Naphthoquinone derivatives and their applying for treatment and control of tuberculosis

FIELD: organic chemistry, medicine, phthisiology.

SUBSTANCE: invention proposes applying naphthoquinone derivatives for treatment and/or control of tuberculosis caused by Mycobacterium tuberculosis and a method for tuberculosis treatment. The claimed naphthoquinone derivatives are known as extracts from South Africa medicinal plants, for example, diospyrin and O-juglone. Indicated compounds are effective as against strains that are sensitive to M. tuberculosis and strains that are resistant to isoniazid and rifampicin or strains with the multiple resistance.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl

 

Background of the invention

This invention relates to the treatment and control of tuberculosis, caused by Mycobacterium tuberculosis, and in particular to the use of naftochinona derivatives for such care and control.

Tuberculosis (TB) remains a serious health problem in many regions of the world, particularly in developing countries. He is an infectious disease and is reaching epidemic proportions in some parts of the world. Estimated 30-60% of the adult population in developing countries is infected with Mycobacterium tuberculosis. Approximately 8-10 million people develop clinical TB and 3 million die each year from TB (WHO/IUATLD, 1989).

In South Africa, more than 3 out of every thousand people die from TB - the highest percentage in the world, with one out of every 200 people suffers from active tuberculosis. Tuberculosis is the most recorded disease in South Africa and is in fifth place of the most serious causes of death among the black population (South African Tuberculosis Association, 1998).

In the United States, the number of TB cases has steadily decreased until 1986, when it was noted the increase. Since then, the number of TB cases continues to grow. Ten million people infected in the United States, with approximately 26000 new cases of active disease each year (National Jewish Medical and Research Center, 1994).

People infected with the virus IMM is nondeficit human (HIV), very susceptible to tuberculosis, and the disease often develops before become apparent other manifestations of AIDS (Grange and Davey, 1990). The epidemic of TB associated with HIV infection, obviously depends on appropriate TB treatment and possibly from the effective chemical prevention not only for HIV-infected people, but also for society in General (WHO/IUALTD, 1989).

Therapy TB has undergone a revolution in the existing system of TB treatment based on multidrug therapy usually 3 or 4 anti-TB drugs. However, the problem arises of multidrug resistance of tubercle bacilli to various drugs, such as isoniazid, ethambutol, rifampicin, and streptomycin (Girling, 1989; Grange and Davey, 1990). Drug-resistant TB is difficult to treat, requiring a greater number and variety of drugs over a longer period of treatment. The need for new anti-TB agents is urgent due to the increasing resistance of bacteria to these classic anti-TB drugs. In a recent WHO report notes that a total of 2% of all cases of tuberculosis are megalokastro stable, which is determined by the resistance to rifampicin plus isoniazide (plus/minus other sustainability). Such cases can Le is to build in the U.S. and other developed countries, but with a high cost (in each case a>250000 USD!) and using very long courses of treatment are quite toxic drugs, putting a major problem of compliance with the requirements of the world health organization (who) (WHO, 1997). South Africa is evidence of an explosion in the number of cases of drug resistant tuberculosis. In some parts of South Africa, 1 out of 10 cases of TB is resistant to treatment (New Scientist, March 1997). It is quite possible to have new anti-TB agents, preferably those which can be easily obtained from some local sources.

Brief description of the invention

According to the first aspect of the invention provides nattokinese derived formula 1

in which R is the HE group, methyl simple ether, ethyl simple ether or similar ether;

R1 is stands, ethyl or similar aliphatic hydrocarbon derivative;

R2 and R3 each independently is hydrogen or a group selected from the

in which R5 is a group, methyl simple ether, ethyl simple ether or similar ether and R6 is stands, ethyl or similar aliphatic uglevodorodnogo; R4 is hydrogen or a group selected from the

in which R7 is HE group, methyl simple ether, ethyl simple ether or similar ether and R8 is stands, ethyl or similar aliphatic hydrocarbon derivative;

or its pharmaceutically acceptable salt for use in the method of treatment and/or TB patients, caused by Mycobacterium tuberculosis.

According to the second aspect of the invention provides the use of naftochinona derivative having the formula 1, above, in the manufacture of pharmaceutical preparations for the treatment and/or TB patients, caused by Mycobacterium tuberculosis.

According to a third aspect of the invention provides a method of treating and/or TB, caused by Mycobacterium tuberculosis, comprising the administration to a patient in need, an effective amount naftochinona derivative having the formula 1, above.

Nattokinese derivative of formula 1 in a typical case is a compound of formula 1A or formula 1b

in which R and R1 have the meanings defined for formula 1 above.

R in the compound of formula 1A or 1b is the tsya preferably IT is a group.

R1 in the compound of formula 1A or 1b is preferably CH3group.

In particular, naftochinona derivative of formula 1 is 5,5'-dihydroiso-7,7'-binaphthyl (diaspirin) or 5-hydrocity-7-methyl-1,4-naphthoquinone (metroplan).

Description of the preferred versions of the invention

The present invention is directed to the use of naftochinona derivatives for the treatment and/or TB, caused by Mycobacterium tuberculosis. In particular found that nattokinese derivatives of General formula 1

in which R is the HE group, methyl simple ether, ethyl simple ether or similar ether;

R1 is stands, ethyl or similar aliphatic hydrocarbon derivative;

R2 and R3 each independently is hydrogen or a group selected from the

in which R5 is a group, methyl simple ether, ethyl simple ether or similar ether and R6 is stands, ethyl or similar aliphatic hydrocarbon derivative; R4 is hydrogen or a group selected from the

in which R7 is HE group, methyl simple ether, E. the silt simple ether or similar ether and R8 is stands, the ethyl or similar aliphatic hydrocarbon derivative;

effective against Mycobacterium tuberculosis.

Found that particularly effective specific nattokinese derivatives of formulas 1A and 1b

In particular found that diaspirin (diospyrin) and metroplan (methyljuglone), nattokinese derivatives of formula 1A and formula 1b, respectively, in which R is HE and R1 is a methyl group, inhibit several are resistant to the antibiotic, and susceptible to the antibiotic strains of Mycobacterium tuberculosis. Although diaspirin (diospyrin) and metroplan (methyljuglone) is particularly preferred, are also provided nattokinese derivatives of formulas 1A and 1b, in which R is methyl ether, ethyl ether or similar ester, and R1 is ethyl or similar aliphatic hydrocarbon derivative.

Was undertaken extensive research program for the identification of anti-TB agents, which can be easily obtained from local sources.

Twenty South African medicinal plants used for the treatment of lung diseases, were investigated for activity against resistant and drug-sensitive strains of M. tuberculosis. A preliminary study of the acetone and aqueous extracts of plants against Chu is responsive to medications strain M tuberculosis H37Rv was carried out according to the method using agar plates. Fourteen of the 20 acetone extracts showed hiberus activity against this strain at a concentration of 0.5 mg/ml Acetone and water extracts Cryptocarya latifolia, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Thymus vulgaris inhibited growth of M. tuberculosis. Taking activity 14 acetone extracts in 0.5 mg/ml against drug-sensitive strain of M. tuberculosis by the method of agar plates, were carried out further research with the use of a rapid radiometric method for confirmation of inhibitory activity.

The data of the active acetone extracts was investigated against H37Rv strain and against strains resistant to drugs, isoniazid and rifampicin. Minimum inhibitory strain H37Rv concentration Croton pseudopulchellus, Ekebergia capensis, Euclea natalensis, Nidorella anomala and Polygala myrtifolia by radiometric method was 0.1 mg/ml of the Extracts of Chenopodium ambrosioides, Ekebergia capensis, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Polygala myrtifolia were active against the resistant strain at 0.1 mg/ml Eight plants showed activity against both strains at a concentration of 1.0 mg/ml

The following procedure was developed by the applicant to highlight diaspirin and metrogon from E. natalensis and other species of this genus, as well as from any other plants that can synthesize dispirin or m is truglo or other quinone derivatives.

1. Identification of plant species.

Roots and aerial parts of the plant E. natalensis were collected near Durban and identified in HGWJ Schweickerdt Herbarium of the University of Pretoria and also in the herbarium of the National Botanical Institute, Pretoria.

2. The extraction.

Dried roots of E. natalensis were crushed into powder in a dry mill and were extracted for 48 hours with acetone. The extract was filtered and concentrated to dryness on a rotary evaporator.

3. Thin-layer chromatography.

Applied direct antibacterial bioanalysis (Dilika & Meyer, 1996) on the TLC plates to accelerate the selection of anti-TB compounds in accordance with the activity. M. tuberculosis cannot be tested this way because of the very low rate of growth. Direct antibacterial bioassays acetone extract was performed on TLC plates (Merck), show a mixture of chloroform-hexane (1:1). After developing TLC plates were dried and sprayed them 24-hour culture of Staphylococcus aureus in nutrient broth. After 24-hour incubation, the plates were sprayed with an aqueous solution of 2 mg/ml p-iodonitrotetrazolium violet for visualization of bacterial cells. Plates then were incubated at 37° C for 2-3 hours. On TLC plates sprayed with S. aureus, it was possible to see two zones of inhibition of bacterial growth. The activity was more pronounced in the area of Rf,30 (chloroform-hexane (1:1)), than the area Rf0,54.

4. Column chromatography.

The crude extract of the plant was dried, is determined by its mass and re-suspended in chloroform. Column chromatography was performed on silica gel 60 using chloroform as eluent. Collected antibacterial fractions were then subjected to Sephadex LH-20 column chromatography using ethanol as eluent. The collected fractions were again tested for antibacterial activity on TLC to detect fractions containing the active compound Rf0.30 Rf0,54.

5. High-performance liquid chromatography.

The compound was further purified by HPLC using an analytical Phenomenex 250× 4,60 mm column with reversed phase, at a flow rate of 1.0 ml/min, oven temperature 40° and a wavelength of 206 nm. A solution of ethanol-water (50:50) was used as mobile phase. Net connection once was subjected to Sephadex LH-20 column chromatography and confirmed that they are clean. Data1H and13With NMR and mass spectrometry confirmed that the chemical structures represent

diaspirin (5,5'-dihydroxy-7,7'-binaphthyl); C22H14O6. Molecular weight 374,35

7-metrogon (5-hydrocity-7-IU the Il-1,4-naphthoquinone); With11H8About3. Molecular weight 188,19.

Influence diaspirin and metrogon on the growth of the sensitive strain (H37Rv) and resistant strains of Mycobacterium tuberculosis, certain radiometric method, are presented in table. 1 and 2.

Table 1
Influence diaspirin on the growth of the sensitive strain (H37Rv) and resistant strains Mycobacterlum tuberculosis, certain radiometric method
Strains Mycobaterium tuberculosisMIC (mg/ml)Δ GIavalues of plant extracts (mg/ml)Δ GI values of the control vessel (mg/ml)
Sensitive H37Rv strain0,1-1± 1,4120± 4,24
A strain that is resistant to 2 drugs (ostoich. to isoniazid and rifampicin)0,13,5± 0,7025± 7,07
Strain resistant to 3 drugs (ostoich. to streptomycin, isoniazid and ethambutol)0,14± 2,1229± 1,41
The strains resistant to 4 drugs (ostoich. to streptomycin, isoniazid, rifampicin and ethambutol)0,15± 2,8225± 2,82
Strain resistant to 5 drugs (Usto the hours to isoniazid, streptomycin, rifampicin, Thiacetazone and cycloserine)0,110± 1,4122,5± 3,53
A strain that is resistant to 6 drugs (ostoich. isoniazid, rifampicin, ethionamide, terizidone, Thiacetazone and ofloxacin)0,19± 2,8230± 1,0
A strain that is resistant to 7 drugs (ostoich. to isoniazid, streptomycin, ethambutol, kanamycin, rifampin and ethionamide)0,113,5± 3,228± 3,1
aΔGI values are average ± standard deviation

Table 2
The influence of 7-metrogon as a single agent and in combination with diaspirin on the growth of the sensitive strain H37Rv and resistant strains of Mycobacterium tuberculosis, certain radiometric method.
Strains of Mycobacterium tuberculosisLaboratory reference numberConnectionMICa(ág/ml)Δ GIbvalues of plant extractsΔ GI values of the control vessel
Sensitive H37Rv strainATS7-Metrogon 500± 115± 3,78
A strain that is resistant to 2 drugs (isoniazid and rifampicin)CCK28469V7-Metrogon500± 030± 4,94
Sensitive H37Rv strainATSDiaspirin+ 7-metrogon103± 115± 3,78
A strain that is resistant to 2 drugs (isoniazid and rifampicin)CCK028469VDiaspirin+ 7-metrogon103,33± 3,0530± 4,94
andMinimum inhibitory concentration

bΔGI values are average ± standard deviation

The results show that diaspirin and metroplan effective against Mycobacterium tuberculosis. Or for the treatment of TB in the typical case will be used for oral administration dispirin or metrogon in suitable pharmaceutical compositions with suitable diluents and carriers. This will be tablets, liquids, or similar oral dosage forms because diaspirin and metroplan easily absorbed in the intestine.

However, it is believed that dispirin or metrogon, intravenous or nutramigen is, will also be effectively absorbed via the blood vessels and the blood flow of the patient.

Transcutaneous introduction, using tape or similar media for intradermal injection, is also possible.

It is also envisaged combinational treatment diaspirin and methyleugenol, which can be more effective compared with treatment in one of two naftochinona.

The applicant believes that it is possible to increase the concentration diaspirin, metrogon or other quinones in E. natalensis or similar using phytoalexins stimulation or biotechnological manipulation of tissue cultures and/or intact plants.

In the General case, the quinones are synthesized from catechin (1,2-quinones) or hydroquinone (1,4-quinones) mild oxidation

As far as the applicant was able to install diaspirin was once synthesized in laboratory conditions (Yoshida, M. and Mori, K. 2000. European Journal of Organic Chemistry, pp. 1313-1317). However, a similar unattaching can be also synthesized by the reaction plumbagin (94 mg in methanol, 10 ml) and hydroquinone (190 mg in methanol and 14 ml), buffered with phosphate to pH 6.8 at 30° (Sankaram et al. 1975; Kumari et al. 1982).

It should be assumed that diaspirin, metroplan and related nattokinase derivatives are isnsp is capable alternatives to traditional medicine in the treatment and TB control person.

1. Application naftochinona derivative having the formula 1

in which

R is IT the group;

R1 is stands;

R2 and R3 each independently is hydrogen or a group selected from the

in which R and R1 have the meanings defined above;

R4 is hydrogen or a group selected from the

in which R and R1 have the meanings defined above;

or its pharmaceutically acceptable salts, as agent of the pharmaceutical composition for treatment and/or control in patients with tuberculosis caused by Mycobacterium tuberculosis.

2. The use according to claim 1, wherein naftochinona derivative of formula 1 is a compound of formula 1A or formula 1b

in which R and R1 have the meanings defined for formula 1 in claim 1.

3. The use according to claim 1, wherein naftochinona derivative of formula 1 is 5,5'-dihydroiso-7,7'-binaphthyl or 5-hydrocity-7-methyl-1,4-naphthoquinone or a mixture.

4. The method of treatment is the development and/or TB, caused by Mycobacterium tuberculosis, including an introduction to the needy in this patient an effective amount of naftochinona derivative having the formula 1

in which R is IT the group;

R1 is stands;

R2 and R3 each independently is hydrogen or a group selected from the

in which R and R1 have the meanings defined above;

R4 is hydrogen or a group selected from the

in which R and R1 have the meanings defined above;

or its pharmaceutically acceptable salt.

5. The method according to claim 4, in which nattokinese derivative of formula 1 is a compound of formula 1A or formula 1b

in which R and R1 have the meanings defined for formula 1 in paragraph 4.

6. The method according to claim 4, in which naftochinona derivative of formula 1 is 5,5'-dihydroiso-7,7'-binaphthyl (diaspirin) or 5-hydrocity-7-methyl-1,4-naphthoquinone (metroplan) or their mixture.

7. The method according to claim 4, in which nattokinese produced is water formula 1 is administered orally, intravenous, intramuscular, or intradermal.



 

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