WO2000029389A1

WO2000029389A1 - 6-(3-carboxymethylphenyl)-aminouracyl having a biological activity

Info

Publication number: WO2000029389A1
Application number: PCT/RU1998/000387
Authority: WO
Inventors: Elena Alexandrovna Izaxon
Original assignee: Elena Alexandrovna Izaxon
Priority date: 1998-11-18
Filing date: 1998-11-18
Publication date: 2000-05-25
Also published as: AU2645299A; RU2207337C2; RU2001114504A

Abstract

The present invention pertains to the field of medicine, more precisely to that of pharmacology, and essentially relates to synthetic biologically active substances. This invention can be used for treating viral diseases induced by chlamydiae as well as accompanied with immunodeficiency, mainly malignant tumours. The compound of the present invention can further be used in veterinary medicine. The purpose of this invention is to create a new substance that stimulates the production of endogenous interferons and has an antiviral activity, i.e. an immuno-stimulating and antiviral action. To this end, this invention provides the synthesis of a new derivative of 6-aminouracyl, namely a 6-(3-carboxymethylphenyl)-aminouracyl. This chemical compound of the heterocyclic series belongs to a new group of the class of substituted 6-aminopurines and corresponds to formula (1). This invention also relates to a synthesis example, to identifications and to experimental results concerning the definition of the antiviral and immuno-modulating activities and of the toxicity of this compound relative to known substances used for the same purposes.

Description

ννθ 00/29389 ΡСΤ / Κϋ98 / 00387

ΜΚand 6

6- (3-carboxymethylphenyl) aminouracil, which is biologically active.

The area of technology.

The invention is related to medicine, more specifically, to pharmacology, veterinary medicine; Comparative - a synthetic, biologically active, 6-aminouracil-derived, which is potent and immune-stimulating. The aforementioned derivative has an expressed activity as an industry, as well as an activity in case of viruses of an outgrowth. The main purpose of the compound is to be used in medical practice. The compound is indicated for the treatment of viral diseases caused by chlamydia, as well as diseases that are associated with immunodeficiency, in particular, malignant diseases. Otherwise, the recommended connection may be used in veterinary medicine - for the same purpose. Level of technology.

One of the most serious problems of modern medicine is diseases caused by microbes. The treatment of infections caused by viruses is very difficult due to the lack of effective drugs and the variability of the viruses. As it is known, in the fight against viral and bacterial diseases, an important role is played by the interactions produced by the cells of the organism [1]. For the treatment of microscopic infections, both exogenous bacteria and endogenous bacteria are used. The number of recent ones is limited. One of the most urgent problems of combating microbial diseases is the creation of new drugs, which are useful for the induction of synthesis in the human body of an industrial accident. It is also well-known that the stimulation of the synthesis of interactions with the body helps to fight against the malignant malignancies [1].

Certain 6-aminouracil derivatives are known [2-7]. Β parts in operation Μ. Β .Kubtsova and others. [7] Allacyl (1-allyl-3-ethyl-6-aminouracil) is described as an active diuretic, which is used as a urea and is associated with an intermittent injury. This site is listed below. \ ΥΟ 00/29389 ΡСΤ / ΚШ8 / 00387

For certain 6-amine derivatives, specific biological activity is indicated, which is described, in particular, in the work of D. D. Μashkovskogo [5] - see, for example, 6- [[3- [4- (2-Methoxyphenyl) -1- π-pyrazinyl] προπyl] -amino] -1,3-dimethyl-acyl. In general, chemical, structural analogs of the new product are the derivatives of the 6-amine formula of the general formula

where Κ = phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-bromophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2-methylphenyl, 3-methylphenyl, 1-on , 2-naphthyl, cyclohexyl [6]. Known sources of information do not contain information about any expressed biological activity. The closest to the claimed compound is a chemical structure -

6 - [[3- [4- (2-Methoxyphenyl) -1-pyrprazinyl] προπyl] amine] -1,3-dimethyl uracyl, structured below, is given below.

It has already been noted that this compound is described in [5]. It indicates a hypotensive effect. Conventionally indicated medication is used to reduce the arterial pressure and the hypercritical pressure. Other applications of the product for the accessible sources of information are unknown to us. They were chosen by us on a commercial basis. \ νθ 00/29389 ΡСΤ / Κυ98 / 00387

OBJECT OF THE INVENTION

The objective of the invention is the creation of a new substance that stimulates the production of endogenous interactions, as well as a non-hazardous, non-immune substance.

SUMMARY OF THE INVENTION

The posed problem is solved by the synthesis of a new product

6-aminouracil, and named-6- (3-carboxymethylphenyl) aminouracil. This chemical compound of the hetero-cyclic series is not related to the new group of the substituted 6-amine group.

The compound has a chemical formula (1)

DSP and the results of the analysis of the plate, more than 300 ° C. The connection structure has been proven by the method of

(Immediate Magnetic Resonance).

The claimed connection is new - there is no information in it from any of the available sources of information.

Zayavlyaemοe sοedinenie and egο biοlοgichesκaya aκτivnοsτ neοchevidny for sπetsialisτa, isχοdya iχ πρivedennyχ above information οb analοgaχ and προτοτiπe having biοlοgichesκuyu aκτivnοsτ in sοveρshenο dρugοy οblasτi, niκaκ οchevidnym οbρazοm not svyazannοy with the task izοbρeτeniya.

Obtaining an original and effective biological substance

- A useful result of a large number of experiments, experience and intuition.

SUMMARY OF THE INVENTION The following explains:

An example is a synthesis of the claimed substance and the results of its identification,

Exactive studies of the biological activity of the connected compounds, α named: EXPERIMENT 1. Investigation of the anti-virus activity (the activity of the connected connection)

EXPERIMENT 2. Investigation of the intrinsic activity of the claimed compounds,

EXCEPTION 3. DISTRIBUTION OF ORDER TOXICITY, \ νθ 00/29389 ΡСΤ / ΚШ8 / 00387

Бαbliiα 1. The effect of the claimed compounds on the virus of a simple group and the concentration of the tested compounds 100 mg / l,

2. Ταbliiα Κοlichesτvennaya οtsenκa IΦΗ - indutsiρuyuschey aκτivnοsτi zayavlyaemοgο sοedineniya: sοdeρzhanie IΦΗ in induκtsiοnnοy ποsle mixture 24 chasοv inκubatsii πρi ρazlichnyχ κοntsenτρatsiyaχ πρeπaρaτοv, ΜΕ / 3 * ¹⁰ April limφ / ml..

The synthesis of the claimed compounds.

The method of obtaining the target product is based on the interaction of a 6-coolant with the corresponding aromatic amine in the process.

For example, a synthesis of a compound. Κ 10 g of hydrochloride methyl ester of m-aminobenzoic acid and 10 g of amine add 6 g of 6-aminouracil and thoroughly dissolve the mixture in the mixture. When heated to 160 ° С, the mixture is melted and becomes easily movable, but already after 0.5 hours it has stopped, the heating has been stopped for 1.5 hours, the mixture is allowed to be washed. Re-installation from a mixture of isopropanol-DΜΦΜ (1: 1) produces a target product. The structure of the obtained compound is proved by using the method of nucleation on the nucleus ^! Η and S. In the sector ΜΡ are signals of the primary group of the pyrimidine ring in the region of 10-12 ppm and metropolitan areas of the pyridine ring 4-6 ppm ΜΡ SPECTRACHA ΜΡ ¹³ C are characteristic signals from ³ 70-100 ppm. - for carbon atoms of the aryl ring.

Exceptional research on the biological activity of the connected compound.

Examination U. The study of anti-virus activity (the actions of the claimed connection to the virus). Antiviral activity was studied in relation to the resistance to the type I virus type on a transplantable cell culture. Experiment circuitry.

The caterpillar was added to the cages with a medium ΚΡΜΙ-1640, containing 10% of calf food, which were received in a 96-well payment. The initial concentration of the virus is 10-12 particles per ml. The concentration of material and research χ was 100, 10 and 1 mg / l. After incubation at 38 ° С in the СΟ2-incubator, the virus was removed and the medium was changed. The results were evaluated by the virulent effect of the virus on the cells after incubation at 38 ° C in the SΟ2-incubator for 36 hours. \ νθ 00/29389 ΡСΤ / ΚШ8 / 00387

Бαbliiα 1. The effect of the claimed compounds on the virus of a simple group and the concentration of the tested compounds 100 mg / l

* number of unapproved cells

The results indicate that the claimed connection possesses anti-reactive activity, which is comparable to that of the most popular drug -.

EXPERIMENT 2. Investigation of the intrinsic activity of the claimed compounds.

The induction of the synthesis of the compounds of the claimed preparation was carried out on the human culture of human lymphocytes. A fresh health facility was used (no more than 12 hours after the fence). Allocation of the limbs was carried out as follows. The integrated circuit of the center was located in a density range of 1.71 g / cm ^l for the density of the fiber unit to isolate the function of the immune cells. The indicated fraction after its treatment was divorced from a healthy environment ΚΡΜΙ-1640. The indicated nutritional product consisted of 5% fetal calf serum, 0.3 mg / ml L-glutamine, 100 units / ml penicillin, 50 mg / ml strutomycin. Lymphocytes were overwhelmed with methyl blue in the chamber of Goryaev, after which they shared their accentuation. Concentrations of substances, after the corresponding dilutions of the original compounds of the claimed substances of healthy medium ΚΡΜΙ-1640, were made in the range: 100 mg / l, 10 mg / l, 1 mg / l, 1 mg The final concentration of lymphocytes in the industrial mixture was 3 * 10 ^b cells / ml. Incubation of commercial and experimental products took 24 hours at 37 ° С.

Then they were planted in 2000 § for the precipitation of cellular elements. From προb οτbiρalsya IΦΗ-sοdeρzhaschy suπeρnaτanτ, κοτορy analiziροvalsya on κοlichesτvennοe sοdeρzhanie IΦΗ. Οsadοκ κleτοκ ρesusπendiροvali in πρezhnem οbeme πiτaτelnοy sρedy, οκρashivali viτalnym κρasiτelem - τρiπanοvym blue - and ποdschiτyvali chislο κleτοκ in κameρe Gορyaeva (κaκ οπisanο above) for οπρedeleniya tsiτοτοκsichesκοgο deysτviya πρeπaρaτοv. The private division of the content of the test equipment into commercial and experimental samples was carried out using an immunodeficiency test system \ νθ 00/29389 ΡСΤ / ΚШ8 / 00387

ΡgοSοη GΡ2 ρϊsh (προizvοdsτva ΤΟΟ "Pροτeiiοvy κοnτuρ" πρednaznachennοy for οπρedeleniya IΦΗ-a. To οπρedeleniya κοlichesτva inτeρφeροna in προbe isποlzοvali τveρdοφazny immunοφeρmenτny meτοd with isποlzοvaniem πeροκsidazy χρena in κachesτve indiκaτορnοgο φeρmenτa. Ακτivnοsτ svyazannοy πeροκsidazy izmeρyali with ποmοschyu avτοmaτichesκοgο φοτοmeτρa for miκροπlansheτοv with miκροπροtsessοροm πρi wavelength 450 nm.

In parallel, they shared the activity of standard products with standard products containing a known quantity of the drug. On the basis of the results obtained, a calibrated calibration was made. Ηa οsnοvanii κalibροvοchnοy κρivοy with ποmοschyu miκροπροtsessορa avτοmaτichesκοgο φοτοmeτρa ποlucheny data vyρazhennye in Μezhdunaροdnyχ Εdinitsaχ (ΜΕ) aκτivnοsτi IΦΗ per ml in dannοy induκtsiοnnοy sisτeme, sοdeρzhaschey limφοtsiτοv 3x10 ⁶ / ml. Each experimental and contact point was studied in 4 parallel parameters.

As a result of the above studies, it was found that the claimed compound has the ability to induce the synthesis of INF (Table 2).

Ταbliiα 2.Κοlichesτvennaya οtsenκa IΦΗ-indutsiρuyuschey aκτivnοsτi zayavlyaemοgο sοedineniya:. Sοdeρzhanie IΦΗ in induκtsiοnnοy mixture ποsle 24 chasοv inκubatsii πρi ρazlichnyχ κοntsenτρatsiyaχ πρeπaρaτοv, ΜΕ / 3 * ¹⁰ April limφ / tϊ.

EXPERIMENT 3. Separation of the toxicity.

Separation of simple toxicity was produced for free white mice weighing 18-20 g. Emulsions of the claimed compounds were prepared in different concentrations: 1500, 20, 5, 500, 100 mg. For the study of each concentration of the compound, 5 live animals were used. The drug was injected one after the other through or through the internal. The follow-up period was 14 days. On days 1, 8, and 15, weighed the animals in each group. For control \ νθ 00/29389 ΡСΤ / ΚШ8 / 00387

We used live animals, which introduced an emulsion, prepared without tested compounds.

For a great study of the internal groups, all the living things that died in the course of experience and survived at the end of the experiment were brought to fruition.

The claimed compound has a low rate of rapid toxicity (L ₅ ο) - 470 mg / kg.

The results obtained testify that, in addition, through or in the abovementioned percentages, the claimed connection does not predominate in any case.

Intended use.

The inventive connection is subject to the possibility of interruption in the use of medical devices, medications, and medical devices. The results of the analysis show that the common methods of contact are used to clearly identify them.

Eκsπeρimenτy πο οπρedeleniyu biοlοgichesκοy aκτivnοsτi, πρivedennye in πρedsτavlennyχ οτcheτaχ, ποκazali, chτο claimed sοedineniya οbladayuτ biοlοgichesκοy aκτivnοsτyu πο οτnοsheniyu κ viρusu προsτοgο geρπesa and τaκzhe inτeρφeροnindutsiρuyuschey aκτivnοsτyu. The latter is indicated for the possibility of their use in the treatment of other viral and some common diseases. In this case, through or through the internal connection in the indicated concentrations, the claimed compound does not have a direct toxicity to mice. Pρivedennye information ubediτelnο dοκazyvayuτ dοsτizhenie tasks ποsτavlennyχ izοbρeτeniem: sοzdanο nοvοe biοlοgichesκi aκτivnοe veschesτvο, sτimuliρuyuschee vyρabοτκu endοgennyχ inτeρφeροnοv and τaκzhe having προτivοviρusnuyu aκτivnοsτ, το esτ οbladayuschegο immunοsτimuliρuyuschim and προτivοviρusnym deysτviem. The problem was solved by the synthesis of a new 6-aminouracil - a chemical compound of a heterocyclic series. The resulting material is 6- (3-carboxymethylphenyl) aminouracil - there is a new group from the class of substituted 6-aminepurines. As it was indicated in the section “The Essence of the Invention”, it is new and not obvious.

In our opinion, in our opinion, the claimed material satisfies all the requirements of the invention: it is new, not obvious and intentionally used. \ νθ 00/29389 ΡСΤ / ΚШ8 / 00387

Literature

1. Ερшов Φ.I. The system is interfaced in news and practice. Medicine, Russia, 1996, 240 pp.

2. Α.S. СССΡ Νο 170061, ΜΚИ4 СΟ7ϋ 239/10, published on BI Νο 08 - 65.

3. Α.S. СССΡ Νο 176910, ΜΚИ4 С07ϋ 239/10, published on BI Νο 24 - 65

4. Application ΦΡГ Νο 206453.

5. Μ. D. Kashkovsky. MEDICINES. 4.1. Russia, Medicine, 1993, p. 550 - pp. 142;

// Αηη.Set., 1966, Λз 698, ρ. 145;

// Αηη.Set., 1966, 699, ρ. 145. 7.Kubtsov Μ.Β., Baychikov Α.G. Synthetic Chemicals and Pharmaceuticals, Moscow, .Medicine, 1971, p. 255

Claims

\ УΟ 00/29389 ΡСΤ / ΚШ8 / 00387

ΦΟΡΜУЛΑ ИБΟБΡΕΤΕΗИЯ

6- (3-carboxymethylphenyl) aminouracil formula

biologically active