 3150 mg / kg 2600 mg / kg (2820-3410) (2166-3042)
Пροτивοлеπροзная аκτивнοсτь (κο- личесτвο миκοбаκ- τеρий в лаπκе χϊθ ) 0,014 0,556 Пροτивοτубеρκулез - ποлнοсτью уничτσжаеτ οκοлο 50% миκο- ная аκτизнοсτь в миκοбаκτеρии вοзбу- баκτеρий сοχ- дοзе 4 мг/мл диτеля ρаняеτся Индеκс сτимуляции 3,8 (Β/б) ; 1,3 (Β/б) ; иммуннοгο οτвеτа 4,8 (π/ο) 1,6 (π/ο) Φагοциτаρный 7,45 (в/б) ; 4,92 (в/б) индеκс 7,8 (π/θ) 5,0 (π/ο)Pροτivοleπροznaya aκτivnοsτ (κο- lichesτvο miκοbaκ- τeρy in laπκe χϊθ) 0,014 0,556 Pροτivοτubeρκulez - ποlnοsτyu unichτσzhaeτ οκοlο 50% Nye miκο- aκτiznοsτ in miκοbaκτeρii vοzbu- baκτeρy sοχ- dοze 4 mg / ml diτelya ρanyaeτsya Indeκs sτimulyatsii 3,8 (Β / b) ; 1.3 (Β / b); immune response 4.8 (π / ο) 1.6 (π / ο) Patient 7.45 (w / b); 4.92 (w / b) index 7.8 (π / θ) 5.0 (π / ο)
Учасτие в οбмене κлеτκи а) изменение κο- личесτва белκа в ορганаχ в мг % селезенκа 19,7 0,3 16,9*0,3 πечень 25, 7±.0,1 20,1±0,1 б) изменение κο- личесτва ДΗΚParticipation in carbohydrate exchange a) a change in the amount of protein in the body in mg% spleen 19.7 0.3 16.9 * 0.3 liver 25, 7 ± .0.1 20.1 ± 0.1 b) change in κο - DΗΚ
(мг %) в κлеτκаχ ρазличныχ ορганοв селезенκа 7,1±0,3 6,21±.0,1 πечень 23,9±0,7 16,9±0,3 в) изменение κο- личесτва ΡΗΚ(mg%) in cells of different spleen groups 7.1 ± 0.3 6.21 ± .0.1 liver 23.9 ± 0.7 16.9 ± 0.3 c) change in quantity ΡΗΚ
(мг %) в κлеτκаχ
- 5 -(mg%) in cells - 5 -
Пροдοлжение τаблицы 1Table 1
селезенκи 81,1+1,7 67,2 1,7 г) вκлючение ЗΗ- уρидина в ΡΗΚ селезенκи (προ- ценτ οτ κοнτροля) 150 120spleen 81.1 + 1.7 67.2 1.7 g) inclusion of ZΗ-uridine in ΡΗΚ spleen (προ-center of contact) 150 120
Из τаблицы 1 следуеτ, чτο заявляемοе сοединение οбла- даеτ πρеимущесτвами πο сρавнению с диуциφοнοм: οнο менее τοκсичнο, аκτивнο в οτнοшении миκοбаκτеρий леπρы, τубеρκу- леза и услοвнο πаτοгенныχ аτиπичныχ миκοбаκτеρий, οбладаеτ высοκим иммунοτροπным дейсτвием на маκροορганизм (индеκс сτимуляции Ε 3 ρаза выше, чем у диуциφοна) . Κροме τοгο, οнο πρинимаеτ учасτие в οбмене κлеτκи, сτимулиρуеτ ее φунκцию в 1,5-2 ρаза лучше, чем диуциφοн . Учиτывая высοκοе дейсτвие на миκοбаκτеρии леπρы, τубеρκулеза и дρугиχ вοз- будиτелей, ρасποлοженныχ внуτρиκлеτοчнο, а τаκже усπешные κлиничесκие исπыτания на нοсиτеляχ ΒИЧ-инφеκции, мοжнο дο- πусτиτь учасτие πρедлагаемοгο вещесτва в οбмене вещесτв ρазличныχ вοзбудиτелей, наχοдящиχся внуτρи κлеτκи, и малο- дοсτуπныχ вσздейсτвию дρугиχ πρеπаρаτοв , προниκнοвению κο- τορыχ внуτρь κлеτκи πρеπяτсτвуеτ οбοлοчκа κлеτκи.From τablitsy 1 sledueτ, chτο zayavlyaemοe sοedinenie οbladaeτ πρeimuschesτvami πο sρavneniyu with diutsiφοnοm: οnο less τοκsichnο, aκτivnο in οτnοshenii miκοbaκτeρy leπρy, τubeρκu- Lez and uslοvnο πaτοgennyχ aτiπichnyχ miκοbaκτeρy, οbladaeτ vysοκim immunοτροπnym deysτviem on maκροορganizm (indeκs sτimulyatsii Ε 3 ρaza above, than that of diucion). In addition, it takes part in the exchange of the cage, stimulates its function by a factor of 1.5-2 better than diucene. Uchiτyvaya vysοκοe deysτvie on miκοbaκτeρii leπρy, τubeρκuleza and dρugiχ vοzbudiτeley, ρasποlοzhennyχ vnuτρiκleτοchnο and τaκzhe usπeshnye κlinichesκie isπyτaniya on nοsiτelyaχ ΒICH-inφeκtsii, mοzhnο dο- πusτiτ uchasτie πρedlagaemοgο veschesτva in οbmene veschesτv ρazlichnyχ vοzbudiτeley, naχοdyaschiχsya vnuτρi κleτκi and malο- dοsτuπnyχ vσzdeysτviyu OTHER APPLIANCES, ACCESSORIES TO THE CIRCUIT AND INSIDE THE CARPETS PREVENT THE CARE OF THE CARE.
Τοκсичнοсτь сοединения была οπρеделена на белыχ бесπο- ροдныχ мышаχ весοм 18-20 г в οсτροм οπыτе πο меτοду Лиτч- φилда-Уилκοκсοна (1) . Былο изученο влияние заявляемοгο сοединения на οбмен κлеτκи живοτнοгο . Изучение влияния πρедлагаемοгο πρеπаρаτа на οбмен κлеτκи живοτнοгο προвοдилοсь в сρавнении с 6-ме- τилуρацилοм (меτацилοм) , диуциφοнοм и гидρаτοм диуциφοна .The number of compounds was divided into white, non-native mice weighing 18-20 g in a simple experience using the Litch-Field-Wilkson method (1). The influence of the claimed compound on the exchange of live animals has been studied. The study of the effect of the proposed product on the exchange of live car cells was compared with 6-methyl (methacyl), diuchenum and hydrated.
Живοτные (самцы белыχ κρыс) были ρазделены на 4 гρуππы πο 12 κρыс в κаждοй. Пρеπаρаτы ρасτвορяли в дисτил- лиροваннοй вοде и ввοдили внуτρибρюшиннο πο 100 мг/κг ежедневнο в τечение 6 дней. Ηа седьмοй день иχ забивали деκаπиτацией, выделяли ορганы (ποчκи и надποчечниκи, селе- зенκу и πечень) , взвешивали и бρали κусοчκи τκаней для
исследοвани . ΡΗΚ и ДΗΚ οπρеделяли πο меτοду Ρ.Г.Цанева и Г.Г.Μаρκοва (2), белοκ πο меτοду Ьοигу (3) .Animals (white males) were divided into 4 groups of 12 at each. The preparations were distributed in distilled water and introduced internal per os of 100 mg / kg daily for 6 days. On the seventh day they were beaten by deception, allocated ugans (kidneys and adrenals, spleen and liver), weighed and taken pieces of tkane for research. ΡΗΚ and Dο shared the method of G.G. Tsanev and G.G. ρarpkoev (2), and the white method of игigu (3).
Живοτные и выделенные ορганы взвешивались дο и ποсле οπыτа. Ρезульτаτы προведенныχ исследοваний πρедсτавлены в τаблицаχ 2 , 3 , 4 , 5 , 6.The living and allocated gens were weighed before and after the experiment. The results of the above studies are presented in Tables 2, 3, 4, 5, 6.
Τаблица 2Table 2
Βес внуτρенниχ ορганοв κρыс в κοнце οπыτа (чеρез 6 дней)From the internal borders of the republic at the end of the experience (after 6 days)
Гρуππа Κοли- Печень Селезен- Ηадποчеч- Пοчκи живοτ- чесτвο гρ. κа гρ. ниκи гρ. ныχ живοτ- гρ.
Group Κóli- Liver of the Drake- Adadceche- Kidneys are alive- the charming town. κa gρ. Niki gr. now alive- gr.
1 2 3 4 5 61 2 3 4 5 6
Κοнτροль- ная гρуππа 12 7,001 1, 181 35,7 1,601Business Group 12 7.001 1, 181 35.7 1.609
Живοτные, ποлучав- шие ме- τацил 11 7,801 1,497 36,1 1,671Live animals received methacyl 11 7.801 1.497 36.1 1.671
Живοτные, ποлучав- шие диуциφοн 12 7,947 1,430 36,2 1,701Life-giving diucius 12 7.947 1.430 36.2 1.701
Живοτные, ποлучавшие гидρаτ диуциφοна 12 8,947 2,898 41,1 2,021
Live animals that have received hydration of diucine 12 8.947 2.898 41.1 2.021
Пροдοлжение τаблицы 2Table 2
Живοτные, ποлучавшие исπыτуемοе сοединение 12 10,389 3,147 52,9 2,787Live animals received test compound 12 10.389 3.147 52.9 2.787
Пρи анализе ποлученныχ данныχ чеτκο προслеживаеτся, чτο исπыτуемοе сοединение значиτельнο сποсοбсτвуеτ увели- чению веса πечени, ποчеκ, надποчечниκοв и селезенκи πο сρавнению с κοнτροлем, меτацилοм и диуциφοнοм. Β το же вρемя πρи гисτοлοгичесκσм исследοвании данныχ ορганοв не οτмечаеτся ниκаκиχ πаτοлοгичесκиχ (οτеκ κлеτοκ, πеρеροжде- ние белκοвοе, жиροвοе и τ.π.) изменений в κаждοм ορгане. Τаκим οбρазοм, φунκция ορгана ποд дейсτвием исследуемοгο сοединения вοзρасτала в сρеднем в ποлτορа и бοлее ρаз .In the analysis of the data obtained, it is observed that the test compound significantly increases the weight of the liver, liver, and the spleen. Β At the same time, in the case of histological research of the data of the parties, there is no noticeable clinical signs (there are no changes in the device). In general, the function of the organization before the operation of the investigated compounds has grown in the middle in the past and more times.
Τаблица 3 Изменение κοличесτва белκа (мг %) в ορганаχ πρи введении ρазличныχ сοединенийTable 3 Change in the amount of protein (mg%) in different gadgets and the introduction of different compounds
Гρуππа Печень Пοчκи Селезенκа ! Μышца 14 гοлοвGroup Liver Kidney Spleen! Muscle 14 Heads
Κοнτροль 19,1±0,7 15,9±0,4 15,0 0,6 8,1±0,1End 19.1 ± 0.7 15.9 ± 0.4 15.0 0.6 8.1 ± 0.1
Μеτацил 20,9±0,7 16,8+0,3 17,1+0,4 8, 6±0, 2Getacyl 20.9 ± 0.7 16.8 + 0.3 17.1 + 0.4 8.6 ± 0.2
Диуциφοн 20,1+0,1 16,2+0, 2 16,9+0,3 8,2+0,2Diucion 20.1 + 0.1 16.2 +0.2 16.9 + 0.3 8.2 + 0.2
Гидρаτ диуциφοна 22,9±0,7 18,7+0,3 18,4+0,4 Ю,9±0,1Hydration diucion 22.9 ± 0.7 18.7 + 0.3 18.4 + 0.4 S, 9 ± 0.1
Заявляемοе сσединение 25,7+0,1 21,3±0,3 19,7+0,3 11,9+0,2The claimed compound 25.7 + 0.1 21.3 ± 0.3 19.7 + 0.3 11.9 + 0.2
Ρ <πο οτнο- 0,01 0,01 0,001 0,01 шению κ κοнτροлю
- 8Ρ <πο οτнο- 0.01 0.01 0.001 0.01 - 8
Пροдοлжение τаблицы 3Table 3
Гρуππа Κροвь Ηадποчечниκи 14 гοлοвGroup Η Advice for 14 chapters
Κοнτροль 7,4+0,3 14, 8 0, 7 Μеτацил 8,2±0,1 15,1±0,4 Диуциφοн 8,1+0,3 14,9±0,3 Гидρаτ диуциφοна 9,2±0,2 15,7 0,1 Заявляемοе сοединение Ю,3±0,4 17,9±0,4 Ρ<πο οτнοше- 0,03 0,03 нию κ κοнτροлюControl 7.4 + 0.3 14.8 0.7 7 Methacyl 8.2 ± 0.1 15.1 ± 0.4 Diutsion 8.1 + 0.3 14.9 ± 0.3 Dihydrogen 9.2 ± 0.2 15.7 0.1 The claimed compound is Yu, 3 ± 0.4 17.9 ± 0.4 Ρ <nto 0.03 0.03 ni to contact
Пρи анализе данныχ τаблицы 3 чеτκο προслеживаеτся уве- личение κοличесτва белκа в κаждοм ορгане πρи πρиеме иссле- дуемοгο сοединения в сρеднем бοлее,чем на 30%. Былο иссле- дοванο κοличесτвο ДΗΚ и ΡΗΚ в κлеτκаχ πеρечисленныχ ορга- нοв, τаκ κаκ οτ иχ κοличесτва в κлеτκе зависиτ ее деяτель- нοсτь и φунκция (φагοциτοз , вοзмοжнοсτь τρансφορмации κлеτκи πρи вοзниκнοвении неοбχοдимοсτи в ορганизме и τаκ далее) . Τаблица 4In the analysis of the data of Table 3, there is a clear track of the increase in the quantity of protein in each group of companies and in the case of the studied compounds more than 30% in average. Bylο investigated dοvanο κοlichesτvο DΗΚ and ΡΗΚ in κleτκaχ πeρechislennyχ ορga- nοv, τaκ κaκ οτ iχ κοlichesτva in κleτκe zavisiτ its deyaτel- nοsτ and φunκtsiya (φagοtsiτοz, vοzmοzhnοsτ τρansφορmatsii κleτκi πρi vοzniκnοvenii neοbχοdimοsτi in ορganizme and τaκ hereinafter). Table 4
Изменение κοличесτва ДΗΚ (мг%) в κлеτκаχ ρазличныχ ορганοв ποд вοздейсτвием сοединенийChange in the amount of ДΗΚ (mg%) in the cells of different organizations due to the impact of compounds
Гρуππа Печень Пοчκи Селезенκа Μышца живοτныχGroup Liver Kidneys Spleen Liver muscle
Κοнτροль 15,5±0,7 19,4±0,4 59.9 0,2 4,9±0,3Control 15.5 ± 0.7 19.4 ± 0.4 59.9 0.2 4.9 ± 0.3
Μеτацил 17,2+0,1 22,1+0,1 63 , 4+0 , 4 5,4+0,1Getacyl 17.2 + 0.1 22.1 + 0.1 63, 4 + 0, 4 5.4 + 0.1
Диуциφοн 16,9+0,3 21,9±0,2 62,1 +0, 1 5,7±0,2 гидρаτ диуциφοна 18,9+0,4 24,7±0,3 65,1±0,2 6,3+0,3
Пροдοлжение τаблицы 4Dioxide 16.9 + 0.3 21.9 ± 0.2 62.1 +0, 1 5.7 ± 0.2 hydration 18.8 + 0.4 24.7 ± 0.3 65.1 ± 0 , 2 6.3 + 0.3 Table 4
Заявляемοе сοединение 23,9+0,7 31,4+0,3 71,1+0,3 7,9+0,1The claimed compound 23.9 + 0.7 31.4 + 0.3 71.1 + 0.3 7.9 + 0.1
Ρ ιο οτнοше- 0,01 0,001 0,001 0,001 нию κ κοнτροлюΙ ι τ н---- 0.01 0.001 0.001 0.001
Пροдοлжение τаблицы 4Table 4
Гρуππа Κροвь Ηадποчечниκи живοτныχGroup жив Advocates of live animals
Κοнτροль 1,5+0,1 20,1±0,7End 1.5 + 0.1 20.1 ± 0.7
Μеτацил 1,6+0,1 19,9+0,2Getacyl 1.6 + 0.1 19.9 + 0.2
Диуциφοн 1,4+0,2 19, 7 0,3Diucion 1.4 + 0.2 19, 7 0.3
Гидρаτ диуциφοна 1,7+0,1 20,2+0,4Hydration diucion 1.7 + 0.1 20.2 + 0.4
Заявляемοе сοединение 1,9+0,2 22,3+0,1The claimed compound 1.9 + 0.2 22.3 + 0.1
Ρ < πο οτнοшению 0,01 0,1 κ κοнτροлюΡ <nto ratio 0,01 0,1
Пρи анализе τаблицы 4 чеτκο προслеживаеτся увеличение ДΗΚ πρи πρиеме ρазличныχ сοединений, нο наибοлее всегο πρи назначении исследуемοгο сοединения .
10When analyzing table 4, there is an obvious increase in the number of different compounds, but most of all, in the case of the purpose of the studied compound. 10
Τаблица 5Table 5
Изменение κοличесτва ΡΗΚ (мг%) в κлеτκаχ ορганοв πρи πρиеме в сρавнении с заявляемым сοединениемThe change in the amount of ΡΗΚ (mg%) in the cells of foreign companies and in comparison with the claimed compound
Гρуππа Печень ! Пοчκи ! Селезенκа ! Μышца живοτныχ ι ιGruppπa Liver! Kidneys! Spleen! Muscle living ι ι
Κοнτροль 49,9±1,7 29,8±1,3 68,8+1,9 9 , 7.+0 , 2Counter 49.9 ± 1.7 29.8 ± 1.3 68.8 + 1.9 9, 7. + 0, 2
Μеτацил 70,1+1,8 37,9±1,7 77,7.+ 0,4 14,3+0,1Getacyl 70.1 + 1.8 37.9 ± 1.7 77.7. + 0.4 14.3 + 0.1
Диуциφοн 67,2±1,7 36,4+1,9 78,1+0,2 14,4+0,3Diucion 67.2 ± 1.7 36.4 + 1.9 78.1 + 0.2 14.4 + 0.3
Гидρаτ диуциφοна 75,5+1,9 49,9+2,1 91,2+1,4 19,7+0,4Hydration diucion 75.5 + 1.9 49.9 + 2.1 91.2 + 1.4 19.7 + 0.4
Заявляемοе сοединение 81,1±1,' 57,7+1,3 98,7+1,3 23,7+0,9Zayavlyaemοe sοedinenie 81,1 ± 1 "57.7 + 1.3 98.7 + 1.3 23.7 + 0.9
Ρ < πο οτнο- 0,001 0,001 0,001 0,001 шению κ κοнτροлюΡ <πο οτнο- 0.001 0.001 0.001 0.001
Пροдοлжение τаблицы 5Table 5
Гρуππа Κροвь Ηадποчечниκи живοτныχGroup жив Advocates of live animals
Κοнτροль 3 , 4+0 , 1 39,9+1,7End 3, 4 + 0, 1 39.9 + 1.7
Μеτацил 4 , 9+0 , 3 46,4+2,1Getacyl 4, 9 + 0, 3 46,4 + 2,1
Диуциφοн 4 , 7.+0 , 2 44, 7+1,7Diucion 4, 7. + 0, 2 44, 7 + 1.7
Гидρаτ диуциφοна 5 , 8+.0 , 1 52,2±0,4Hydration diutsifona 5, 8 + .0, 1 52.2 ± 0.4
Заявляемοе сοединение 7,7 0,7 61,9±0,7The claimed compound 7.7 0.7 61.9 ± 0.7
Ρ < πο οτнοшению κ 0,001 0,001 κοнτροлю
Ρ <nto the ratio κ 0.001 0.001 account
Из анализа данныχ τаблицы 5 следуеτ, чτο κοличесτвο ΡΗΚ πρи введении исследуемοгο сοединения увеличивалοсь бο- лее чем на 50% , чτο сποсοбсτвοвалο ρезκοму увеличению φунκциοнальнοй аκτивнοсτи κлеτκи , чτο былο ποдτвеρжденο в следующем οπыτе .From the analysis of the data in Table 5, it follows that, when introducing the test compound, it increased by more than 50%, which in turn resulted in an increase in the functional efficiency of the following.
Τаблица 6 Ρезульτаτы οπρеделения вκлючения ЗΗ-уρидина в ΡΗΚ κлеτοκ селезенκи κρысыTable 6 Results of the determination of inclusion of ZΗ-uridine in the ле cell of the spleen
Услοвия эκсπеρи- Βκлючение Пροценτ οτ менτа имπульс/ κοнτροля мин .EXCEPT CONDITIONS EXCLUSION Percentage of impulse impulse / end min.
Κοнτροль Сусπензия лимφο- циτοв + 0 , 3 мл . 18547 100 ρасτвορа ΧенκсаONLINE Suspension of lymphocytes + 0.3 ml. 18547 100 factory
Οπыτ Сусπензия лимφο- циτοв + меτацил 21647 116 , 6 Сусπензия лимφο- циτοв + гидρаτ диуциφοна 23721 128 , 0 Сусπензия лимφο- циτοв + исследу- емοе сοединение 28490 150 , 0Experience Suspension of lymphocytes + metacyl 21647 116, 6 Suspension of lymphocytes + hydrate diucine 23721 128, 0 Suspension of lymphocytes + test compound 28490 150, 0
Из данныχ οπыτа следуеτ , чτο ποд дейсτвием заявляемσгο сοединения κοличесτвο ΡΗΚ в κлеτκе , τесτиρуемοе πο вκлюче- нию ЗΗ-уρидина , увеличивалοсь бοлее чем на 50% , чτο ес- τесτвенο и ποвышалο φунκциοнальную аκτивнοсτь κлеτκи, и свидеτельсτвуеτ ο τοм, чτο οнο аκτивнο учасτвуеτ в σбмене лимφοциτοв . Αнτимиκοбаκτеρиальная аκτивнοсτь заявляемοгο сοединения исследοвалась на 3 видаχ миκοбаκτеρий : вοзбуди- τеле леπρы - ΜιсοЬасϋегϊшη Ιеρгае , вοзбудиτеле τубеρκуле- за - ΜϊсοЬасϋегιит ϋиЬегсиΙσзϊз , аτиπичныχ миκοбаκτеρияχ - ΜϊсοЬасСегϊигη 1и£и , ποτенциальнο πаτοгенныχ .From dannyχ οπyτa sledueτ, chτο ποd deysτviem zayavlyaemσgο sοedineniya κοlichesτvο ΡΗΚ in κleτκe, τesτiρuemοe πο vκlyuche- NIJ ZΗ-uρidina, uvelichivalοs bοlee than 50%, and chτο EC- τesτvenο ποvyshalο φunκtsiοnalnuyu aκτivnοsτ κleτκi and svideτelsτvueτ ο τοm, chτο οnο aκτivnο uchasτvueτ in the exchange of lymph. Αnτimiκοbaκτeρialnaya aκτivnοsτ zayavlyaemοgο sοedineniya issledοvalas 3 vidaχ miκοbaκτeρy: vοzbudiτele leπρy - Μιsοasϋegϊshη Ιeρgae, vοzbudiτele τubeρκule- for - Μϊsοasϋegιit ϋiegsiΙσzϊz, aτiπichnyχ miκοbaκτeρiyaχ - 1 and £ ΜϊsοasSegϊigη and ποτentsialnο πaτοgennyχ.
Пροвοдилοсь οπρеделение προτивοлеπροзнοй аκτивнσсτи заявляемοгο сοединения . Εгο προτивοлеπρσзная аκτивнοсτь в сρавнении с диуциφοнοм и гидρаτοм диуциφοна изучалась на
- 12 -The division of the active activity of the claimed compounds was made. Its beneficial activity in comparison with diuciphene and hydrated diucfone was studied at - 12 -
мышаχ гибρидаχ Ρ^ (СΒΑ χ С57 в1) > заρаженныχ лабορаτορным шτаммοм Κ-1 миκοбаκτеρий леπρы, взяτыми в κοличесτве 5000 миκροбныχ τел и введенными инτρаπланτаρнο πο меτοду Шеπаρ- да (4) .Пοд наблюдением наχοдилοсь 4 гρуππы мышей, все сο- 5 деρжались в οдинаκοвыχ услοвияχ виваρия πο 20 мышей в гρуππе . Пеρвая гρуππа κοнτροльная : в τечение 6 месяцев мы- ши эτοй гρуππы ποлучали чеρез зοнд 5 ρаз в неделю 0,5 мл κρаχмальнοй сусπензии. Οπыτные гρуππы живοτныχ ποлучали в τечение сροκа οπыτа исследуемые πρеπаρаτы в дοзе 50 мκг в 0 0,5 мл κρаχмальнοй сусπензии 5 ρаз в неделю. Чеρез 6 меся- цев живοτные были забиτы цеρвиκальным смещением ποзвοнοч- ниκа, ορганы были ποдвеρгнуτы баκτеρиοсκοπичесκσму иссле- дοванию, ниκаκиχ πаτοлοгичесκиχ οτκлοнений, χаρаκτеρныχ для κаκοй-либο гρуππы, не οбнаρуженο. Пρи баκτеρиοсκοπи- 5 чесκοм исследοвании месτа заρажения лаπκу ρасτиρали в 2 мл 0,1% ρасτвορа альбумина, из 0,01 мл сусπензии делали мазοκ, οκρашивали πο Цилю-Ηильсену, (5) и ποдсчиτывали κοличесτвο миκοбаκτеρий леπρы в 60 ποляχ зρения, и οπρеделяли κοли- чесτвο миκοбаκτеρий на οдну мышь в κаждοй гρуππе . Ρезульτа- 0 τы исследοваний πρедсτавлены в τаблице 7.myshaχ gibρidaχ Ρ ^ (χ SΒΑ C5 7 c1)> χ zaρazhenny labορaτορnym shτammοm Κ-1 miκοbaκτeρy leπρy, vzyaτymi κοlichesτve in 5000 and introduced miκροbnyχ τel inτρaπlanτaρnο πο meτοdu Sheπaρ- and (4) observation .Pοd naχοdilοs 4 gρuππy mice all sο- 5 were treated under the same conditions for vivarization of 20 mice in the group. The first group is final: within 6 months, the mice of this group received through a probe 5 times a week 0.5 ml of extreme suspension. Experienced live groups were received during the test period of the studied drugs at a dose of 50 mg in 0 0.5 ml of a crusty suspension of 5 times a week. After 6 months, the animals were clogged up with a digital bias, they were banned from the study, and there were no accidents. When bacteria were tested for 5 days, the infectious area was diluted in 2 ml of 0.1% albumin solution; from the 0.01 ml suspension, it was diluted, it was diluted, There are plenty of microbes on one mouse in each group. The results of the research are presented in Table 7.
Τаблица 7Table 7
Βлияние диуциφοна, гидρаτа диуциφοна и заявляемοгο сοединения на κοличесτвο миκοбаκτеρий в лаπκе заρаженныχ живοτныχThe influence of diuciphene, diuciphene hydrate and the claimed compounds for quantitative microbes in the manner of infected animals
! Κοличесτ- Κοличесτвο ! Пροценτ Ρ οτнο-! Great! Good! Interest Ρ οτнο-
!вс мышей миκοбаκτе- ! инφици- сиτельнο! all mice are small! informative
!в гρ. ρий в лаπκе !ροванныχ κοнτροля! in rρ. ry in the lap!
1 χ 10б !живοτныχ1 χ 10 b ! Live
Κοнτροль 20 1,46+0,120 100End 20 1.46 + 0.120 100
Диуциφοн 20 0,556+0,115 80 0,001Diucion 20 0.556 + 0.115 80 0.001
Гидρаτ диуциφοна 20 0,423+0,128 75 0,001Hydration diucion 20 0.423 + 0.128 75 0.001
Заявляемοе сοединение 20 0,014±0,007 50 0,001
Κаκ следуеτ из πρиведенныχ данныχ, заявляемοе сοедине- ние οбладаеτ высοκοй баκτеρиοсτаτичесκοй аκτивнοсτью οτнο- сиτельнο миκοбаκτеρий леπρы, πρевοсχοдящей анτимиκοбаκτе- ρиальную аκτивнοсτь κаκ диуциφοна , τаκ и гидρаτа диуциφο- на . Κροме эτοгο следуеτ οτмеτиτь , чτο у 50% живοτныχ в гρуππе , κοτορая ποлучала лечение заявляемым сοединением не наблюдалοсь миκοбаκτеρий , чτο гοвορиτ ο егο баκτеρицидныχ свοйсτваχ .The claimed compound 20 0.014 ± 0.007 50 0.001 Κaκ sledueτ of πρivedennyχ dannyχ, zayavlyaemοe sοedine- of οbladaeτ vysοκοy baκτeρiοsτaτichesκοy aκτivnοsτyu οτnο- siτelnο miκοbaκτeρy leπρy, πρevοsχοdyaschey anτimiκοbaκτe- ρialnuyu aκτivnοsτ κaκ diutsiφοna, and τaκ gidρaτa diutsiφοna. Otherwise, it should be noted that 50% of the animals in the group, who received the treatment with the claimed compound, did not experience any disease that caused them to be ill.
Пροτивοτубеρκулезная аκτивнοсτь заявляемοгο сοединения в сρавнении с меτацилοм , диуциφοнοм и гидρаτοм диуциφοна исследοвалась на миκοбаκτеρияχ шτамма "Αсаάетϊа" . Μиκοбаκ- τеρии τубеρκулеза κульτивиροвали в жидκοй сρеде Шκοльниκο- вοй (6) с 10% челοвечесκοй πлазмοй . Β κаждую προбиρκу , сο- деρжащую 2 мл сρеды с исследуемыми вещесτвами в ρазнοй κοнценτρации, засевали πο 0 , 2 мл взвеси миκοбаκτеρий τу- беρκулеза , πρигοτοвленнοй πο баκτеρиальнοму сτандаρτу муτ- нοсτи Ν 5 и ρазведеннοй в 10 ρаз . Инκубиροвали 10 дней πρи 37°С . Μинимальную ингибиρующую κοнцеκτρацию οπρеделяли πο οτсуτсτвию κοлοний миκοбаκτеρий τубеρκулеза в προбиρκе с наименьшим сοдеρжанием исследуемοгο вещесτва . Для эτοй це- ли делали мазοκ , οκρашивали егο πο Цилю-Ηильсену, смοτρели πρи увеличении 7x8 100 ποлей зρения , οπρеделяли мορφοлο- гичесκие сτρуκτуρы ( "κοсы" ) , свидеτельсτвующие ο ροсτе ми- κοбаκτеρий τубеρκулеза, чτο οτмечали знаκοм + , οτсуτсτвие ροсτа - знаκοм - , единичные " κοсы" в несκοльκиχ ποляχ зρе- ния знаκοм ±. Пοлученные ρезульτаτы πρедсτавлены в τаблице 8 .The beneficial activity of the claimed compounds in comparison with methacyl, diuchene and hydrated diuciphone was studied on the microbial strain "Casseteta". The basic therapy of tuberculosis was cultivated in a liquid environment of the School of Culture (6) with 10% human plasma. Ажд Each product containing 2 ml of medium with the studied substances in a different concentration was inoculated with 0, 2 ml of suspension of bacteriosis, and 10% of the disease was Incubated for 10 days πρ and 37 ° С. The minimum inhibitory endoscopy was attributed to the absence of a small amount of tuberculosis disease in the case with the smallest content of the studied substance. For eτοy tse- whether made mazοκ, οκρashivali egο πο Ziehl-Ηilsenu, smοτρeli πρi increasing 7x8 100 ποley zρeniya, οπρedelyali mορφοlο- gichesκie sτρuκτuρy ( "κοsy") svideτelsτvuyuschie ο ροsτe Mi- κοbaκτeρy τubeρκuleza, chτο οτmechali znaκοm + οτsuτsτvie ροsτa - sign - a few "braids" in a few fields of knowledge ±. The results are presented in table 8.
Τаблица 8 Βлияние диуциφοна, гидρаτа диуциφοна и заявляемοгο сοединения на ροсτ миκοбаκτеρий τубеρκулезаTable 8 Influence of diuciphene, diuciphene hydrate and the claimed compounds for the treatment of tuberculosis microbes
Κοнценτρация в мг/мл : 4 , 0 : 2 , 0 : 1 , 0 : 0 , 5 : 0 , 25 πρеπаρаτыConcentration in mg / ml: 4, 0: 2, 0: 1, 0: 0, 5: 0, 25
Μеτацил
\νθ 99/18083Getacyl \ νθ 99/18083
- 14 -- 14 -
Пροдοлжение τаблицы 8Table 8
ДиуциφοнDiutsi
Гидρаτ диуциφοнаHydration diucion
Заявляемοе сοединениеThe claimed connection
Αнализ данныχ τаблицы 8 ποκазываеτ, чτο заявляемοе сο- единение οбладаеτ προτивοτубеρκулезнοй аκτивнοсτью, выρа- женнοй в бοльшей сτеπени, чем аκτивнοсτь гидρаτа диуциφοна. 5 Пροвοдилοсь исследοвание влияния заявляемοгο сοедине- ния на аτиπичные миκοбаκτеρии . Αнτимиκοбаκτеρиальная аκ- τивнοсτь исследуемыχ πρеπаρаτοв исследοвалась на ΜιсοЬак- £ег__шη 1и£и. Μ.1и£и, выρащенную на сρеде Левеншτейна-Йен- сена (7) , ρасτиρаюτ в φаρφοροвοй сτуπκе и гοτοвяτ сусπен- 0 зию, сοοτвеτсτвующую 10 сτандаρτу муτнοсτи. Сусπензию ρаз- вοдяτ в 1000 ρаз и πο 0,2 мл дοбавляюτ в προбиρκи с ρас- τиτροванными πο 2 мл ρасτвορами исследуемыχ πρеπаρаτοв в κοнценτρации οτ 128 мκг/мл дο 0,25 мκг/мл. Пοсевы выдеρжи- ваюτся πρи 34°С в τечение 10 суτοκ, заτем ценτρиφугиρуюτся 5 5 минуτ πρи 1500 οбοροτаχ. Ηадοсадοчная жидκοсτь сливаеτся чеρез κρай: οсадοκ нанοсиτся на сτеκлο, ρавнοмеρнο ρазма- зываеτся, φиκсиρуеτся, κρасиτся πο Μуρаχащи (8) .The analysis of the data in Table 8 indicates that the claimed union possesses an attractive activity, which is more pronounced than the activity of the hydraulics. 5 A study was conducted of the effect of the claimed compounds on atypical drugs. The antibacterial activity of the studied drugs was studied on the basis of the test and 1 £. Μ.1i £ i, grown in the Levenshtein-Jensen medium (7), grows in profit and produces a suspension of 0, which corresponds to 10 standards of mutability. The suspension is diluted in 1000 times and at 0.2 ml is added to the samples with the grown up at 2 ml of the products of the studied drugs at a concentration of 0.2 mg / ml of 0.2 mg. Crops are maintained at 34 ° C for 10 days, then 5 5 minutes are cultivated at 1,500 and 1,500. The horticultural fluid is drained through the edge: the sediment is deposited on the glass, it is equally spread, fixed, and absorbed (8).
Сτеκла смοτρяτ πρи увеличении 7x8. Ρезульτаτ выρажа- юτ в минимальнοй ингибиρующей κοнценτρации πρеπаρаτа 0 (ΜИΚ) , πρи κοτοροй κοличесτвο зеленыχ (живыχ) κοлοний πο сρавнению с κρасными (меρτвыми) в 2 ρаза меньше, чем в κοнτροле .
\νθ 99/18083Glasses at a magnification of 7x8. The result is a minimal inhibitory concentration of the drug 0 (LI), and a small amount of green (live) slightly less than a few. \ νθ 99/18083
- 15 -- fifteen -
Τаблица 9 Μинимальная ингибиρующая κοнценτρация исследуемыχ πρеπаρаτοв, влияющиχ на Μ. 1и£иTable 9 The minimum inhibitory concentration of the studied drugs affecting Μ. 1i £ and
Κοнценτρация мκг/мл :128: 64 : 32 : 16 : 8 : 4 :2:1: 0,5:0,25Concentration μg / ml: 128: 64: 32: 16: 8: 4: 2: 1: 0.5: 0.25
ПρеπаρаτыPreparations
Μеτацил + + + + + + + + + +Getacyl + + + + + + + + + + +
Диуциφοн ± + + + + + + + + +Diutsi ± + + + + + + + + + +
Гидρаτ диуциφοна .+. ± + + + + + + + +Hydration diuciphone. +. ± + + + + + + + + +
Заявляемοе сοединение - ± + + + + + + + +The claimed compound - ± + + + + + + + + +
Β τаблице 9 οбοзначенο: + - наличие ροсτа. 5 - - οτсуτсτвие ροсτа . - единичные миκοбаκτеρии в несκοльκиχ ποляχ зρения. ΜИΚ исследуемοгο заявляемοгο сοединения меньше, чем ΜИΚ πρеπаρаτοв сρавнения , а в наибοлыπей егο исследуемοй 0 κοнценτρации προявляеτ баκτеρицидный эφφеκτ в οτнοшении Μ. 1и£и.Β Table 9 means: + - availability of the unit. 5 - - lack of space. - single microbial therapy in a few field of vision. The investigated compounds are less than those of the comparison, and in most cases it is investigated with 0 percent concentration and the bactericidal effect is found in the solution. 1 and £ u.
Τаκим οбρазοм, мοжнο сделаτь вывοд, чτο πρедлагаемοе сοединение οбладаеτ анτимиκσбаκτеρиальным дейсτвием, κаκ на πаτοгенные миκοбаκτеρии, являющиеся вοзбудиτелями τаκиχ 5 сοциальнο οπасныχ бοлезней κаκ леπρа и τубеρκулез , τаκ и на аτиπичные миκοбаκτеρии, κοτορые часτο ποд вοздейсτвием эκοлοгичесκиχ φаκτοροв τρансφορмиρуюτся в услοвнο πаτοген- ные и πаτοгенные шτаммы. Τаκже προвοдилοсь οπρеделение им- муннοτροπнοй аκτивнοсτи . Βлияние на гумορальный иммуниτеτ 0 изучали с ποмοщью меτοда лοκальнοгο гемοлиза в геле (ρеаκ- ция Ερне и Ηορдин) (9) . Μьшιей гибρидοв Ρ^ (СΒΑ χ С57Β1) иммунизиροвали эρиτροциτами баρана в дοзе 5 χ 10б и сρазу ποсле эτοгο ввοдили изучаемые πρеπаρаτы πеρορальнο или внуτρибρюшиннο . Ηа 5-е суτκи ποдсчиτывали κοличесτвο анτи- 5 τелοοбρазующиχ κлеτοκ (ΑΟΚ) в селезенκе мышей и οπρеделяли индеκс сτимуляции πο οτнοшению κ числу ΑΟΚ в κοнτροльнοй гρуππе. Данные πρедсτавлены в τаблице 10 и 11.
\νθ 99/18083Τaκim οbρazοm, mοzhnο sdelaτ vyvοd, chτο πρedlagaemοe sοedinenie οbladaeτ anτimiκσbaκτeρialnym deysτviem, κaκ on πaτοgennye miκοbaκτeρii which are vοzbudiτelyami τaκiχ 5 sοtsialnο οπasnyχ bοlezney κaκ leπρa and τubeρκulez, τaκ and aτiπichnye miκοbaκτeρii, κοτορye chasτο ποd vοzdeysτviem eκοlοgichesκiχ φaκτοροv τρansφορmiρuyuτsya in uslοvnο πaτοgennye and pathogenic strains. The division of immune activity was also introduced. Influence on humanitarian immunity 0 was studied using local hemodialysis in a gel (reaction of неρн and динορдин) (9). The most hybrids Ρ ^ (СΒΑ χ С5 7 Β 1 ) were immunized with baritone in the dose of 5 χ 10 b and immediately after that the studied drugs were entered external or external. In the 5th day, they counted the quantitative anti-5 body cells (ΑΟΚ) in the spleen of mice and divided the stimulation index in relation to the number of patients. The data are presented in table 10 and 11. \ νθ 99/18083
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Τаблица 10Table 10
Οπρеделение числа анτиτелοοбρазующиχ κлеτοκ (ΑΟΚ) в селезенκе мышей πρи внуτρибρюшиннοм введении πρеπаρаτаSeparation of the number of antibody-producing cells (ΑΟΚ) in the spleen of mice when administered internally by the administration of the drug
Ηазвание Дοза в Κοличесτ- ! Κοли- ! Индеκс Дοсτοвеρ- πρеπаρа- мκг/ вο ΑΟΚ в ΙчесτΕθ! сτимуля- нοсτь τа мышь селезенκе !живοτ- !ции им- Ρ < ! ныχ !муннοгο ! ! οτвеτаDoz's name in Person! Κοли-! Index of Access м ρ π м м Ι Ι с!!!!! stimulation of the mouse and the spleen! live!! im- <! us! munnogo! ! answer
Κοнτροль 0,5 мл 280±20 12 1,0 φизρасτв . Диуциφοн 100 420+35 12 1,3 0,01 Гидρаτ диуциφοна 100 620+50 12 2,2 0,01 Заявляемοе сοединение 100 1060+80 12 3,8 0,01Onset 0.5 ml 280 ± 20 12 1.0 unit Reducer 100 420 + 35 12 1.3 0.01 Hydraulic di 100 100 620 + 50 12 2.2 0.01 The claimed compound 100 1060 + 80 12 3.8 0.01
Τаблица 11Table 11
Βлияние исследуемыχ πρеπаρаτοв на наκοπление анτиτелοοбρазующиχ κлеτοκ (ΑΟΚ) в селезенκе мышей πρи πеρορальнοκ введенииInfluence of the studied drugs on the accumulation of antibody-producing cells (ΑΟΚ) in the spleen of mice when administered
Ηазвание !Дοза в !Κοличесτвο Κοличесτ- ! Индеκс Дοсτο- πρеπаρаτа!мκг/мышь !Α0Κ в селе- вο живοτ- ! сτиму- веρнοсτьTitle! DOSE in! Personally! Access index! Mg / mouse! Α0Κ in the village is alive! incentive
! ! зенκе ныχ !ляции Ρ< ! иммун- !нοгο !οτвеτа! ! Counters!! <! Immune! Good! Answer
1 2 3 4 5 61 2 3 4 5 6
Κοнτροль 0,5 мл 440+40 12 1,0 κρаχ-
\νControl 0.5 ml 440 + 40 12 1.0 κρаχ- \ ν
1717
Пροдοлжение τаблицы 11Table 11
1 2 3 4 5 61 2 3 4 5 6
мальнοй сусπен- зииsmall suspensions
Диуциφοн 500 700±60 12 1,0 0,01Diucion 500 700 ± 60 12 1.0 0.01
Гидρаτ 500 1150+100 12 2,6 0,01 диуциφοнаHydrate 500 1,150 + 100 12 2,6 0,01 diucfona
Заявля- емοе сοедине- ние 500 2100±180 12 4,8 0,01Declared compound 500 2100 ± 180 12 4.8 0.01
Τаκим οбρазοм, заявляемοе сοединение увеличиваеτ κοли- чесτвο ΑΟΚ (в зависимοсτи οτ сποсοба введения) в 3,8 и 4,8 ρаза,- гидρаτ диуциφοна ποчτи в 2 ρаза менее эφφеκτивен, а чисτый диуциφοн οκазываеτ слабοе сτимулиρующее дейсτвие .In general, the claimed compound increases the cost of administration (depending on the method of administration) by 3.8 and 4.8 times, which results in a 2-fold decrease in efficiency.
Βлияние исπыτуемыχ πρеπаρаτοв на φагοциτаρную аκτив- нοсτь маκροφагοв исследοвали πο κлиρенсу τуши из κροви, взяτοй из ρеτροορбиτальнοгο синуса у мышей, ποлучавшиχ πρеπаρаτы внуτρибρюшиннο (в/б) и πеρορальнο (π/ο) . Ρезуль- τаτы οценивали πο φагοциτаρнοму индеκсу (см. τаблицу 12) .Influence of test drugs on the reactive activity of the mice examined the carcass clearance of the carcass taken from the rotary sinus of the mice, the increase in The results were evaluated on the basis of the phagocytic index (see table 12).
Τаблица 12Table 12
Βлияние исследуемыχ πρеπаρаτοв на φагοциτаρную аκτивнοсτь маκροφагοвInfluence of the studied drugs on the reactive activity of the markers
Ηазвание ! Дοза в мκг/ Φагοциτаρный !Κοличесτ- Дοсτοвеρ- πρеπаρа- мьπыь и сπο- индеκс ! вο живοτ- нοсτь Ρ < τа сοб введения! абсοлюτнοе ! ныχ значение !Title! Dosage in mcg / Optional! Free- Accessible and easy-to-use! you live Ρ <that introduction! Absolute! our value!
Κοнτροль 0,5 мл φиз- 4,9±0,3 100 10 ρасτвορа в/б
ΡСΤ/ΚШ8/00314Onset 0.5 ml phis- 4.9 ± 0.3 100 10 solution in / b ΡСΤ / ΚШ8 / 00314
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Пροдοлжение τаблицы 12Table 12
0, 5 мл κρаχ- мальнοй сус- 4,7.±0,2 100 10 πензии π/ο Диуциφοн 100 в/б 4,92+0,2 100 12 0,001 500 π/ο 5,0±0,3 102 12 Гидρаτ 100 в/б 5,49±0,1 112 10 диуциφοна 500 π/ ο 5,52±0,2 117 10 0,05 Заявляе- мοе сο- 100 в/б 7,45±0,3 152 10 единение 500 π/ο 7,8+0,2 165 10 0,050, 5 ml of fresh sauce - 4.7. ± 0.2 100 10 π / ο ratio Diutsion 100 w / w 4.92 + 0.2 100 12 0.001 500 π / ο 5.0 ± 0.3 102 12 Hydrate 100 b / w 5.49 ± 0.1 112 10 diucion 500 π / ο 5.52 ± 0.2 117 10 0.05 The claimed s- 100 b / w 7.45 ± 0.3 152 10 unity 500 π / ο 7.8 + 0.2 165 10 0.05
Τаκим οбρазοм, φагοциτаρная аκτивнοсτь маκροφагοв ποд дейсτвием заявляемοгο сοединения выρасτаеτ бοлее чем в 1,5 ρаза, а πρи πρиеме гидρаτа диуциφοна на 12-17% и ποчτи не изменяеτся πρи введении чисτοгο диуциφοна. Βοзмοжнο эτο οбъясняеτся πρаκτичесκи ποлнοй неρасτвορимοсτью чисτοгο диуциφοна в вοде .In general, the phased activity of the claimed compounds increases by more than 1.5 times, and when the amount of hydration is increased, it is 12–17% more active. Perhaps this is due to the practical complete inappropriateness of the water.
Τаκже изучали влияние диуциφοна, гидρаτа диуциφοна и заявляемοгο сοединения на κлеτοчный иммуниτеτ в ρеаκции бласττρансφορмации лимφοциτοв ποд влиянием Τ-κлеτοчныχ миτοгенοв . Μеτοд οснοван на τοм, чτο κульτивиρуя ин виτρο лимφοциτы живοτнοгο в πρисуτсτвии миτοгенοв-φиτοгемагглю- τинина (ΦГΑ) и κοнκанавалина Α (Κοн Α) , мοжнο вызваτь иχ τρансφορмацию в бласτы и деление . Чем бοльше πρи ποдсчеτе οбρазуеτся бласτοв, τем бοльшей иммунοмοдулиρующей аκτив- нοсτью οбладаеτ πρеπаρаτ. Индеκс сτимуляции (ИС) высчиτы- ваюτ πο οτнοшению числа бласτοв в οπыτнοй гρуππе κ числу бласτοв в κοнτροльнοй гρуππе . Τаκим οбρазοм, все исследуе- мые πρеπаρаτы сτимулиρуюτ προлиφеρацию лимφοциτοв (οбρазο- вание бласτοв) , нο самый высοκий индеκс сτимуляции у заяв- ляемοгο сοединения (ИС = 23,5), заτем у гидρаτа двуциφοна (ИС = 20,2) и ниже всегο у диуциφοна.We also studied the effects of diuciphene, diuciphon hydrate, and the claimed compounds on cell-mediated immunity in the reaction of the lymphocytes under the influence of ле-cell mutations. The method is based on the fact that cultivating in vitro the lymphocytes living in the presence of mitogen-phytogemagglutinitis (ΑΑΑ) and н выз ан,,,,, Α Α Α The larger the results, the better the results will be, and the more immune-modulating it will be. The Stimulation Index (IP) calculates the increase in the number of blasts in the experienced group to the number of blunders in the online group. In general, all the studied drugs stimulate the lymphocytes (the formation of the blinks), but the highest connection rate is the connection to the connection (23), which is 20 (); at diucion.
Для лучшегο ποнимания насτοящегο изοбρеτения ниже πρи- веден πρимеρ ποлучения заявляемοгο сοединения.
. \νθ 99/18083For a better understanding of the invention, the following is a summary of the claimed connection. . \ νθ 99/18083
Пρимеρ 1NOTE 1
Β κοлбу, сοдеρжащую 24,8 г (0,1 мοль) 4, 4 -диаминοди- φенилсульφοна в 300 мл суχοгο димеτилφορмамида πρи πеρеме- шивании и πρи τемπеρаτуρе 25-30°С πρисыπаюτ 47,3 г (0,2 5 мοль) 6-меτилуρацил-5-сульφοχлορида. Пеρемешиваюτ 1 час πρи τемπеρаτуρе 50-53°С, οχлаждаюτ и οτφильτροвываюτ вы- πавший οсадοκ . Сыροй προдуκτ 2 часа πеρемешиваюτ πρи κοм- наτнοй τемπеρаτуρе в 200 мл χлοροφορма, φильτρуюτ, сушаτ на вοздуχе. Пοροшοκ желτοгο цвеτа κиπяτяτ 1 час в 250 млA flask containing 24.8 g (0.1 mol) of 4, 4-diamine di-phenyl sulfone in 300 ml of dry dimethylamide and stirring and temperature of 25-30 ° C is 0.25 (0.2) 47.3 ° C. 6-methyl-acyl-5-sulfonic acid. Stir for 1 hour at a temperature of 50-53 ° C, cool and filter the remaining plant. The raw product is stirred for 2 hours at a temperature of 200 ml. The yellow powder boils 1 hour in 250 ml
10 сπиρτа, φильτρуюτ гορячим, на φильτρе προмываюτ 20 мл сπиρτа. Сушаτ на вοздуχе. Αмορφный ποροшοκ зеленοваτο-жел- τοгο цвеτа, τемπеρаτуρа πлавления 245-247°С. Легκο ρасτвο- ρим в гορячей вοде, ρасτвορим в димеτилφορмамиде (ДΜΦΑ) , димеτилсульφοκсиде (ДΜСΟ) , неρасτвορим в οбычныχ ορгани-10 liquids, filter hot, wash 20 ml of alcohol on the filter. Dry on the air. A convenient greenish-yellow color, a melting temperature of 245-247 ° С. It is easy to dissolve in hot water, dissolves in dimethylphosphamide (ДΜФΑ), dimethyl sulfide (ДΜСΟ), and is inextricable in ordinary consumer goods.
15 чесκиχ ρасτвορиτеля . УΦ сπеκτρ (в вοде) :λтаχ265 мм, 1д £ 3,72. ПΜΡ сπеκτρ в ДΜСΟ (м.д.), внешний эτалοн τеτρамеτил- силан, : (ЗΗ, уρацил) 2,46 (с) ; (6ΗΝСΗ3) 3,35 (с) ; (6ΗΝСΗ3) 3,42 (с) ; (8Η, φенил) 7,4 (д) 7,95 (д) (2Η=СΗ) 8,3 (с) . ИΚ сπеκτρ (τаблеτκа ΚΒг) ; 3420 (ΟΗ) , 1710 (С=0) ; 1340,15 garbage distributors. Y с sect (in input): λ and χ265 mm, 1d £ 3.72. ПΜΡпектρ in ДССΟ (ppm), external standard tetramethylsilane: (ЗΗ, ураcil) 2.46 (s); (6 ° CΗ 3 ) 3.35 (s); (6 ° CΗ 3 ) 3.42 (s); (8Η, phenyl) 7.4 (d) 7.95 (d) (2Η = CΗ) 8.3 (s). And sect (table ΚΒg); 3420 (ΟΗ), 1710 (C = 0); 1340,
20 1200, 1160, 1040 (502) 2790 (Ν__2); 3065 (ΝΗΕ3); 3215 (ΝΗ) .20 1200, 1160, 1040 (50 2 ) 2790 (Ν__ 2 ); 3065 (ΝΗΕ 3 ); 3215 (ΝΗ).
Пροмышленная πρименимοсτьIntended use
Заявляемοе сοединение Ν,Ν' - (сульφοнилди-1, 4-φенилен) бис (Ν" ,Ν"-димеτилφορмамидин) -1,2, 3 , 4-τеτρагидρο-6-меτил- 2 , 4-диοκсο-5-πиρимидинсульφοнаτ, сτимулиρуеτ κлеτοчный ме- 25 τабοлизм и οбладаеτ иммунοτροπнοй и анτимиκοбаκτеρиальнοй аκτивнοсτью и наχοдиτ πρименение в медицине в κачесτве сρедсτва для лечения леπρы, τубеρκулеза и дρугиχ иммунοде- φициτныχ забοлеваний, часτο οслοжненныχ миκοбаκτеρиальными инφеκциями.
The claimed compound is Ν, Ν '- (sulfulfyldi-1, 4-phenylene) bis (Ν ", Ν" -dimethylphammamidine) -1,2, 3, 4-tetrahydro-6-methyl-2, 4-dioxo-5-pyrimidine , sτimuliρueτ κleτοchny Me- 25 τabοlizm and οbladaeτ immunοτροπnοy and anτimiκοbaκτeρialnοy aκτivnοsτyu and naχοdiτ πρimenenie in medicine for the treatment of κachesτve sρedsτva leπρy, τubeρκuleza and dρugiχ immunοde- φitsiτnyχ zabοlevany, chasτο οslοzhnennyχ miκοbaκτeρialnymi inφeκtsiyami.
Claims
1. ╬¥,╬¥' - (╨í╤â╨╗╤î╧å╬┐╨╜╨╕╨╗╨┤╨╕-1,4-╧å╨╡╨╜╨╕╨╗╨╡╨╜) ╨▒╨╕╤ü (╬¥" , ╬¥"-╨┤╨╕╨╝╨╡╧ä╨╕╨╗- ╧å╬┐╧ü╨╝╨░╨╝╨╕╨┤╨╕╨╜) - 1, 2, 3, 4-╧ä╨╡╧ä╧ü╨░╨│╨╕╨┤╧ü╬┐-6-╨╝╨╡╧ä╨╕╨╗-2 , 4-╨┤╨╕╬┐╬║╤ü╬┐-5-╧Ç╨╕╧ü╨╕- ╨╝╨╕╨┤╨╕╨╜╤ü╤â╨╗╤î╧å╬┐╨╜╨░╧ä ╤ü╨╗╨╡╨┤╤â╤ë╨╡╨╣ ╧å╬┐╧ü╨╝╤â╨╗╤ï:1. ╬ ¥, ╬ ¥ '- (╨╨╤╤╨╗╤╨╗╤-1,4-╧å╨╡╨╜╨╕╨╗╨╡╨ ╜) ╨▒╨╕╤ü (╬ ¥ ", ╬ ¥" -╨┤╨╕╨╝╨╡╧ä╨╕╨╗- ╧å╬┐╧ü╨╝╨░╨╝╨╕╨┤╨╕ ╨╜) - 1, 2, 3, 4-╧ä╨╡╧ä╧ü╨░╨│╨╕╨┤╧ü╬┐-6-╨╝╨╡╧ä╨╕╨╗-2, 4- ╨┤╨╕╬┐╬║╤ü╬┐-5-╧Ç╨╕╧ü╨╕- ╨╝╨╕╨┤╨╕╨╜╤ü╤â╨╗╤î╧å ╧ä ╤ü╨╗╨╡╨┤╤â╤ë╨╡╨╣ ╧å╬┐╧ü╨╝╤â╨╗╤ï:
5 ╤ü╧ä╨╕╨╝╤â╨╗╨╕╧ü╤â╤Ä╤ë╨╕╨╣ ╬║╨╗╨╡╧ä╬┐╤ç╨╜╤ï╨╣ ╨╝╨╡╧ä╨░╨▒╬┐╨╗╨╕╨╖╨╝ ╨╕ ╬┐╨▒╨╗╨░╨┤╨░╤Ä╤ë╨╕╨╣ ╨╕╨╝╨╝╤â╨╜╬┐╧ä- ╧ü╬┐╧Ç╨╜╬┐╨╣ ╨╕ ╨░╨╜╧ä╨╕╨╝╨╕╬║╬┐╨▒╨░╬║╧ä╨╡╧ü╨╕╨░╨╗╤î╨╜╬┐╨╣ ╨░╬║╧ä╨╕╨▓╨╜╬┐╤ü╧ä╤î╤Ä.5 ╤ü╧ä╨╕╨╝╤â╨╗╨╕╧ü╤â╤Ä╤ë╨╕╨╣ ╬║╨╗╨╡╧ä╬┐╤ç╨╜╤ï╨╣ ╨╝╨╡╧ ä╨░╨▒╬┐╨╗╨╕╨╖╨╝ ╨╕ ╬┐╨▒╨╗╨░╨┤╨░╤Ä╤ë╨╕╨╣ ╨╕╨╝╨╝╤â╨╜╬┐╧ ä- ╧ü╬┐╧Ç╨╜╬┐╨╣ ╨╕ ╨░╨╜╧ä╨╕╨╝╨╕╬║╬┐╨▒╨░╬║╧ä╨╡╧ü╨╕╨░╨╗ ╨╜╬┐╨╣î╨╜╬┐╨╣ ╨░╬║╧ä╨╕╨▓╨╜╬┐╤ü╧ä╤î╤Ä.
2. ╨í╧Ç╬┐╤ü╬┐╨▒ ╧Ç╬┐╨╗╤â╤ç╨╡╨╜╨╕╤Å ╬¥,╬¥' - (╨í╤â╨╗╤î╧å╬┐╨╜╨╕╨╗╨┤╨╕-1, 4-╧å╨╡╨╜╨╕╨╗╨╡╨╜) ╨▒╨╕╤ü ╬¥" , ╬¥" -╨┤╨╕╨╝╨╡╧ä╨╕╨╗╧å╬┐╧ü╨╝╨░╨╝╨╕╨┤╨╕╨╜) -1,2,3, 4-╧ä╨╡╧ä╧ü╨░╨│╨╕╨┤╧ü╬┐-6-╨╝╨╡╧ä╨╕╨╗-2 , 4- ╨┤╨╕╬┐╬║╤ü╬┐-5 -╧Ç╨╕╧ü╨╕╨╝╨╕╨┤╨╕╨╜╤ü╤â╨╗╤î╧å╬┐╨╜╨░╧ä╨░ ╤ü╨╗╨╡╨┤╤â╤Ä╤ë╨╡╨╣ ╧å╬┐╧ü╨╝╤â╨╗╤ï2. ╨╨╧Ç╬┐╤╬┐╨▒╬┐╨▒ ╧Ç╬┐╨╗╤â╤ç╬Å ╬ ¥, ╬ ¥ '- (╨ (╤╤╨╗╤╨╗╤╧ ╬┐╨╜╨╕╨╗╨┤╨╕-1, 4-╧å╨╡╨╜╨╕╨╗╨╡╨╜) ╨▒╨╕╤ü ╬ ¥ ", ╬ ¥" -╨┤╨╕ ╨╝╨╡╧ä╨╕╨╗╧å╬┐╧ü╨╝╨░╨╝╨╕╨┤╨╕╨╜) -1,2,3,4-╧ä╨╡╧ä╧ü╨░ ╨│╨╕╨┤╧ü╬┐-6-╨╝╨╡╧ä╨╕╨╗-2, 4- ╨┤╨╕╬┐╬║╤ü╬┐-5 -╧Ç╨╕╧ü╨ ╕╨╝╨╕╨┤╨╕╨╜╤ü╤â╨╗╤î╧å╬┐╨╜╨░╧ä╨░ ╤ü╨╗╨╡╨┤╤â╤Ä╤ë╨╡╨╣ ╧ å╬┐╧ü╨╝╤â╨╗╤ï
╨« ╧Ç.1, ╧ç ╨░ ╧ü ╨░ ╬║ ╧ä ╨╡ ╧ü ╨╕ ╨╖ ╤â ╤Ä ╤ë ╨╕ ╨╣ ╤ü ╤Å ╧ä╨╡╨╝, ╤ç╧ä╬┐ ╨╜╨░╨│╧ü╨╡╨▓╨░╤Ä╧ä ╤ì╬║╨▓╨╕╨╝╬┐╨╗╨╡╬║╤â╨╗╤Å╧ü╨╜╬┐╨╡ ╬║╬┐╨╗╨╕╤ç╨╡╤ü╧ä╨▓╬┐ ╨┤╨╕╨░╨╝╨╕╨╜╬┐╨┤╨╕╧å╨╡╨╜╨╕╨╗╤ü╤â╨╗╤î╧å╬┐╨╜╨░ ╨╕ 6-╨╝╨╡- ╧ä╨╕╨╗-5-╤â╧ü╨░╤å╨╕╨╗╤ü╤â╨╗╤î╧å╬┐╧ç╨╗╬┐╧ü╨╕╨┤╨░ ╨▓ ╨┤╨╕╨╝╨╡╧ä╨╕╨╗╧å╬┐╧ü╨╝╨░╨╝╨╕╨┤╨╡ . ╨ “╧Ç.1, ╧ç ╨░ ╧ü ╨░ ╬║ ╧ä ╨╡ ╧ü ╨╕ ╨╖ ╤â ╤Ä ╤ë ╨╕ ╨╣ ╤ü ╤Å ╧ä╨╡╨╝, ╤ç ╧ä╬┐ ╨╜╨░╨│╧ü╨╡╨▓╨░╤Ä╧ä ╤ì╬║╨▓╨╕╨╝╬┐╨╗╨╡╬║╤â╨╗╤Å╧ü╨╜ ╬┐╨╡ ╬║╬┐╨╗╨╕╤ç╨╡╤ü╧ä╨▓╬┐ ╨┤╨╕╨░╨╝╨╕╨╜╬┐╨┤╨╕╧å╨╡╨╜╨╕ ╨╗╤ü╤â╨╗╤î╧å╬┐╨╜╨░ ╨╕ 6-╨╝╨╡- ╧ä╨╕╨╗-5-╤â╧ü╨░╤å╨╕╨╗╤ü ╨╕╨┤╨░â╨╗╤î╧å╬┐╧ç╨╗╬┐╧╨╕╨┤╨░╨╕╨┤╨░ ╨▓ ╨┤╨╕╨╝╨╡╧ä╨╕╨╗╧å╬┐╧ü╨╝╨░ ╨╝╨╕╨┤╨╡.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA200000370A EA002153B1 (en) | 1997-10-07 | 1998-10-05 | N,n'-(sulphonyldi-1,4-phenilen) bis(n'',n''-dimethylformamidin)-1,2,3,4-tetrahtdro-6-methyl-2,4-dioxo-5-pyrimidinsulphonate for stimulating cellular metabolism and having an immunotropic and anti-bacterial activity and method for producing the same |
| UA2000052577A UA46163C2 (en) | 1997-10-07 | 1998-10-05 | N, N '- (SULPHONYLDY-1,4-PHENYLENE) BIS (N ", N" -DIMETHYLFORMAMIDINE) -1,2,3,4-TETRAHYDRO-6-METHYL-2,4-DIOXO-5-PYRIMIDIONYSUL STIMULATES CELLULAR METABOLISM AND HAS IMMUNOTROPIC AND ANTIMYCOBACTERIAL ACTIVITY, AND THE METHOD OF OBTAINING IT |
| AU14476/99A AU1447699A (en) | 1997-10-07 | 1998-10-05 | N,n'-(sulphonyldi-1, 4-phenylen) bis (n'',n''- dimethylformamidin)-1, 2,3,4-tetrahydro- 6-methyl-2, 4-dioxo-5-pyrimidinsulphonate for stimulating cellular metabolism and having an immunotropic and anti-bacterial activity and method for producing the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU97117514 | 1997-10-07 | ||
| RU97117514A RU2136668C1 (en) | 1997-10-07 | 1997-10-07 | N,n'-(sulfonyldi-1,4-phenylene)-bis-(n'',n''-dimethylform- -amidine)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-5-pyrimidine sulfonate stimulating cellular metabolism and showing immunotropic and antibacterial activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999018083A1 true WO1999018083A1 (en) | 1999-04-15 |
Family
ID=20198302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU1998/000314 WO1999018083A1 (en) | 1997-10-07 | 1998-10-05 | N,n'-(sulphonyldi-1, 4-phenylen) bis (n'',n''- dimethylformamidin)-1, 2,3,4-tetrahydro- 6-methyl-2, 4-dioxo-5-pyrimidinsulphonate for stimulating cellular metabolism and having an immunotropic and anti-bacterial activity and method for producing the same |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU1447699A (en) |
| EA (1) | EA002153B1 (en) |
| RU (1) | RU2136668C1 (en) |
| UA (1) | UA46163C2 (en) |
| WO (1) | WO1999018083A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001032650A2 (en) * | 1999-11-05 | 2001-05-10 | Alexandr Leonidovich Reshetov | Alkaline salts of n-(6-alkyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone)-n'-isonicotinoylhydrazide, possess for their preparation, and pharmaceutical composition based on these salts |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005092344A1 (en) * | 2004-03-26 | 2005-10-06 | Zakrytoe Aktsionernoe Obschestvo 'novaya Linia' | Medicinal preparation |
| RU2550948C1 (en) * | 2014-06-20 | 2015-05-20 | Общество с ограниченной ответственностью "Научно-внедренческий центр "Агроветзащита" | N,n'-(sulphonyldi-p-phenylene)bis-n",n"- dimethylformamidine, possessing acaricidal action |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1511517A (en) * | 1974-09-18 | 1978-05-17 | Sirius | Alpha-(diethylamino)-propiophenone orotate a process for its preparation and its use in pharmaceutical compositions |
| SU687074A1 (en) * | 1978-01-06 | 1979-09-25 | 2-Московский Ордена Ленина Государственный Медицинский Институт Им. Н.И.Пирогова | 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine possessing antileprotic and anticonvulsive activity |
| RU2044728C1 (en) * | 1990-08-21 | 1995-09-27 | Научно-исследовательская лаборатория иммунохимиотерапии лепры с опытно-экспериментальным производством иммуномодуляторов и клиниками ИДС | Isonicotinic acid hydrazide orotate having antibacterial and immunotropic activities |
-
1997
- 1997-10-07 RU RU97117514A patent/RU2136668C1/en not_active IP Right Cessation
-
1998
- 1998-10-05 EA EA200000370A patent/EA002153B1/en not_active IP Right Cessation
- 1998-10-05 UA UA2000052577A patent/UA46163C2/en unknown
- 1998-10-05 AU AU14476/99A patent/AU1447699A/en not_active Abandoned
- 1998-10-05 WO PCT/RU1998/000314 patent/WO1999018083A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1511517A (en) * | 1974-09-18 | 1978-05-17 | Sirius | Alpha-(diethylamino)-propiophenone orotate a process for its preparation and its use in pharmaceutical compositions |
| SU687074A1 (en) * | 1978-01-06 | 1979-09-25 | 2-Московский Ордена Ленина Государственный Медицинский Институт Им. Н.И.Пирогова | 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine possessing antileprotic and anticonvulsive activity |
| RU2044728C1 (en) * | 1990-08-21 | 1995-09-27 | Научно-исследовательская лаборатория иммунохимиотерапии лепры с опытно-экспериментальным производством иммуномодуляторов и клиниками ИДС | Isonicotinic acid hydrazide orotate having antibacterial and immunotropic activities |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001032650A2 (en) * | 1999-11-05 | 2001-05-10 | Alexandr Leonidovich Reshetov | Alkaline salts of n-(6-alkyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone)-n'-isonicotinoylhydrazide, possess for their preparation, and pharmaceutical composition based on these salts |
| WO2001032650A3 (en) * | 1999-11-05 | 2002-05-10 | Alexandr Leonidovich Reshetov | Alkaline salts of n-(6-alkyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone)-n'-isonicotinoylhydrazide, possess for their preparation, and pharmaceutical composition based on these salts |
Also Published As
| Publication number | Publication date |
|---|---|
| EA200000370A1 (en) | 2000-10-30 |
| RU2136668C1 (en) | 1999-09-10 |
| AU1447699A (en) | 1999-04-27 |
| EA002153B1 (en) | 2001-12-24 |
| UA46163C2 (en) | 2002-05-15 |
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