The way to obtain macrocyclic compounds

 

(57) Abstract:

Usage: agriculture as nematodes for the treatment of animals and people affected endoparasites and/or fungal infection, and as a pesticide. The inventive product - macrocyclic compounds f-crystals of I are given in the description, where R1=CH3C2H5or ISO - C3H7, R2and R3= H, OR4= OH, OCH3C1-C6= alkanoyloxy, optionally substituted fenoxaprop or -- OCOOR5where R5- C1-C5- alkyl. Reagent 1: compound f-ly I, where R2and R3together form an L-group, where L = R OCOSO-group, where R-(C1-C6) = alkyl)phenyl or phenyl, OR4= OH. Reagent 2: tin-hydraulical, as for example tert. -n butylaldehyde. Reaction conditions: in the presence of initiator radicals, as for example, azobisisobutyronitrile, or under the action of light, and the compound obtained f-ly I, where OR4=OCH3or C1-C6- alkanoyloxy, optionally substituted phenoxypropane, and if necessary translate it in connection f-ly 1, where OR4- OH, which, if necessary, by the action of galodamadruga acid transferred in the table 2.

The invention relates to a method of obtaining new compounds with antibiotic.

Known to produce antibiotics S541, which can be distinguished from the products of fermentation of Streptomyces species. Antibiotics S541 are a group of related compounds having the partial formula I

So, was identified an additional group of compounds with antibiotic activity, which can be obtained through chemical modification of antibiotics S541 or by selecting them from the culture of microorganisms of the genus Streptomyces.

The new compounds of the proposed method have antibiotic activity and/or are used as intermediate products in the production of other active compounds and/or selecting or clearing the compounds of antibiotics S541.

The compounds of this invention represent a 23-deoxy and 23-hydroxyl or substituted hydroxyl analogues of antibiotics S541, which have a hydroxyl or substituted hydroxyl group in position 5.

Thus, this invention proposes, in particular, the compounds of formula II

where R1is methyl. ethyl or isopropyl group;

R2and R3is a hydrogen atom,

OR4the nutrient replaced phenoxy-group or group LLC R5where R5- C1-C6-alkyl.

As mentioned previously, the compounds of the invention can be used as antibiotics and/or as intermediate compounds for other active compounds and/or during the separation and purification of compounds of antibiotics S541. In the case where the proposed connection is necessary to use as intermediates, R2and/or4can be protected hydroxyl groups. It is clear that such a group must have a minimum number of additional functional groups to avoid further reaction of the circuit should be such that it became possible to selectively restore from it a hydroxyl group. Examples of hydroxyl protective groups are known and described.

The claimed compounds have antibiotic activity, such as anthelmintic activity, for example against nematodes, and in particular antiendomysium and antiquefurniture activity.

Ectoparasites and endoparasites infecting people and a number of animals, and especially have a wide distribution among farm animals, such as pigs, sheep, cattle, goats and home p to anemia, malnutrition and weight loss, is a major cause of economic losses worldwide.

Representatives of endoparasites infecting these animals and/or people are Ancylostoma, Ascarida, Ascaris, Aspicularis, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Dictyocaulus, Dirofilaria, Dracunculus, Enterobius, At, Heterahis, Loa, Necator, Nematodirus, Nematospiroides (Heligo-moroides), Nippostrongylus, Oesopha - gostomum, Onchaceroa, Ostertagia, Oxyuris, Parascaris, Strongylus, Strongyloides, Syphacia, Tohascaris, Toxocara, Iricxonema, Irichostrongylus, Irichinella, Irichuris, Uncinaria and Wucharecia.

Examples of parasites that infect animals and/or people are arthropod ectoparasites, such as stinging insects, padolina fly, fleas, lice, ticks, sucking insects, Academie mites and other two-winged insects.

Examples of these types of parasites that infect animals and/or people are Ambylomma, Boophilus, Choriop - tes,Culliphore, Demodex, Demallenia, Dermatobia, Gastrophilus, Haematobia, Naematopinus, Naemophysalis, Hyalomma, Hyperderma, Ixodes, Linognathus, Lucilia, Melophagus, Oestrus, Otobius, Otodectes, Psoregates, Psoroptes, Rhipicephalus, Sarcoptes, Stomoxys and Tabanus.

Found that the proposed compounds have been effective both in vitro and in vivo against a wide range of endoparasites and ectoparasites. In particular, it is found that the compounds of the present invention are active against nematodes ziliensis and parasitic mites, such as Sarcoptes and Psoroptessp.

Thus, the proposed compounds find use in the treatment of animals and people with endoparasites and/or ectoparasitic infections.

Parasites vary in accordance with the host (animal) and the predominant site of infection. Therefore, for example, agents At contortus, Ostertagia circumcineta and Trichostrongylus culubi Pormis usually infect sheep and mostly localized in the stomach and the small intestine, while Dictyocaulus viviparus, Cooperia oncophora and Ostertagia ostertagi usually infect cattle and is localized mainly in the lungs, the intestines or the stomach, respectively.

The antibiotic activity of the proposed compounds can be demonstrated, for example, by their activity in vitro against free living of nematodes, for example Caenerhabiditis elegans.

In addition, the claimed compounds are used as antifungal substances, for example against Candida species such as Candida albicans and Candida glabrata and yeasts, such as Saceharomyces carlsbergensis.

Connection of the proposed method, in addition, can find application in pest control-insects, mites and nematodes in agriculture, horticulture, leceister cultures, including cereals, for example wheat, barley, maize, rice, vegetables such as soy, fruits, such as apples, grapes and citrus fruits, along with root crops such as sugar beets, potatoes. Typical examples of such pests are fruit mites and aphids, for example Aphisfabae, Nulacorthum circumflexum, Myzus Nersicae, Nephoteltix cineticeps, nilparvata Lugens, Panomychus ulmi, Phorodon humuli, Phyllocoptruta oleivora, Tetranychys urticae and representatives of the genus Trialeuroides; nematode worms, for example members of the genus Aphelencoides, Globodera, Heterodeta, Meloidogyne and Panagrellus; scaly, such as Heliothis, Plutella and Spodoptera; weevil-calandrino, such as Anthonomus grandis and Sitophilus granarius; larval flour, such as Tribolium castaneum flies, for example Musca olomestica; ants Richter; moth-minelayers number; Pearpsilla; thrips tobacco; such relic species, such as Blatella germanica and Periplaneta mosquito, for example Aedes aegypti.

In accordance with the proposed invention the compounds of formula II, which can be used as antibiotic. In particular, they can be used in the treatment of animals and people affected endoparasites, antiparasitary and/or fungal infections, and as pesticides for pest control-insects, mites and nematodes in agriculture, horticulture or forestry. They can be used, in addition to that is the R places or places of localization of pests. Essentially, the proposed connection can be applied either to the host (animal or human) or cultivated plants or other vegetation, or to the pests or their location.

The claimed compounds can be made for reception in any convenient form for use in veterinary or medical practice. Thus, the invention includes within its scope pharmaceutical compositions containing the compound according to the claimed method, suitable for use in veterinary medicine or therapy. Such compositions may be presented for use in the traditional manner using one or more suitable carriers or excipients. The proposed compositions are compositions in the form, especially suitable for parenteral (including the introduction inside the breast), oral, rectal, topical application in the form of the implant, for use in eye, ear, or diseases of the genitourinary system. Suitable methods and agents for the preparation of the compounds of the present invention, suitable for use in veterinary medicine or therapy, are known methods for compounds of antibiotics S541.

The total daily dose of the proposed compounds used in veterinary medicine and therapy will be appropriate - but in the range of 1-2000 mg/kg body weight, preferably 50-1000 mg/kg and above dose can be taken in fractional doses, for example of 1-4 times a day.

The claimed compounds can be in any convenient form suitable for farming or gardening. Thus, the invention includes within its scope compositions containing compound that is intended for use in agriculture or horticulture. Such formulations include dry or liquid form, such as dusty, including pulverulent substrates or concentrates, powders, including soluble or wettable powders, granules, including microspheres and disperser - administered granules, tablets, liquid substances, emulsions, such as diluted emulsion or emulsifiable concentrates, impregnating compositions, for example compositions for impregnation roots and seeds, seed treaters, seed, pellets, oil concentrates, oil solutions, injections, for example, injection into the barrel, solutions for spraying, smokes and mists.

Suitable methods and agents for the preparation of the formulation of the proposed compounds for skin is URS the concentration of the active substance is usually from 0.01 to 99 wt.% and more preferably 0.01 to 40 wt.%.

Industrial (commercial) products are usually prepared in the form of concentrated compositions that, when used diluted to the desired concentration - way radios, for example of 0.001 and 0.0001 wt.%.

When used in veterinary medicine or in horticulture and agriculture, and in the case when the proposed compounds are products produced by fermentation, it is desirable to use the entire fermentation broth as a source of active compounds. In addition, it may be appropriate to use dehydrated broth (containing mycelium or mycelium is separated from the broth and pasteurized, or more preferably dried. If desired, the specified broth or mycelium may be made in the compositions, as mentioned above, including typical inert carriers, excipients or diluents.

The antibiotic compounds of the invention can be introduced and used in combination with other assets - governmental ingredients.

In particular, the proposed connection of the antibiotic can be used together with compounds of antibiotics S541 or in combination with other antibiotic compounds of the present invention. This may occur, for example, when abusage Department; this may be preferred, for example when using compounds in agriculture, where it is important to ensure (save) low cost of production.

Activity against Nematospirorides dubius.

Was determined the effectiveness of the compounds of this invention against Mematospiroides dubius, which infected mice. Female mouse CR/H (18-22 g) were infected with 100 larvae L 3 larvaed N. dubius and infection allowed to develop fully (usually 3 weeks). Then the mouse is handled by one stomatitis who receive the proposed compounds in dosage 3/4 titrated dose. The compound was administered in propylene glycol. Then the mouse survived for at least 3 days (usually 5 days) in order to kill the infection in place of its development, and the small intestine removed. Cut part of the intestine is cut with scissors with blunt ends to release from intestinal mucus. Mature worms were collected through a modified apparatus Baarmanna. The migration time was 5 hours and during this period of migratory worms were when supporting a temperature of 37aboutC. After 5 h the nylon mesh through which migrated worms, checked with a magnifying glass, with an increase in 2 times. Worms collected on the grid and migrated calculated to receive the dick, it was found that the dose of the proposed compounds 10 mg/kg total number of worms treated mice decreased significantly. For example, the compound of example 3 resulted in the decrease of worms as a percentage of the treated mice to control more than 80%.

Activity against a variety of ecto - and endoparasites for different types of animals

A single dose (800 mg/kg) compound of example 3 accepted intravenously or injected subcutaneously, eliminated worms in calves infected with a worm Cooperia oncophera. During the 5-day treatment of rabbits infected with the larvae of Rhipicephalus appendiculolus using the compounds of example 3, these larvae were destroyed by 97%.

The product of example 3 showed absolute efficiency when it tematicheskie at a dose of 200 mg/kg was administered to horses infected with Parascaris.

The product of example 3 was as effective as ivermectin, when it was introduced tematicheskie with a dose of 200 mg/kg, larvae and Mature Namatodirus bottus and adults Ostertggia circumcincta, Irichostrongylus axci, At contortus, Nematodirus spat - higer, Cooperia curticei and Trichostrongylus vitrinus.

The product of example 3 was absolutely effective when it was administered at a dose of 150 mg/kg infected with Toxocara.

The compound of example 3, introduced by PNCA 23-Deoxy Factor a (example 3) on insecticidal activity.

All concentrations listed here, are relative to the active ingredients. Experimental solutions were prepared by dissolving the active ingredient in 35% acetone solution with water at a concentration of 1000 h-a-million, then diluted with water, if necessary.

Tetranychus urticae (R. direct resistance) 2-marked spider mite.

Were selected seedlings of leguminous plants, which evolved reached 7-8 cm, were cut so that each pot has remained one plant. From leaf, selected from the entire group of plants cut off a small piece and placed on each leaf of the test plants. Did two hours prior to processing to allow the clamp to move to experience - subject to the plants and lay them eggs. The size of the cut piece is changed to get about 100 mites per leaf. During the processing of a piece of sheet used to transfer the mites are removed and thrown away. A small proportion of infected plants immersed in the experimental solution 3 with stirring and maintained under the cap for drying. The plants are incubated for 2 days before making an estimate of the amount destroyed Mature parasites, using to whom she eggs and/or newly emerged insect larvae.

Empoasca abrupta, Mature flea beetle on potato leaves. The leaves of bean plants, Litskai beans with a length of 5 cm, dipped in the experimental solution at 3 under stirring and placed under the cap to dry. The sheet was placed in a Petri dish 10 x 10 mm, containing at the bottom of the wet filter paper. In each Cup was placed about 10 Mature deciduous flea beetles and spent processing within 3 days before he made the counting of dead insects.

Heliothis virescens. Cotyledons of cotton dipped in the experimental solution and dried under a cap. After drying, each cut into quarters and ten parts placed separately in a medical reservoir mass of Cup with a volume of 30 ml containing chunks of moist dental tampons length 5-7 mm One third of larvae introduced into each Cup and covered cardboard cover. Processing was carried out for 3 days, then calculated the number of deaths and reduced portions damage.

Rating scale

0 - No effect

1 - 10-25% of the dead

2 - 26-35% of the dead

3 - 36-45% of the dead

4 - 46-55% of the dead

5 - 56-65% of the dead

6 - 66-75% of the dead

7 - 76-85% of the dead

8 - 86-99% of the dead

9 - 100% dead

The results are given in table.1.

In compliance
where R1and-OR4have the specified values, in addition to OR4the hydroxy - group; L is a group RIIOCSO, where RII- (C1-C6-alkyl)phenyl or phenyl, with a regenerating agent, such as allowoveride (for example, tri-n-butylaldehyde) in the presence of initiator radicals, such as peroxides, azobisisobutyronitrile or under the action of light.

The reaction can also be carried out in an appropriate solvent, which can be selected from the group of a ketone, for example acetone, simple ether, for example dioxane, hydrocarbons such as trichlorobenzene; or of ester, for example ethyl acetate. You can also use combinations of these solvents or the most, or with water.

The above reaction can be conducted at a temperature of 0-200aboutWith, preferably in the range of 20-130aboutC.

The proposed method is represented by the following preparations and examples. All temperatures are given at 0aboutC.

Connections marked with reference to the source of the "Factors", which are the above compounds of formula V

and summarized in table.2.

The factors A, B, C. D, E, F can be obtained in a known manner (see patent South Africa N 85/7049).

P R(747 mg) in dichloromethane (10 ml) at 0aboutC in nitrogen atmosphere is treated with pyridine )0,81 ml) and then 4-methylphenylethylamine (0.75 g) in dichloromethane (2 ml). The obtained dark solution was thoroughly stirred for 15 minutes at a temperature of 0aboutWith and then for a further 22 h without cooling. The resulting mixture was poured into cold water and salt solution (brine) and extracted with simple ether. Joined layers of simple ether washed with water and saline solution, dried and evaporated . The residue is purified by chromatography on a column of silica and preparative liquid chromatography reverse phase with obtaining this compound (430 ml), (Cl3): to 3.34 (m, 1H), to 3.58 (m, 1H), 3,97 (l 10, 1H), 4.72 in (s, 2H), 5,4 (m, 1H), 559 (d 6, 1H), 6.9 to 7.4 (m, N), m/z includes 728, 616, 576, 466, 464, 448, 354, 297, 247, 219 and 151.

P R I m m e R 2. 5-phenoxyacetate-23-deoxy Factor A.

The compound of example 2 (350 g) and azobisisobutyronitrile (25 ml) in dry toluene (20 ml) in nitrogen atmosphere at a temperature of 120aboutWith treated dropwise with a solution of tri-n-butylaldehyde (0.5 ml) in dry toluene (10 ml) and the solution heated under reflux for 90 min, cooled and evaporated. The remainder chromatographic through silica using a mixture of dichloromethane with acetone (40:1) quality is 6, 1H) and 6.8 to 7.4 (m, 5H), m/z contains 730, 712, 578, 560, 468, 450, 356, 314, 299, 249, 248, 221 and 151.

P R I m e R 3. 23-deoxy Factor A.

The compound of example 2 (240 mg) is added to a saturated solution of ammonia in methanol (10 ml) at a temperature of -5about. The resulting solution is stirred at a temperature of 0 to 10aboutC for 2 h before evaporation until dry. The remainder chromatographic through silica using a mixture of dichloromethane with acetone (20: 1) to obtain the compound (180 mg), (CDCl3): of 3.27 (m, 1H); 3.42 points (on 9, 1H, of 3.54 (m, 1H), 4,29 (6 mb, 1H), m/z contains 596, 578, 560, 468, 450, 356, 314, 299, 249, 248, 221 and 151.

P R I m e R 4. 23-Deoxy-Factor And 5-methylcarbonate (57 mg) []D20+152about(from 0.6, l3):max(Et OH) 244,5 nm ( 28200),max(ADHD3) 3530 and 3460 (OH), 1740 (carbonate) and 1707 cm-1(ester, (CDCl3) consists of 5.55 (s, 1H, 3,82 (s, 3H), 3,42 (d, I, 10 Hz, 1H), and 0.69 (d, I 4 Hz, 3H), of 23-deoxy-Factor A (90 mg) and methylchloroform (0.3 ml of 1 M solution in dichloromethane).

P R I m e R 5, (1) 23-p-Tolylacetylene Factor IN,

The factor In (600 mg) was dissolved in dry dichloromethane (5 ml) and to this solution was added dry pyridine (800 mg) and p-tailgatenation (750 mg). Spusta 24 hours at ambient temperature the mixture is poured is in dichloromethane, and column worked in the same solvent. Elution of the column with a mixture of dichloromethane : ether (95:5) was allowed to identify the main component, which was further purified preparative reversible phase HP C. This compound was selected as a colourless foam (417 mn), [ ]D23+160about(0,40, Cl3),maxEtoH238 nm ( max 35,900max(ADHD3) 3770, 3530 (OH), 1705 (ester); (CDCl3): 7,18 (d 9 Hz, 2H), 6,98, d, 9 Hz, 2H), 5,49 (kV, NC, 1H), was 4.02 (d, 5 Hz, 1H), to 3.58 (m, 1H), and 3.31 (m, 1H), 3,49 (s, 3H), of 2.36 (s, 3H), of 1.81 (s, 3H), 1,68 (d, 6, 3H), 1,61 (C. 3H), 1.53 (s, 3H), to 1.00 (d, 6 Hz, 3H) and 0.82 (d, 7 Hz, 3H); m/z = 748 (M+).

(2) 23+Deoxy Factor IN,

Melting point 184-186about, [ ]D22+ 158about(0,40, l3),maxEtoH238,5 (28, 150) and 244,5 nm (max30,650),max(CHBr3)3450 (OH) and 1705 cm-1(ether). (CDCl3including 4,01 (d, 6 Hz, 1H), 3,95 (d, 6 Hz, 1H), 3,49 (s, 3H), 3,29 (m, 1H), 1,80 (s, 3H), 1,64 (d, 6 Hz, 3H), 1,58 (s, 3H), of 1.53 (s, 3H), of 0.93 (d, 7 Hz, 3H) and 0.69 (d, 6 Hz, 3H). m/z = 582 (M+) from compound 1 (350 mg), except that the residue was chromatographically using dichloromethane, followed by a mixture of dichloromethane and ether (95: 5) to obtain the titled compound in the form of crystallites who solids when grinding with n-Penta dry pyridine (0.5 ml) was added acetic anhydride (71 mg). After 20 h at room temperature the mixture was poured into dichloromethane, and the solution was processed to obtain a neutral material. Thus obtained crude material was purified by chromatography on Merck 60, with the pore size of the silica 230-400 mesh mesh (28 g). Elution of the column with a solution of dichloromethane and ether (9:1) resulted in the receipt of the above compound (210 mg), which was allocated in the form of a solid crystalline substance with a melting point 135aboutC []D23+142o(s, 0, 64, CHCl3) maxEtoH244,5 nm (max31,250),max(ADHD3) 3490 (OH), 1718 (ether) and 1730 (acetoxy); (CDCl3including a 4.03 (d, 6 Hz, 1H), 3,79 (d, 10 Hz, 1H), 3,54 (d, 10 Hz, 1H), and 3.31 (m, 1H), and 2.14 (s, 3H), of 1.74 (s, 3H), of 1.66 (d, 7 Hz, 3H), 1,60 (s, 3H), of 1.52 (s, 3H), and 0.98 (d, 6 Hz, 3H) and 0.78 (d, 7 Hz, 4H) m/z = 626 (M+).

(2) 5-Acetoxy, 23-p-tolylacetylene Factor (430 mg), [ ]D23+133about(0,48, Cl3),maxEtoH237,5 (36,900), 244 (36,900) and 273 nm (max2,400),max(ADHD3) 3500(OH), 1732 (acetate) and cm-1(ether). CDCl3: 7,17 (d, 8 Hz, 2H), 6,99 (d, 8.0 Hz, 2H), Android 4.04 (d, 6 Hz, 1H), 3,98 (d, 10 Hz, 1H), only 3.57 (m, 1H), and 3.31 (m, 1H), 2,34 (s, 3H), and 2.14 (s, 3H), of 1.74 (s, 3H), of 1.66 (d, 6N Hz, 3H), 1,60 (s, 3H), of 1.52 (s, 3H), 0,99 (d, 6 Hz, 3H) and 0.81 (d, 7 Hz, 3H), m/z= 776 (M+) of the joint is the melting temperature value 230aboutC (with decomposition), [ ]D23147about(0,32, CHCl3);maxEtoH238,5 (28000), 244,5 nm (max30300),max(CHBr3) 3440 (OH), 1730 (acetoxy) and 1710 cm-1(ether). (CDCl3): of 4.05 (d , 5 Hz, 1H), only 3.57 (m, 1H), 3.33 and (m, 1H), 2,15 (s, 3H), of 1.75 (s, 3H), 1,64 ( , 6 Hz, 3H), of 1.59 (s, 3H), of 1.53 (s, 3H), 0,99 ( d, 6 Hz, 3H) and 0.68 (d , 5 Hz, 3h). m/z= 610 (M+) from compound 2 (385 mg) after crystallization from n-pentane (way of example 23). (4) 23-Deoxy Factor C (80 mg) []D23+104about(from 0.56, CHCl3);maxEtoH244.5 nm (max28050); max(ADHD3) 3540, 3450 (OH), 1702 cm-1(ester), ( Cl3): to 4.28 (m, 6 Hz, 1H), 3,95 (d , 6 Hz, 1H), only 3.57 (m, 1H), 3.45 points (d , 10 Hz, 1H), 3,26 (m, 1H), 1,87 (s, 3H), of 1.65 (d , 7 Hz, 3H), of 1.59 (s, 3H), 1.53 (s, 3H), 0,99 ( d, 6 Hz, 3H) and 0.69 (poorly resolved doublet, 5 Hz, 3H). m/z = 568 (M+) of compound 3 (125 mg) as colorless foam.

P R I m e R 7. Factor a 5-acetate and 24-p-tolylthiourea.

A solution of Factor a 5-acetate (4,000 g) in dry dichloromethane (50 ml) and dry pyridine (4.9 ml) in a stream of nitrogen was treated with p-tailgatenation (3,7 ml) dropwise within 10 minutes Received the dark solution was stirred at room temperature for 45 hours the Solution was diluted with dichloromethane (200 ml), washed sequentially 2 N. hydrochloric colormania), and the solvent was evaporated and formed a dark green foam. She was re-dissolved in ethylacetate (200 ml) and treated with activated charcoal. After filtration and steam solvent was obtained a pale green foam, which was chromatographically on silica (Merck Kieselgel 60, particle size 0,040-0,063 mm, pore size 230-400 mesh mesh at atmospheric pressure, with elution by the mixture hexane-ethyl acetate (2:1) to obtain the titled compound as a pale yellow foam (3,946 g).max(in ethanol) 245 nm ( 34200),maxCHBr3) 3620-3340 (HE) 1731 (acetat), 1710 cm-1(carbonyl), (DCl3): for 6.81 ( d, 6 Hz, 3H), of 2.16 (s, 3H), of 2.36 (s, 3H), 3,34 (m, 1H), 6,99 (d , 9 Hz, 2H), 7,20 ( d, 9 Hz, 2H).

(2) 23-deoxy-Factor A 5-acetate.

A solution of Factor a 5-acetate 23-p-tolylthiourea (10,194 g) in dry toluene (100 ml) was heated to boiling under reflux in a stream of nitrogen and processed-azo-bis-isobutyronitrile (509 mg). Dropwise added a solution of tri-n-buildingdata (of 10.25 ml) in dry toluene (60 ml) for 25 min, while boiling under reflux. The mixture was stirred for another 25 minutes, then cooled to room temperature and the solvent was evaporated to obtain a yellow oil. It was dissolved in acetonitrile (600 ml) and washed hexane the size of the particles 0,040-0,063 mm and pore diameter of 230-400 mesh mesh), was suirable a mixture of hexane-ethyl acetate (4:1) to obtain the titled compound (2,442 g), []D22+144about(from 0.43 chloroform), max(in ethanol) 245,5 nm ( 29650),max(ADHD3) 3420-3340 (OH), 1732 (acetate), 1710 cm-1(carbonyl), (l3includes 0,68 (d, 5 Hz, 3H), of 2.16 (s, 3H), of 3.32 (m, 1H).

P R I m e R 8. (1) 5-Acetoxy Factor D (923 mg) [ ]D21+143about(from 0.9, CHCl3)maxEtoH239 (28700) and 245 nm (max31000),max(CHBr3) 3490 (OH) 1730 and 1710 (ester), (Cl3) 0,81 (d, 7 Hz, 3H), 0,99 (d, 7 Hz, 3H), 1.00 m (m, 7 Hz, 3H), of 1.53 (s, 3H), of 1.59 (s, 3H), of 1.75 (s, 3H), of 2.16 (s, 3H), of 3.32 (m, 1H), 3,65 (m, 1H), 4.04 (d, 6 Hz, 1H), and of 5.53 (m, 2H). m/zx = =640 (M+), Factor D (205 g) and acetic anhydride (0,47 ml).

(2) 23-p-tolylacetylene Factor D 5-Acetat (610 mg), []D21+132about(0.4, Hl3)maxEtoH238,5 (34800) and 244,5 nm (max35400),max(ADHD3) 359 and 3560 (OH) and 1730 cm-1(ether); 0 (l3) 0,81 (d, 7 Hz, 3H), 0,99 (d, 7 Hz, 3G), and 1.00 (m, 7H, 3H), of 1.53 (s, 3H), 1,61 (C. 3H), of 1.75 (s, 3H), of 2.15 (s, 3H), of 2.36 (s, 3H), of 3.33 (m, 1H), 3,98 (d, 10 Hz, 1H), Android 4.04 (d, 6 Hz, 1H), and 5.5 to 5.6 (m, 2H), 6,98 (d, 9 Hz, 2H) and 7,19 (d, 9 Hz, 2H), m/z = 790 (M+). From 5-acetoxy Factor D (776 mg) and p-tailgatenation (0.75 ml) (method see example 7). (3) 5-Acetoxy, 23-deoxy Factor D )367 mg).

with a melting point 222-224about[]D21+134about(from 0.9, CHCl3),maxEtoH245 nm (max32400),max(ADHD3) 3550, 3460 (M), 1735 and 1710 cm-1(ether) (l3) 0.69 (d, 6 Hz, 3H), 1.00 m (d, 6 Hz, 3H), 1.00 m (m, 7 Hz, 3H), of 1.53 (s, 3H), of 1.59 (s, 3H), of 1.76 (s, 3H), and 2.14 (s, 3H), and 3.31 (m, 1H), 3,44 (d, 10 Hz, 1H), 4,05 (d, 6 Hz, 1H) and 5.5 to 5.6 (m, 2H), m/z = 624 (M+). From 5-Acetoxy, 23-p-tolyloxy - thiocarbonyldi Factor D (582 mg) (method see example 7). (4) 23-Deoxy Factor D (159 mg)

[]D21+123about(0.5, CHCl3),maxEtoHto 244.6 nm (max28300);max(ADHD3) 3550 and 3460 (OH) and 1705 cm-1(ester), (CCl3) 0.69 (d, 6 Hz, 3H), 1.00 m (d, 6 Hz, 3H), 1.00 and ( 6, 7 Hz, 3H), of 1.53 (s, 3H), of 1.59 (s, 3H), of 1.87 (s, 3H), 3,26 (m, 1H), 3,44 (d, 10 Hz, 1H), 3.96 points (d, 6 Hz, 1H) and to 4.28 (m, 6 Hz, 1H). m/z = 582 (M+). From 5-acetoxy, 23-dihydro Factor D (232 mg).

The WAY to OBTAIN MACROCYCLIC COMPOUNDS of General formula I

< / BR>
where R1is methyl, ethyl or isopropyl;

R2and R3is hydrogen;

OR4the hydroxy - group, methoxy group, alkanoyloxy a1- C6is an alkyl fragment, optionally substituted phenoxypropane, or group-OCOOR5where R5- C1- C5-alkyl,

characterized in that the compound of General formula II

< / BR>
where R1UB>6-alkyl)phenyl or phenyl,

subject to recovery action olovarelel, for example tri-n-butylaldehyde, in the presence of initiator radicals, such as azobisisobutyronitrile, or under the action of light and the compound obtained of General formula I, where OR4- methoxy - or alkanoyloxy a1- C6is an alkyl fragment, optionally substituted phenoxypropane, if necessary, transferred to the compound of General formula I, where OR4the hydroxy - group, which, if necessary, by the action of galodamadruga acid transferred in connection with the General formula I, where OR4- OCOOR5-group.

 

Same patents:

The invention relates to new methods of obtaining salt orthocarbonate acids or alcoholate hem-triolo having the structural formula R-Me where R is phenyl, furyl, R1-CH= CH-, CH3-(CH= CH)2- CH= C-CH3; Me - Na, K; Rlis phenyl, furyl, used as an intermediate reagents in organic synthesis, as well as in the printing industry for the regeneration of aluminum plates

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing new 2,4-dialkylindolo[2,3-h]-1-oxaazulenium chlorides of the general formula (I):

wherein Ia: R is -OCH3; R1 is CH3; Ib: R is hydrogen atom (H); R1 is CH3; Ic: R is -O-CH2-O-; R1 is CH3; Id: R is -O-CH2-CH2-O-; R1 is CH3; Ie: R is -OCH3; R1 is C2H5; If: -O-CH2-O-; R1 is C2H5. Method involves passing gaseous hydrogen chloride through solution of the corresponding 2-acetylaminoarylbis-(5-alkylfur-2-yl)methane of the formula (II):

in methanol at boiling for 80-90 min. Method provides preparing new tetracyclic derivatives eliciting the potential anticancer activity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

2 tbl, 5 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new aromatic diketone derivatives of formula I

(R4, R5, R6, and R7 are independently H, OH, X-alkyl, wherein X represents oxygen; K is group of formula II

or III

;

L is group of formula IV

;

or K and L together form group of formula VI ,

wherein R1 and R3 are independently H or alkyl; R2 is H or alkyl; X1-X7 are independently O, NH; and ring "cyclus" together with carbon atom labeled with letters c and d represents anthraquinone, hydroquinone or phenyl, optionally substituted with one or more hydroxyl, alkoxyl, or alkyl groups), as well as pharmaceutically accepts salts thereof, ethers, esters, tautomers, stereomers and mixtures in any ratio. Derivatives of present invention are glucose-6-phosphatetranslocase inhibitors. Also disclosed are method for production of derivatives, pharmaceutical composition containing the same, and uses thereof as drugs, in particular for treatment of diabetes mellitus.

EFFECT: new compounds and pharmaceutical composition for treatment of diabetes mellitus.

20 cl, 4 tbl, 6 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing phthalic anhydride from vat waste resin in manufacture of phthalic anhydride. Method involves treatment of vat waste resin in manufacture of phthalic anhydride with dimethylformamide at stirring at temperature 60-70°C and isolation of phthalic anhydride. Resin is a toxic waste in manufacture. Using a solvent under optimal conditions in resin treatment provides the wasteless manufacture and value product - phthalic acid is recovered. Phthalic acid is used in synthesis of pigment, phthalocyanine.

EFFECT: improved preparing method.

1 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

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