Antimalarial compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formulas I, II, III, IV, V, VIII or to their pharmaceutically acceptable salts, wherein: Z represents , or phenyl; D represents or ; X represents N(R9), O, S, S(=O) or S(O)2; each Y independently represents O or S; G represents or ; the other radical values are described in the patent claim. The invention also refers to pharmaceutical compositions based on the above compounds.

EFFECT: there are prepared new compounds and based compositions which can find application for treating malaria or eliminating or inhibiting the growth of Plasmodium species.

30 cl, 3 tbl, 23 ex

 

2420-174665RU/011

ANTIMALARIAL COMPOUNDS

Description

Cross-reference to related applications

This application claims priority under 35 U.S.C. §119(e) of provisional application U.S. serial number 61/162467, filed on March 23, 2009, and provisional application U.S. serial number 61/083972, filed July 28, 2008, each of which is introduced in the present invention fully by reference.

The technical field to which the present invention

The present invention in part relates to tricyclic compounds, arylamine compounds and other compounds, and containing compositions for the treatment of malaria, and treatment of malaria, including the introduction of these compounds to the animal.

The background to the present invention

Internationally 41% of the population live in areas which are transmitted malaria, such as parts of Africa, Asia, the Middle East, Central and South America, Haiti and Oceania. Every year around the world there are between 350 and 500 million cases of malaria, and an estimated one million people die, most of them young children in Africa South of the Sahara. In areas of Africa with high prevalence of malaria, about 990000 people died from malaria in 1995. In 2002, malaria was a fourth cause of death de is she in developing countries. In addition, malaria was the cause of 10.7% of deaths of all children in developing countries.

Antimicrobial peptides (AMP) are a component of the innate immune system, which is responsible for resistance to a range of pathogenic bacteria. AMP also provide new directions for the development of antibiotics, since they play a Central role in the innate immune system. Some AMP show a very broad spectrum of action against bacteria, yeast, fungi and even viruses. It is also reported that the number of peptides in immune defenses have protivorahiticescoe activity. The most studied organisms includePlasmodium, Leishmania,andTrypanosoma(Vizioli et al., Trends in Pharmacol., 2002, 18, 475-476; Jacobs et al., Antimicrob. Agents Chemother., 2003, 47, 607-613; Brand et al., J. Biol. Chem., 2002, 277, 49332-49340), parasitic agents of malaria, leishmaniasis and Chagas disease, respectively. It was reported that additional protozoa parasites, destroy peptides of immune protection, areCryptosporidium(Giacometti et al., Antimicrob. Agents Chemother., 2000, 44, 3473-3475) and Giardia (Aley et al., Infect. Immun., 1994, 62, 5397-5403), human pathogens transmitted in contaminated drinking water. It turns out that the peptides destroy protozoa microorganisms interaction with the cytoplasmic membrane, causing increased permeability, lysis and death; the mechanism of which is the tsya similar to their mechanism of action against bacteria. Specificity regarding parasitic organisms compared to the host cells can be attributed to differences in the phospholipid composition and the absence of cholesterol in the membrane of the simplest. As a place of action is the membrane and not a specific receptor or molecular target, the development of resistance to the cytotoxic properties of antimicrobial peptides is extremely unlikely.

As for antimalarial activity, shows that the natural proteins of immune protection and their analogues inhibit the development of oocysts of several species ofPlasmodiumdifferent owners, which mosquitoes (Gwadz et al., Infect. Immun., 1989, 57, 2628-2633; Possani et al., Toxicon, 1998, 36, 1683-1692) and are directly cytotoxic against early stages of sporogonic developmentPlasmodiumin cell culture (Arrighi et al., Antimicrob. Agents Chemother., 2002, 46, 2104-2110). Also, found several antimicrobial peptides that selectively destroy the parasites developing in erythrocytes (Plasmodiumdevelop into red blood cells) or with the attack of infected erythrocytes in "sparring" normal erythrocytes (Feder et al., J. Biol. Chem., 2000, 275, 4230-4238; and Krugliak et al., Antimicrob. Agents Chemother., 2000, 44, 2442-2451) or in the interaction and the destruction of the intracellular parasite without harming the infected red blood cell (Dagan petrol et al., Antimicrob Agents Chemother., 2002, 46, 1059-1066; and Efron et al., J. Biol. Chem., 2002, 277, 24067-24072). After the discovery of important therapeutic limitations of peptides, develop ones mimetics data protoplasmatic peptides could represent a new and powerful therapy for malaria.

The essence of the present invention

The present invention relates to compounds of the formula I:

where: X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(O)2; R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group; R1and R2independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN; R3and R4independently represent carbocycle(R5)(R6); each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, aromatic group, heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or their pharmaceutically acceptable salts, and compositions containing them, and farmacevtichesky acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula I:

where: X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(O)2; R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group; R1and R2independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN; R3and R4independently represent carbocycle(R5)(R6); each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, aromatic group, heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or its pharmaceutically acceptable salt.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula I:

where: X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(=O)2; R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group; R1and R2independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN; R3and R4independently represent carbocycle(R5)(R6); each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3aromatic group, a heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula II:

where: X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; and each R 1independently represents a together with Y a 5 - or 6-membered heterocycle; each R2independently represents H, CF3C(CH3)3, halogen, or OH; and each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salts, and compositions containing them, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula II:

where: X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R1independently represents a together with Y a 5 - or 6-membered heterocycle; each R2independently represents H, CF3C(CH3)3, halogen, or OH; and each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or agopermalink acceptable salt.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula II:

where: X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R1independently represents a together with Y a 5 - or 6-membered heterocycle; each R2independently represents H, CF3C(CH3)3, halogen, or OH; and each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula III:

where: Z is aor phenyl; each Q independently representsor-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 1 to 4; each X independently represents O, S or N; each R1nez is performance represents H, CF3C(CH3)3, halogen or OH; each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1-3 and each y independently represents 1 or 2; each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;

each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and each R5independently represents H or CF3; or their pharmaceutically acceptable salts and compositions containing them, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula III:

where: Z is aor phenyl; each Q independently representsor-C(=O)-(CH2)b-NHC(=NH)-NH 2where each b independently represents 1 to 4; each X independently represents O, S or N; each R1independently represents H, CF3C(CH3)3, halogen or OH; each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;

each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and each R5independently represents H or CF3; or their pharmaceutically acceptable salts.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula III:

where: Z is aor phenyl;each Q independently represents or-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 1 to 4; each X independently represents O, S or N; each R1independently represents H, CF3C(CH3)3, halogen or OH; each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;

each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and each R5independently represents H or CF3; or their pharmaceutically acceptable salts.

The present invention also relates to compounds of the formula IV:

where: G is aoreach X independently represents O or S; each R1nez the performance is a or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4, or their pharmaceutically acceptable salt, and compositions containing them, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula IV:

where: G is aoreach X independently represents O or S; each R1independently representsor the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each of n independent who represents 1-4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4, or its pharmaceutically acceptable salt.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula IV:

where: G is aoreach X independently represents O or S; each R1independently representsor the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where is IDY n independently represents 1-4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4, or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula V:

where: each X independently represents O, S or S(=O)2; each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=0)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(C 2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salts, and compositions containing them, and a pharmaceutically acceptable carrier, provided that the compound is not:

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula V:

where: each X independently represents O, S or S(=O)2; each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1is Soboh is H, and every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula V:

where: each X independently represents O, S or S(=O)2; each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2n is dependent represents-S-R 5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or their pharmaceutically acceptable salts, and compositions containing them, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or its pharmaceutically acceptable salt.

The present invention t is the train relates to a method of destroying or inhibiting the growth of a species of Plasmodiumthat includes contacting the species with an effective amount of the compounds of formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or its pharmaceutically acceptable salt.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula VII:

where: each R1independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or CN; each R2independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula VII:

where: each R1independently represents H, C1-C8 alkyl, C1-C8alkoxy, halogen, OH, CF3or CN; each R2independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula VIII:

where: D is aeach B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4,or; and each X independently represents O or S, or their pharmaceutically acceptable salts, and compositions containing them, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula VIII:

where: D is a; each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4,or; and each X independently represents O or S, or its pharmaceutically acceptable salt.

Now izaberete is s also relates to methods of destroying or inhibiting the growth of a species of Plasmodiumthat includes contacting the species with an effective amount of the compounds of formula VIII:

where: D is aor;each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4,or; and each X independently represents O or S, or its pharmaceutically acceptable salt.

Description of embodiments

Together and separately each of the compounds described in this invention, also referred to as in the present invention as anti-malarial compounds.

As used in the present invention and unless otherwise specified, it is assumed that the term "animal" includes, but is not limited to, humans and vertebrates, non-humans, such as wild, domestic and farm animals.

As used in the present invention and unless otherwise specified, it is assumed that the term "about" means ± 5% of the value of that change. Thus, approximately 100 denotes 95-105.

As used in the present invention and unless otherwise specified, it is assumed that the term "alkyl" includes saturated aliphatic hydrocarbon group with razvetvlenno the th or the normal chain, having a specific number of carbon atoms. For example, it is assumed that C1-C8as in "C1-C8the alkyl" includes groups containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms with linear or branched arrangement. It is assumed that "C1-C6alkyl" includes groups containing 1, 2, 3, 4, 5 or 6 carbon atoms with linear or branched arrangement. It is assumed that "C1-C3alkyl" includes groups containing 1, 2 or 3 carbon atoms with linear or branched arrangement. Examples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl,n-butyl,tert-butyl, isobutyl, 2-methyl-1-propyl, 2-methyl-2-propyl, pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, isopentyl, neopentyl, hexyl, 2-methyl-1-pentyl, 3-methyl - 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, heptyl and octyl or any combination of them. The alkyl group may be substituted or substituted one, two or three suitable substituents. The same alkyl groups can be applied to "alkoxy" groups "halogenosilanes" groups "alkenyl" groups "alkynylaryl" groups and "cycloalkenyl" groups, if necessary.

As used in the present invention and the EU is not specified, the term "halogen" denotes fluorine, chlorine, bromine or iodine.

As used in the present invention and unless otherwise indicated, the phrase "5 - or 6-membered heterocycle" refers to monocyclic ring containing carbon atoms, hydrogen atoms and one or more heteroatoms, such as 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 5-Membered heterocycles include, but are not limited to, thienyl, 2-thienyl, 3-thienyl, furyl, 2-furyl, 3-furyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, pyrrolidyl, imidazolidinyl, imidazolyl, pyrazolidine and pyrazolines. 6-membered heterocycles include, but are not limited to this, pyranyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinil and morpholinyl. 5 - and 6-membered heterocycles can be substituted or substituted one, two or three suitable substituents.

As used in the present invention and unless otherwise indicated, the phrase "carbonyl" denotes a 5 - or 6-membered, saturated or unsaturated cyclic ring, optionally containing O, S, or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopent-1,3-diene, phenyl and any of the heterocycles listed above.

As used in the present invention and unless otherwise indicated, the term "phenyl" oboznachaet the-C 6H5. The phenyl group may be substituted or substituted one, two or three suitable substituents.

As used in the present invention and unless otherwise indicated, the phrase "therapeutically effective amount" of a composition or compound is measured therapeutic efficacy of the introduced compound in which at least one adverse effect is alleviated or partially removed. therapeutic effect depends on the condition being treated, or the desired biological effect. By itself, therapeutic effect can be a reduction in the severity of symptoms associated with the disease, and/or inhibition (partial or full) of disease development, or improved treatment, healing, prevention or elimination of the disease or side effects. Required to cause a therapeutic response quantity can be determined on the basis of age, health, size and sex of the subject. The optimal number can also be determined on the basis of monitoring the susceptibility of a subject to treatment.

When administered to a mammal (e.g., animal for veterinary use or to a human for clinical use) antimalarial compounds described in this invention, can be selected. As used in this the future of invention and unless otherwise indicated, the term "isolated" means that the anti-malarial compounds described in the present invention, isolated from other components of either (a) a natural source, such as a plant or cell, such as bacterial culture, or (b) is recovered from the reaction mixture during the synthesis methods of organic chemistry, methods such as standard methods.

As used in the present invention and unless otherwise indicated, the term "purified" means that when selected, the selected substance contains at least 90%, at least 95%, at least 98% or at least 99% of antimalarial compounds described in this invention, relative to the weight of the selected substance.

As used in the present invention and unless otherwise indicated, the phrase "pharmaceutically acceptable salt (salt)" includes, but is not limited to, salts of acidic or basic groups. Compounds which are basic in nature are capable of forming a large number of salts with various inorganic and organic acids. Acids that can be used to obtain pharmaceutically acceptable salts accession acids are acids which form non-toxic salts accession acid, i.e. salts containing pharmacologically acceptable anions, including but not limited to, salts of sulfuric, whether the Onna, maleic, acetic, oxalic, hydrochloric, Hydrobromic, itestosterone, nitric, sulfuric, hydrosulphate, phosphoric, hydroporinae, isonicotinic, acetic, lactic, salicylic, citric acid, acid citrate; wine salt, oleic acid, tannins, Pantothenic acid; the bitartrate salt, ascorbic, succinic, maleic, hentaimovi, fumaric, gluconic, glucuronic, sugar, formic, benzoic, glutamic, methanesulfonic, econsultancy, benzosulfimide,p-toluensulfonate and Paveway acids (i.e., 1,1'-methylene-bis(2-hydroxy-3-aftout)). Compounds that contain an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds which are basic in nature are capable of forming salts with various pharmacologically acceptable cations. The examples of these salts include, but are not limited to, salts of alkali and alkaline earth metals and, in particular, salts of calcium, magnesium, sodium, lithium, zinc, potassium and iron.

As used in the present invention and unless otherwise indicated, the phrase "suitable Deputy" means a group that does not invalidate synthetic or pharmaceutical utility of antimalarial compounds described in this invention, is whether the intermediate compounds able to receive them. Examples of suitable substituents include, but are not limited to: (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)quinil, (C5-C6)aryl, (C3-C5)heteroaryl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C5-C6)aryloxy, -CN, -OH, oxo, halogen, -NO2, -CO2H, -NH2, -NH((C1-C8)alkyl), -N((C1-C8)alkyl)2, -NH((C6)aryl), -N((C5-C6)aryl)2, -CHO, -CO((C1-C6)alkyl), -CO((C5-C6)aryl), -CO2((C1-C6)alkyl) and -- CO2((C5-C6)aryl). Specialists in the art can easily choose a suitable Deputy, on the basis of stability and pharmacological and synthetic antimalarial activity of the compounds described in this invention.

As used in the present invention and unless otherwise indicated, the terms "treatment" or "treat" refers to the relief of malaria, or at least one discernible symptom. In another embodiment, "treatment" or "treat" refers to the relief of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibiting the development of malaria, or physically, for example, stabilizationalism symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the emergence of malaria.

In some embodiments, the implementation of the anti-malarial compound or containing composition is administered to the patient, such as a person, as preventative tools against malaria. As used in the present invention and unless otherwise indicated, "prevention" or "preventing" refers to reducing the risk of acquiring malaria.

Antimalarial compounds described in this invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as isomers on double bond (i.e., geometric isomers), enantiomers or diastereomers. Therefore, antimalarial compounds described in this invention includes all enantiomers and stereometry corresponding compounds, i.e. stereoisomers pure form (e.g., geometrically pure, enantiomerically pure or diastereomers pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be divided into their component enantiomers or stereoisomers are well-known ways, such as gas chromatography with a chiral phase, Vysokoe the objective liquid chromatography with chiral phase, crystallization of the compounds as chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomono or enantiomerically pure intermediates, reagents, and catalysts are well known methods of asymmetric synthesis.

The present invention relates to compounds of the formula I:

where:

X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(=O)2;

R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group;

R1and R2independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN;

R3and R4independently represent carbocycle(R5)(R6); each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, aromatic group, heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-8;

or their pharmaceutically p is yimlamai salt.

In some embodiments, implementation, X represents N(R9), O, S, or S(=O)2; or X represents NH, O or S; or X represents NH or S.

In any of the above embodiments, R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen, OH, Gialos1-C3alkyl or CN; or R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen or OH; or R1and R2independently represent H, C1-C3alkyl or halogen; or R1and R2represent H.

In any of the above embodiments, R3and R4independently represent carbocycle(R5)(R6), where R5and R6can be located in any position of carbocycle. In any of the above embodiments, R3and R4independently represent

where each of W, Y and Z independently represent C or N, each of A, D and Q independently represent C(R10)C(R11), C(=O)N(R12), O or S, and each R10, R11and R12independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group.

In any of the above variants of the OS is supervising R 3and R4independently represent

where each of W, Y and Z independently represent C or N; or R3and R4independently represent

where each of W, Y and Z represent C, or each Y and Z are C, and each W represents n

In any of the above embodiments each R5independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8 and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or each R5independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 8; or each R5 independently represents H, C1-C3alkyl, halogen or OH; and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R5independently represents H, C1-C3alkyl, halogen or OH; and each R6independently represents a 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5independently represents H or halogen; and each R6represents piperazinil or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil; and each R6independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3; or each R5represents piperazinil; and each R6represents H, C1-C3alkyl, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O, S, or S(=O)2; R1and R2represent H; R3and R4independently represent

where: b is th W Y and Z independently represent C or N; each R5and each R6independently represent H, heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3.

In some embodiments, implementation of the X represents NH, O or S; R1and R2represent H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5independently represents H or halogen, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil, and each R6independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O, or S; R1and R2represent H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5represents H, and each R6is Soboh the piperazinil or the free base or salt form of the group -(CH 2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil; and each R6represent H.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula I:

where:

X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(=O)2;

R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group;

R1and R2independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN;

R and R4independently represent carbocycle(R5)(R6);

each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, aromatic group, heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or its pharmaceutically acceptable salt.

In some embodiments, implementation of the X represents N(R9), O, S, or S(=O)2; or X represents NH, O or S; or X represents NH or S.

In any of the above embodiments, R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen, OH, Gialos1-C3alkyl or CN; or R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen or OH; or R1and R2independently represent H, C1-C3alkyl or halogen; or R1and R2represent H.

In any of the above embodiments, R3and R4independently represent

where each of W, Y and Z independently represent C or N, kadiya, D and Q independently represent C(R10)C(R11), C(=O)N(R12), O or S, and each R10, R11and R12independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group.

In any of the above embodiments, R3and R4independently represent

where each of W, Y and Z independently represent C or N; or R3and R4independently represent

where each of W, Y and Z are C; or each Y and Z are C, and each W represents n

In any of the above embodiments each R5independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8 and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or each R5not avisio represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 8; or each R5independently represents H, C1-C3alkyl, halogen or OH, and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R5independently represents H, C1-C3alkyl, halogen, or OH, and each R6independently represents a 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5independently represents H or halogen, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil, and each R6independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3; or each R5represents piperazinil, and each R6presented yet a H, C1-C3alkyl, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O, S, or S(=O)2; R1and R2represent H; R3and R4independently represent

where each of W, Y and Z independently represent C or N; and each R5and each R6independently represent H, heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3.

In some embodiments, implementation of the X represents NH, O, or S; R1and R2represent H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5independently represents H or halogen, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil, and each R6independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O, or S; R1and R2p is establet a H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5represents H, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil; and each R6represent H.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula I:

where:

X represents C(R7)C(R8), C(=O)N(R9), O, S, S(=O) or S(=O)2;

R7, R8and R9independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group;

R1and R2regardless of predstavlyaet a H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, Gialos1-C8alkyl or CN;

R3and R4independently represent carbocycle(R5)(R6);

each R5and each R6independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, aromatic group, heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or its pharmaceutically acceptable salt.

In some embodiments, implementation of the X represents N(R9), O, S, or S(=O)2; or X represents NH, O or S; or X represents NH or S.

In any of the above embodiments, R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen, OH, Gialos1-C3alkyl or CN; or R1and R2independently represent H, C1-C3alkyl, C1-C3alkoxy, halogen or OH; or R1and R2independently represent H, C1-C3alkyl or halogen; or R1and R2represent H.

In any of the above embodiments, R3and R4independently represents the t of a

where each of W, Y and Z independently represent C or N, each of A, D and Q independently represent C(R10)C(R11), C(=O)N(R12), O or S, and each R10, R11and R12independently represent H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or aromatic group.

In any of the above embodiments, R3and R4independently represent

where each of W, Y and Z independently represent C or N; or R3and R4independently represent

where each of W, Y and Z are C; or each Y and Z are C, and each W represents n

In any of the above embodiments each R5independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 8 and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2, -(CH2)n-NH-(CH2)n-NH2or -(CH 2)n-NH-C(=NH)NH2where each n independently represents 1 to 8; or each R5independently represents H, C1-C3alkyl, C1-C3alkoxy, halogen, OH or CF3and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 8; or each R5independently represents H, C1-C3alkyl, halogen or OH, and each R6independently represents a heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R5independently represents H, C1-C3alkyl, halogen, or OH, and each R6independently represents a 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5independently represents H or halogen, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil, and each R6independently represents H, C1-C3alkyl, C -C3alkoxy, halogen, OH or CF3; or each R5represents piperazinil, and each R6represents H, C1-C3alkyl, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O, S, or S(=O)2; R1and R2represent H; R3and R4independently represent

where each of W, Y and Z independently represent C or N; and each R5and each R6independently represent H, heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3.

In some embodiments, implementation of the X represents NH, O or S; R1and R2represent H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5independently represents H or halogen, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil, and each R6independently represents H, C1-C3alkyl, C1-C 3alkoxy, halogen, OH or CF3.

In some embodiments, implementation of the X represents NH, O or S; R1and R2represent H; R3and R4are

where each Z and Y are C, and each W represents N; or each of W, Y and Z are C; each R5represents H, and each R6represents piperazinil, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1-3; or each R5represents piperazinil; and each R6represent H.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

The present invention also relates to compounds of the formula II:

where:

X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R 1independently represents a together with Y a 5 - or 6-membered heterocycle;

each R2independently represents H, CF3C(CH3)3, halogen, or OH; and

each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, implementation of the X represents O.

In any of the above embodiments, each Y is O or S.

In any of the above embodiments each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2.

In any of the above embodiments each R2independently represents CF3C(CH3)3or halogen. In any of the above embodiments each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R3the stand is made by a -(CH 2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, implementation of the X represents O or S; each Y independently represents O or S; each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; each R2independently represents CF3or C(CH3)3; and each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n is 1-4; each of R2is a CF3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1is a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2is the Wallpaper CF 3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula II:

where: X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R1independently represents a together with Y a 5 - or 6-membered heterocycle; each R2independently represents H, CF3C(CH3)3, halogen, or OH; and each the initial R 3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, implementation of the X represents O.

In any of the above embodiments, each Y is O or S.

In any of the above embodiments each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2.

In any of the above embodiments each R2independently represents CF3C(CH3)3or halogen.

In any of the above embodiments each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, implementation of the X represents O or S; each Y is independently isone O or S; each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; each R2independently represents CF3or C(CH3)3; and each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n is 1-4; each R2is a CF3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1is a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2is a CF3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments done by the compliance connection choose from:

and

or its pharmaceutically acceptable salt.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula II:

where:

X represents O or S; each Y independently represents O, S or N; each R1independently represents H, 5 - or 6-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R1independently represents a together with Y a 5 - or 6-membered heterocycle; each R2independently represents H, CF3C(CH3)3, halogen, or OH; and each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, implementation of the X represents O.

In any of the above embodiments, each Y is predstavljaet a O or S.

In any of the above embodiments each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2.

In any of the above embodiments each R2independently represents CF3C(CH3)3or halogen.

In any of the above embodiments each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, implementation of the X represents O or S; each Y independently represents O or S; each R1independently represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; each R2independently represents CF3or C(CH3)3; and each R3independently represents -(CH2)sub> n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1represents a 5-membered heterocycle, or the free base or salt form of the group -(CH2)n-NH2where each n is 1-4; each R2is a CF3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 1-4.

In some embodiments, implementation of the X represents O or S; each Y is O or S; each R1is a 3-pyrrolyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2is a CF3or C(CH3)3; and each R3represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

The present invention also relates to compounds of the formula III:

where:

Z representsor phenyl;

each Q independently represents or-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 1 to 4; each X independently represents O, S or N; each R1independently represents H, CF3C(CH3)3, halogen or OH; each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and each R5independently represents H or CF3; or their pharmaceutically acceptable salts.

In some embodiments, implementation Z represents.

In any of the above embodiments, each Q independently represents.

In any of the above options is done by the means each X represents O.

In any of the above embodiments each R1independently represents H, CF3or halogen; or each R1is a CF3.

In any of the above embodiments each R3independently represents-NH-R2.

In any of the above embodiments each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O or S; each R1independently represents CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2Nezavisimosty a H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O; each R1is a CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O; each R1is a CF3or halogen; each R3independently represents-NH-R2; each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; it is jdy Q independently represents ; each X independently represents O or S; each R1independently represents H or CF3; each R3represents H; each R4independently represents H or-NH-C(=O)-(CH2)P-NH-C(=NH)-NH2where each p independently represents 3 or 4; and each R5independently represents H or CF3.

In some embodiments, implementation Z represents; each Q independently represents-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 3 or 4; and each X is N.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O or S; each R1independently represents H or CF3; each R3independently represents -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R4represents H; and each R5independently represents H or CF3.

In some embodiments, implementation Z represents or phenyl; each Q independently represents; each X independently represents O or S; each R1independently represents H or CF3; each R3represents H; each R4independently representswhere each q independently represents 1 or 2; and each R5independently represents H or CF3.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula III:

where:

Z representsor phenyl;

each Q independently representsor-C(=O)-(CH2) b-NH-C(=NH)-NH2where each b independently represents 1 to 4; each X independently represents O, S or N;

each R1independently represents H, CF3C(CH3)3, halogen, or OH;

each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2;

each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and each R5independently represents H or CF3; or its pharmaceutically acceptable salt.

In some embodiments, implementation Z represents.

In any of the above embodiments, each Q independently represents.

In any of the above options domestic which each X represents O.

In any of the above embodiments each R1independently represents H, CF3or halogen; or each R1is a CF3.

In any of the above embodiments each R3independently represents-NH-R2.

In any of the above embodiments each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R4and each R5represent H.

In some embodiments, the realization of Z is; each Q independently represents; each X represents O or S; each R1independently represents CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2regardless of performance, is to place a H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O; each R1is a CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O; each R1is a CF3or halogen; each R3independently represents-NH-R2; each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; it is jdy Q independently represents ; each X independently represents O or S; each R1independently represents H or CF3; each R3represents H; each R4independently represents H or-NH-C(=O)-(CH2)P-NH-C(=NH)-NH2where each p independently represents 3 or 4; and each R5independently represents H or CF3.

In some embodiments, implementation Z represents; each Q independently represents-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 3 or 4; and each X is N.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O or S; each R1independently represents H or CF3; each R3independently represents -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R4represents H; and each R5independently represents H or CF3.

In some embodiments, implementation Z represents or phenyl; each Q independently represents; each X independently represents O or S; each R1independently represents H or CF3; each R3represents H; each R4independently representswhere each q independently represents 1 or 2; and each R5independently represents H or CF3.

In some embodiments, the implementation of connection is chosen from:

or its pharmaceutically acceptable salt.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula III:

where:

Z representsor phenyl;

each Q independently representsor-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 1 to 4; each X independently represents O, S, or N;

each R1independently represents the th H, CF3C(CH3)3, halogen, or OH;

each R3independently represents H, -NH-R2, -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2;

each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;

each R4independently represents H, -NH-C(=O)-(CH2)P-NH-C(=NH)-NH2orwhere each p independently represents 1 to 6, and each q independently represents 1 or 2; and

each R5independently represents H or CF3; or its pharmaceutically acceptable salt.

In some embodiments, implementation Z represents.

In any of the above embodiments, each Q independently represents.

In any of the above embodiments, each X represents O.

In any of the above embodiments each R1independently represents H, CF3or halogen; and each R 1is a CF3.

In any of the above embodiments each R3independently represents-NH-R2.

In any of the above embodiments each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O or S; each R1independently represents CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2independently represents H, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents with the battle 1-4; and each R4and each R5represent H.

In some embodiments, the realization of Z is; each Q independently represents; each X represents O; each R1is a CF3C(CH3)3or halogen; each R3independently represents-NH-R2; each R2independently represents a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O; each R1is a CF3or halogen; each R3independently represents-NH-R2; each R2is a free base or salt form of the group -(CH2)n-NH2where each n is 2; and each R4and each R5represent H.

In some embodiments, implementation Z represents; each Q independently represents; each X independently represents O or S; each R1n is dependent represents H or CF 3; each R3represents H; each R4independently represents H or-NH-C(=O)-(CH2)P-NH-C(=NH)-NH2where each p independently represents 3 or 4; and each R5independently represents H or CF3.

In some embodiments, implementation Z represents; each Q independently represents-C(=O)-(CH2)b-NH-C(=NH)-NH2where each b independently represents 3 or 4; and each X is N.

In some embodiments, implementation Z represents; each Q independently represents; each X represents O or S; each R1independently represents H or CF3; each R3independently represents -(CH2)r-NH2, -NH2, -NH-(CH2)W-NH2orwhere each r independently represents 1 or 2; each w independently represents 1 to 3, and each y independently represents 1 or 2; each R4represents H; and each R5independently represents H or CF3.

In some embodiments, implementation Z representsor phenyl; each Q independently represents; each X n is dependent represents O or S; each R1independently represents H or CF3; each R3represents H; each R4independently representswhere each q independently represents 1 or 2; and each R5independently represents H or CF3.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

The present invention also relates to compounds of the formula IV:

where:

G represents

each X independently represents O or S;

each R1independently representsor the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently presented yet a -(CH 2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, implementation, G representsand each X represents S.

In any of the above embodiments each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where n represents 1 to 4; or each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2independently represents a methyl or free is the initial base or salt form of the group -(CH 2)n-NH2where each n independently represents 2; or each R2represents methyl, or a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R3independently represents CF3C(CH3)3or halogen; or each R3is a CF3.

In any of the above embodiments each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R4represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of G is a; each X represents S; each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents a C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R3independently represents CF3C(CH3)3or halogen; and each R4regardless of predstavljaet a -(CH 2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(CH3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2independently represents a methyl, or a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(CH3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n of t is made by a 4.

In some embodiments, the implementation of G is a; each X independently represents O or S; each R1independently represents a free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of G is a; each X independently represents O or S;

each R1represents; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds, opisaniya.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula IV:

where:

G represents

each X independently represents O or S;

each R1independently representsor the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of G is Soboh the and each X represents S.

In any of the above embodiments each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where n represents 1 to 4; or each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2independently represents a methyl, or a free base or salt form of the group -(CH2)n-NH2where each n independently represents 2; or each R2represents methyl, or a free base or salt form of the group -(CH2)n-NH2 where each n is 2.

In any of the above embodiments each R3independently represents CF3C(CH3)3or halogen; or each R3is a CF3.

In any of the above embodiments each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R4represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of G is a; each X represents S; each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents a C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R3independently represents CF3C(CH3)3or halogen; and each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(CH3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2independently represents a methyl, or a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(CH3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of G is a; each X independently represents O or S; each R1ezavisimo is a free base or salt form of the group -(CH 2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of G is a; each X independently represents O or S;

each R1represents; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of connection is chosen from:

and

or their pharmaceutically acceptable salts.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula IV:

where:

G a

each X independently represents O or S;

each R1independently representsor the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents H, C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H, CF3C(CH3)3, halogen or OH; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;

or its pharmaceutically acceptable salt.

In some embodiments, the implementation of G is aand each X represents S.

In any of the above embodiments each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 to 4; or each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each of n independent who represents 1 or 2; or each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2,where n represents 1 to 4; or each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; or each R2independently represents a methyl, or a free base or salt form of the group -(CH2)n-NH2where each n independently represents 2; or each R2represents methyl, or a free base or salt form of the group -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R3independently represents CF3C(CH3)3or halogen; or each R3is a CF3.

In any of the above embodiments each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R 4represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of G is a; each X represents S; each R1independently represents a free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents a C1-C8alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n independently represents 1 or 2; each R3independently represents CF3C(CH3)3or halogen; and each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n represents 1 or 2; each R2independently represents a C1-C3alkyl, or the free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(C 3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the implementation of G is a; each X represents S; each R1is a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R2independently represents a methyl, or a free base or salt form of the group -(CH2)n-NH2where each n is 2; each R3independently represents CF3or C(CH3)3; and each R4represents -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of G is a; each X independently represents O or S; each R1independently represents a free base or salt form of the group -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some the option exercise G represents ; each X independently represents O or S; each R1represents; each R3independently represents H or CF3; and each R4independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of connection is chosen from:

or their pharmaceutically acceptable salts.

The present invention also relates to compounds of the formula V:

where: each X independently represents O, S or S(=O)2; each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and

each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n -NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salts; provided that the compound is not:

In some embodiments, the implementation of each X represents S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents H or methyl; or each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n is 2, and each R4represents H; or each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each R1represents -(CH2)n-NH2or -(CH2 n-NH-C(=NH)NH2where each n is 2.

In any of the above embodiments each R2independently represents H, Br, F, Cl, CF3or C(CH3)3; or each R2represents Br, F, Cl, CF3or C(CH3)3.

In any of the above embodiments, each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 or 2; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2, where is n is 2.

In any of the above embodiments, each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently submitted is a halogen, CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1 or 2.

In some embodiments, the implementation of each X represents S; each R1represents -(CH2)n-NH2where each n represents 1 or 2; each R2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2)n-NH2where each n represents 1 or 2.

In some embodiments, the implementation of each X represents O or S; each R1independently before the hat is -(CH 2)n-NH2or -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H or methyl; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents H or methyl; each R2independently represents a halogen; and each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of each X represents O or S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is independently ol dstanley a 1-4; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=0)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents O or S; each R1represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; each R2represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the implementation of each X independently represents S or S(=O)2; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents a Gal is a gene or CF 3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of connection is chosen from:

or its pharmaceutically acceptable salt.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula V:

where: each X independently represents O, S or S(=O)2; each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-N-C(=O)-R 4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each X represents S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents H or methyl; or each R1independently represents -(CH2)H -NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n is 2, and each R4represents H; or each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each R1represents -(CH2)n-NH2where each n is 2.

In any of the above embodiments each R2independently represents H, Br, F, Cl, CF3or C(CH3)3; or each R2represents Br, F, Cl, CF3or C(CH3)3.

In any of the above embodiments, each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 or 2; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R 3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where n represents 2.

In any of the above embodiments, each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2 )n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents halogen, CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1 or 2.

In some embodiments, the implementation of each X represents S; each R1represents -(CH2)n-NH2where each n represents 1 or 2; R 2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2)n-NH2where each n represents 1 or 2.

In some embodiments, the implementation of each X represents O or S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H or methyl; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents H or methyl; each R2independently represents a halogen; and each V2represents H, and for every V1 represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of each X represents O or S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents O or S; each R1represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; each R2represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the wasp is estline each X independently represents S or S(=O) 2; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents halogen or CF3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of connection is chosen from:

or its pharmaceutically acceptable salt.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula V:

where: each X independently represents O, S or S(=O)2; each R 1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H, C1-C3alkyl or -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents H, halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each X represents S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or and each R4independently represents H or methyl; or each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n is 2, and each R4represents H; or each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each R1represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2.

In any of the above embodiments each R2independently represents H, Br, F, Cl, CF3or C(CH3)3; or each R2represents Br, F, Cl, CF3or C(CH3)3.

In any of the above embodiments, each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C=NH)NH 2where each n independently represents 1 or 2; or each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2; or each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where n represents 2.

In any of the above embodiments, each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2 where each n is 2; or each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 2.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents halogen, CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH2where each n independently represents 1 or 2; each R2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2where each n independently represents 1 or 2.

In n the options which implement each X represents S; each R1represents -(CH2)n-NH2where each n represents 1 or 2; each R2independently represents CF3or C(CH3)3; and each V1represents H, and for every V2represents a-S-R5where each R5represents -(CH2)n-NH2where each n represents 1 or 2.

In some embodiments, the implementation of each X represents O or S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and each R4independently represents H or methyl; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents S; each R1independently represents -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents H or m is Teal; each R2independently represents a halogen; and each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n is 4.

In some embodiments, the implementation of each X represents O or S; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; each R2independently represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each X represents O or S; each R1represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2; each R2represents halogen, CF3or C(CH3)3; and each V2represents H, and for every V1represents a-N-C(=O)-R3where each R3represents -(CH2)n-NH 2or -(CH2)n-NH-C(=NH)NH2where each n represents 3 or 4.

In some embodiments, the implementation of each X independently represents S or S(=O)2; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 or 2, and each R4independently represents -(CH2)P-NH2where each p independently represents 1 or 2; each R2independently represents halogen or CF3; and each V2represents H, and for every V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4.

In some embodiments, the implementation of connection is chosen from:

or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2 where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or their pharmaceutically acceptable salts.

In some embodiments, the implementation of each Y independently represents O or S; or each Y is O or S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2where each n independently represents 2-4; or each R1represents -(CH2)n-NH2where each n is 2-4.

In any of the above embodiments each R2independently represents halogen, CF3or C(CH3)3; or each R2represents halogen, CF3or C(CH3)3.

In some embodiments, the implementation of connection is a

or its pharmaceutically acceptable salt.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention targetnode to methods for treating malaria in an animal, includes introduction to the animal a therapeutically effective amount of the compounds of formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each Y independently represents O or S; or each Y is O or S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2where each n independently represents 2-4; or each R1represents -(CH2)n-NH2where each n is 2-4.

In any of the above embodiments each R2independently represents halogen, CF3or C(CH3)3; or each R2represents halogen, CF3or C(CH3)3.

In some embodiments, the implementation of connection is a

Connection 100

or its pharmaceutically acceptable salt.

In any of the above options is sushestvennee malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula VI:

where: each Y independently represents O, S or NH; each R1independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; and each R2independently represents H, halogen, CF3or C(CH3)3; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each Y independently represents O or S; or each Y is O or S.

In any of the above embodiments each R1independently represents -(CH2)n-NH2where each n independently represents 2-4; or each R1represents -(CH2)n-NH2where each n is 2-4.

In any of the above embodiments each R2independently represents halogen, CF3or C(CH3)3; or each R2represents halogen, CF3or C(CH3)3.

In some embodiments, the implementation of connection is a

it is farmacevtichesky acceptable salt.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula VII:

where: each R1independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3or CN; each R2independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each R1independently represents a C1-C8alkyl, halogen, OH, CF3or CN; or each R1independently represents a C1-C3alkyl, halogen, CF3or CN; or each R1represents methyl or halogen; or each R1represents Br, F or Cl.

In any of the above embodiments each R2independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R2represents -(CH2)n-NH-C(=NH)NH2where each n is 1 to 4; or each R2represents -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2.

In some embodiments, about what westline each R 1independently represents a C1-C8alkyl, halogen, OH, CF3or CN; and each R2independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each R1independently represents a C1-C3alkyl, halogen, CF3or CN; and each R2represents -(CH2)n-NH-C(=NH)NH2where each n is 1-4.

In some embodiments, the implementation of each R1represents methyl or halogen; and each R2represents -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2.

In some embodiments, the implementation of connection is a

Connection 115

or its pharmaceutically acceptable salt.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compounds of formula VII:

where: each R1independently represents H, C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF 3or CN; each R2independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of each R1independently represents a C1-C8alkyl, halogen, OH, CF3or CN; or each R1independently represents a C1-C3alkyl, halogen, CF3or CN; or each R1represents methyl or halogen; or each R1represents Br, F or Cl.

In any of the above embodiments each R2independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each R2represents -(CH2)n-NH-C(=NH)NH2where each n is 1 to 4; or each R2represents -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2.

In some embodiments, the implementation of each R1independently represents a C1-C8alkyl, halogen, OH, CF3or CN; and each R2independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In some embodiments, the implementation of each R1independently represents a C -C3alkyl, halogen, CF3or CN; and each R2represents -(CH2)n-NH-C(=NH)NH2where each n is 1-4.

In some embodiments, the implementation of each R1represents methyl or halogen; and each R2represents -(CH2)n-NH-C(=NH)NH2where each n represents 1 or 2.

In some embodiments, the implementation of connection is a

or its pharmaceutically acceptable salt.

The present invention also relates to compounds of the formula VIII:

where:

each D is a

each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4,; and

each X independently represents O or S; or their pharmaceutically acceptable salts.

In some embodiments, the implementation of D is a.

In any of the above embodiments, each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In any of the above embodiments, each X represents S.

In some embodiments, the implementation of the D made the focus of a ; each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4, or; and each X represents S.

In some embodiments, the implementation of D is a; each B independently represents; and each X independently represents O or S.

In some embodiments, the implementation of connection is chosen from:

and

or their pharmaceutically acceptable salts.

In some embodiments, the exercise of any one or more of the above compounds can be excluded from any of the classes of compounds described above.

The present invention also relates to compositions containing one or more of the compounds or salts described above, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compounds of formula VIII:

where:

D represents

each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4; ; and each X independently represents O or S; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of D is a.

In any of the above embodiments, each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In any of the above embodiments, each X represents S.

In some embodiments, the implementation of D is a; each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4, or; and each X represents S.

In some embodiments, the implementation of D is a; each B independently represents; and each X independently represents O or S.

In some embodiments, the implementation of connection is chosen from:

or its pharmaceutically acceptable salt.

In any of the above embodiments malaria can be sensitive to chloroquine or resistant to chloroquine.

The present invention also relates to methods of destroying or inhibiting the growth of a species of that includes contacting the species with an effective amount of the compounds of formula VIII:

where:

D represents;

each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;; and

each X independently represents O or S; or its pharmaceutically acceptable salt.

In some embodiments, the implementation of D is a.

In any of the above embodiments, each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4.

In any of the above embodiments, each X represents S.

In some embodiments, the implementation of D is a; each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 3 or 4, or; and each X represents S.

In some embodiments, the implementation of D is a; each B independently represents; and each X independently represents O or S.

In some embodiments, the implementation of the connection wybir the ut from:

or its pharmaceutically acceptable salt.

It should be clear that in any particular formula, any one version of the implementation can be combined with any other embodiment (implementation options), if appropriate.

In some embodiments, the implementation of the anti-malarial compound (compound) selected from one or more compounds (i.e., classes, subclasses and specific compounds described in published patent applications US # US 2005/0287108 and/or US 2006/0041023, each of which is introduced in the present invention by reference. The methods described in the present invention can also be implemented using one or more of the compounds described in the form of a class, subclass or specific compounds published patent application U.S. No. US 2005/0287108 and/or US 2006/0041023.

Some of the compounds of the present invention may be able to take amphiphilic conformation that creates the possibility for the separation of polar and non-polar regions of the molecule to separate the spatial domain and provides the basis for a number of applications. For example, some anti-malarial compounds can take amphiphilic conformation, which can compromise the integrity of the cell membrane of microorganisms, which results in ingebyra aniu growth or death, for example, species ofPlasmodium.

Antimalarial compounds may be useful as antimalarial agents in a number of applications. For example, anti-malarial compounds can be used therapeutically for the treatment of malaria in animals, including humans and vertebrates, non-humans, such as wild, domestic and farm animals. Malaria infection in an animal can be treated by introducing the animal an effective amount of anti-malarial compounds or containing pharmaceutical compositions. Antimalarial compound or composition can be entered systemically or locally and you can type in any part of the body or tissue.

Although anti-malarial compounds are suitable, other functional groups can be introduced into the connection, expecting similar results. In particular, it is assumed that thioamides and thioethers have very similar properties. The distance between the aromatic rings may have an impact on the geometric structure of the connection, and this distance can be modified by introduction of aliphatic chains of different lengths, which can not necessarily to replace or which may contain amino acid, dicarboxylic acid or diamine. The distance between the monomers and the relative arrangement of the monomers in the connection can also be changed by replacing the AMI is an explicit relationship Deputy with additional atoms. Thus, the substitution of the carbonyl group carbonyl changes the distance between the monomers and the property dicarbonyl fragment to take enterocolitis two carbonyl functional groups and changes the frequency of the connection. Anhydride pyromellitic acid is another alternative to the simple amide linkages, which can alter the conformation and physical properties of the compound. Modern methods of solid-phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach, IRL Press Oxford 1989) currently allow for the synthesis homodimeric compounds with molecular weights up to 5000 daltons. Other replacement types are equally effective.

The term "malaria", as used in the present invention, indicates that the compound inhibits, prevents or stops the growth or proliferation of the speciesPlasmodium.

Anti-malarial compounds can be entered in tools for polishing, paints, sprays or detergents made for use on surfaces to inhibit the growth of associated speciesPlasmodium. These surfaces include, but are not limited to, surfaces such as kitchen tables, desks, chairs, laboratory desks, tables, floors, counters to the of ovata, tools or equipment, door handles and window. Antimalarial compounds can also type in soap and hand cream. Presents detergents, products for polishing, paints, sprays, Soaps, or detergents contain antimalarial compound, which gives them antimalarial property. Antimalarial compounds may optionally contain a suitable solvent (solvents), the carrier (s), thickeners, dyes, fragrances, deodorants, emulsifiers, surfactants, wetting agents, waxes or oils. For example, in some aspects, the anti-malarial compounds can be introduced into the composition for external use as pharmaceutically suitable means to cleanse the skin, in particular for the surface of human hands. Detergents, products for polishing, paints, sprays, Soaps, hand cream or detergents and the like, containing anti-malarial compounds can be used in homes and institutions, particularly but not exclusively in hospitals to prevent nosocomial infections. In some aspects, the anti-malarial compounds include derivatives, called prodrugs. The expression "prodrug" denotes a derivative known drugs direct action, where derived from ucsay delivery and therapeutic value as compared with the drug and transformed into the active drug by enzymatic or chemical methods.

It should be clear that the present invention includes the application, where the stereoisomers, diastereomers and optical isomers of antimalarial compounds, and mixtures thereof, applicable for the treatment of malarial infection, and/or to destroy or inhibit the growth of species ofPlasmodium. Additionally, it should be clear that the stereoisomers, diastereomers and optical isomers of antimalarial compounds and their mixtures are included in the scope of the present invention. Through neorganicheskoi example, the mixture may be a racemate or a mixture may contain an unequal number one particular stereoisomer relative to another. Additionally, anti-malarial compounds can be provided in the form of almost pure stereoisomers, diastereomers and optical isomers.

In another aspect, the anti-malarial compounds can be provided in the form acceptable salt (i.e., pharmaceutically acceptable salts) for the treatment of malarial infection, and/or to destroy or inhibit the growth of species ofPlasmodium. Salt can be granted for pharmaceutical applications or as intermediate compounds in obtaining pharmaceutically desired form of antimalarial compounds. One salt that can come up with is to Italica acceptable is a salt accession hydrochloric acid. Salt accession hydrochloric acid are often acceptable salt, where the pharmaceutically active agent contains an amino group which may protonemata. Because the anti-malarial compound may be poly-ionic, such as polyamine acceptable salt can be provided in the form of poly(amidohydrolase). Polyamides and polyesters which are suitable, can be obtained by standard means of condensation polymerization and addition polymerization. See, for example, G. Odian, Principles of Polymerization, John Wiley & Sons, Third Edition, (1991), Steven M., Polymer Chemistry, Oxford University Press (1999). Often polyamides receive (a) thermal decomposition of amine salts of carboxylic acids, (b) reaction of acid chloride of the carboxylic acid with an amine and (c) aminolysis esters. Methods (a) and (c) are of limited use in the polymerization of aniline derivatives, which are usually obtained using the carboxylic acid anhydrides. Experienced chemist, however, it is clear that there are many alternative active alleluya agents, for example, phosphoryl anhydrides, active esters or azides, which can replace chloranhydride carboxylic acid and which, depending on the specific polymer, which is obtained may be more suitable than the acid chloride of carbon is th acid. The method using acid chloride of the carboxylic acid is probably the most flexible and can be applied on a large scale for the synthesis of aromatic polyamides.

The homopolymers derived from substituted derivatives of aminobenzoic acid, you can also get step-by-step way. The phasic method comprises the condensation of N-protected amino acid with the amine (or a hydroxyl group) and the subsequent removal of the protective group of the amino group and the repetition method. These methods greatly improved for the synthesis of specific peptides, allowing the synthesis of specific sequences, and solid-phase methods and techniques in the solution for the synthesis of peptides are directly applicable in the present invention. An alternative implementation of the present invention represents the corresponding polysulfonamide, which can be obtained in a similar way by replacing the carboxylic acid anhydrides by sulphonylchloride.

The most common way of obtaining politician represents the reaction of a diamine with a diisocyanate (Yamaguchi, et al, Polym. Bull., 2000, 44, 247). This exothermic reaction can be conducted in solution or by way of separate phases. Specialists in organic chemistry and polymer chemistry clear that the diisocyanate is possible to replace a number of other bis-allerwichtigeste, for example, with phosgene or N,N'-(diimidazole)carbonyl, with similar results. Polyurethanes get similar ways, using the diisocyanate and diology alcohol or by reaction of the diamine with the bis-chloroformiate.

Synthesis of anti-malarial compounds can be standard and/or by known methods such as those described, for example, in published patent application U.S. No. 2005/0287108 and US 2006/0041023, each of which is introduced in the present invention fully by reference. Many ways are suitable for the introduction of polar and nonpolar side chains. Phenolic groups in the monomer can be alkilirovanii. Alkylation of commercially available phenol will be the standard synthesis of ethers by the Williamson for non-polar side chain with ethylbromide as alkylating agent. Polar side chains can be entered using a bifunctional alkylating agents, such as BOC-NH(CH2)2Br. Alternatively, the phenolic group can be alkilirovanii for introducing the desired polar side chain, using the reaction of Mitsunobu using BOC-NH(CH2)2-OH, triphenylphosphine and diethylazodicarboxylate. Standard conditions for recovery of nitro groups and hydrolysis of the ester to give the amino acid. In the presence of aniline and benzoic acid, the condensation can be accomplished PR is the number of conditions. Alternatively, a hydroxyl group, (di)NITROPHENOL can be transformed into a leaving group, and enter in the conditions of nucleophilic aromatic substitution of aromatic molecules functional group. Other potential cores, which can be obtained with similar sequences are methyl 2-nitro-4-hydroxybenzoate and methyl 2-hydroxy-4-nitrobenzoate.

Antimalarial compounds can also be created by applying the calculation methods with the use of computers, such as de novo design methods to impart amphiphilic properties. Usually de novo design of antimalarial compounds carried out by determining the three-dimensional structure of the backbone composed of repeating sequences of monomers, using calculations of molecular dynamics and quantum calculations of the force fields. Then, the side group is transferred using the computer on the frame for maximum diversity and conservation of properties similar to drugs. Then, the best combination of functional groups are selected via computer calculations to obtain cationic, amphiphilic structures. Representative compounds can be synthesized from this selected libraries to test structures and study their biological activity. New modeling molecular dynamics program and coarse-grained delirous program is also designed for this purpose, as existing force fields developed for biological molecules such as peptides, are unreliable in these oligomeric applications (Car, R., and Parrinello, M., Phys. Rev. Lett., 55:2471-2474 (1985); Siepmann, J. L, and Frenkel, D., Mol. Phys. 75:59-70 (1992); Martin, M. G., and Siepmann, J. L, J. Phys. Chem. B 103:4508-4517 (1999); Brooks, B. R., et al, J. Comp. Chem. 4: 187-217 (1983)). Received several series of compounds with different chemical structure. See, for example, WO 02/100295 A2, which is introduced in the present invention fully by reference. Anti-malarial compounds can be obtained in a similar way. Simulating molecular dynamics program and coarse-grained modeling programs can be used in the approach to the design. See, for example, patent application U.S. No. US 2004-0107056 and patent application U.S. No. US 2004-0102941, each of which is introduced in the present invention fully by reference.

After checking the suitability of the force field by comparing the calculated predictions of the structure and thermodynamic properties of molecules that have similar torsion model and for which the available experimental data, selected torsion angles can be combined with the stretching of the connection, the curvature of the connection, van der Waals forces and electrostatic potentials, borrowed from CHARMM (Brooks, B. R., et al., J. Comp. Chem. 4: 187-217 (1983)) and TraPPE (Martin, M. G., and Siepmann, J. L, J. Phys. Chem. B 103:4508-4517 (199); Wick, C. D., et al., J. Phys. Chem. B 104:3093-3104 (2000)) force fields for molecular dynamics. To establish conformations that can take the model with periodic stacking with polar groups and non-polar groups located on opposite sides of the primary structure can be obtained using the Gaussian (Frisch, M., et al., Gaussian 98 (revision A,7) Gaussian Inc., Pittsburgh, Pa. 1998). Then, the CP-MD program using the method of Kara-Parrinello with a parallelized plane wave (Car, R., and Parrinello, M., Phys. Rev. Lett. 55:2471-2474 (1985)) (compare Röthlisberger, U., et al., J. Chem. Phys. 3692-3700 (1996)) can be used to obtain the minimum energy and slow spatial structure. Conformations of compounds without side chains can be investigated in the gas phase. And MD and MC methods can be used to select conformations. The first is suitable for General motion of a joint. With bias means (Siepmann, J. L, and Frenkel, D., Mol. Phys. 75:59-70 (1992); Martin, M. G., and Siepmann, J. L, J. Phys. Chem. B 103:4508-4517 (1999); Vlugt, T. J. H., et al. Mol. Phys. 94:727-733 (1998)), the latter allows you to effectively select connections with many configurations with local minima, which are separated by relatively large energy barriers.

The possible conformations investigated in position for attachment of the side groups that can impart amphiphilic character of the secondary structure. Compounds selected by the research is ovadiah in the gas phase, with suitable conformations backbone and side chains in optimal positions to make amphiphiles can be further evaluated in the modeling phase the system can be selectedn-hexane/water, because this mixture is simple and cheap for calculations, though it is a good imitation bishojou environment lipid/water. Secondary structures of compounds that require interactions within a connection can be identified by repeating the above calculations, applying a periodically recurring series of individual elements of different symmetries (so-called molecular dynamics with variable step or method Monte Carlo) with or without solvent. The results of these calculations can determine the selection of candidates for synthesis.

One example design, synthesis and study arylamine polymers and oligomers, a related group of compounds of the present invention, represented in Tew, G. N., et al, Proc. Natl. Acad. Sci. USA 99:5110-5114 (2002), which is introduced in the present invention fully by reference.

Anti-malarial compounds can be obtained by solid-phase synthesis methods, well known to specialists in this field of technology. See, for example, Tew et al. (Tew, G. N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114 (2002)). See also Barany, G., et al., Int. J. Pept. Prot. Res. 30:705-739 (1987); Solid-phase Synthesis: A Practical Guide, Kates, S. A., Albericio, F., eds., Marcel Dekker, New Yrk (2000); and Dörwald, F. Z., Organic Synthesis on Solid Phase: Supports, Linkers, Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002).

Specialists in the art it is clear that anti-malarial compounds can be tested for antimalarial activity by methods well-known to specialists in this field of technology. Any connection that, as it was discovered, is active, you can clean to the required degree of homogeneity and re-test to get an accurate IC50.

Anti-malarial compounds can be entered by any standard method in any way, in which they are active. The background may be systemic, local or oral. For example, the introduction may be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal or through eye or vnutrivlagalischnye, inhalation, depot injection, or by using implants. Thus, the method of administration of antimalarial compounds (or separately, or in combination with other pharmaceuticals) can be, but is not limited to, sublingual, injectable (including fast-acting, slow-acting forms and implants, pellets, injected subcutaneously or intramuscularly) or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, nutrim the internal devices, and transdermal forms, such as patches and creams. The choice of a particular route of administration and dosage regimen should be implemented or defined by a medical practitioner according to the methods known to the attending physician to obtain the desired clinical performance.

The amount of specific anti-malarial compounds, which will be introduced, is a quantity that is therapeutically effective. The dose that will be entered will depend on the characteristics of the subject, which is treated, for example, the specific cure of animal, age, weight, health status, types of concurrent treatment, if present, and the frequency of treatment, and it can be easily determined by a person skilled in the art (for example, medical practitioner). The number of anti-malarial compounds described in this invention which will be effective in the treatment of malaria will depend on the characteristics of malaria, and it is possible to define a standard clinical methods. In addition,in vitroorin vivotests can optionally be applied in order to facilitate finding the optimal dose ranges. The exact dose that will be used in the compositions will also depend on the route of administration and the severity of the disease, and it should be selected according to the decision of the practitioner and each of the th patient. However, a suitable dose range for oral administration is generally from about 0.001 milligram to about 200 milligrams per kilogram of body weight. In some embodiments, the implementation of the oral dose is from about 0.01 milligrams to 100 milligrams per kilogram of body weight, from about 0.01 milligrams to about 70 milligrams per kilogram of body weight, from about 0.1 milligram to about 50 milligrams per kilogram of body weight, from 0.5 milligrams to about 20 milligrams per kilogram of body weight, or from about 1 milligram to about 10 milligrams per kilogram of body weight. In some embodiments, the implementation of the oral dose is about 5 milligrams per kilogram of body weight.

Pharmaceutical compositions and/or preparations containing anti-malarial compounds and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, starch capsules, pellets, pills, powders and granules; local dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solid substances, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to the Xia this, solutions, suspensions, emulsions, and dry powder; containing an effective amount of anti-malarial compounds. Also in the art it is known that the active ingredients can be contained in these drugs with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic environments, water-soluble fluids, emulsifiers, buffers, wetting agents, humectants, soljubilizatorami, preservatives and the like. Means and methods of administration are known in the art, and the inventor can refer for guidance on various pharmacological links. For example, you can ask for help in Modern Pharmaceutics, Banker &Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman''s The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980).

Anti-malarial compounds can be for parenteral administration by injection, for example bolus injection or continuous infusion. Anti-malarial compounds can be entered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Preparations for injection can be present in unit dosage form, e.g., in ampoules or in containers with multiple doses, with added preservatives. The composition can accept the mother of such forms, as suspensions, solutions or emulsions in oily or aqueous medium, and they may contain agents to obtain drugs, such as suspendida, stabilizing and/or dispersing agents.

As for oral administration, anti-malarial compounds can easily make a mixture of these compounds with pharmaceutically acceptable carriers well known in the art. These carriers allow you to receive antimalarial compounds in the form of tablets, pills, coated tablets, capsules, liquids, gels, syrups, thick slurries, suspensions and the like, for oral administration the patient is treated. Pharmaceutical preparations for oral use can be obtained, for example, by adding solid excipient, optionally, by grinding the resulting mixture, and processing the mixture of granules, after adding suitable excipients, if desired, to obtain core tablets or pills. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol and sorbitol; cellulose preparations such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hypromellose, is carboximetilzellulozu sodium and polyvinylpyrrolidone (PVP). If desired, you can add disintegrant, such as, but not limited to, polyvinylpyrrolidone with crosslinking, agar, or alginic acid or its salt, such as sodium alginate.

Core tablets can be provided with a suitable coating. For this purpose you can use concentrated sugar solutions, which may not necessarily contain the Arabian gum, talc, polyvinylpyrrolidone, carboloy gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the very core of the tablets or dragee for marking or for giving distinctive features of various combinations of doses of active compounds.

Pharmaceutical preparations which can be used orally include, but are not limited to, solid (push-fit capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Solid push-fit capsules can contain the active ingredients in a mixture with fillers, such as lactose, binders, such as starch, and/or lubricants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active compounds can races is to meet or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, you can add stabilizers. All preparations for oral administration should contain dose, appropriate for this introduction.

For the buccal administration, the compositions can take the form of, for example, tablets or lozenges made the conventional way.

For administration by inhalation antimalarial compounds for use according to the present invention is conveniently delivered in the form of a sprayable aerosol from the package under pressure or a nebulizer, with the use of proper spraying of the substance, for example, DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of an aerosol under pressure dosage unit may be determined by attaching a valve to deliver a measured quantity. You can get capsules and capsules, e.g. of gelatin for use in an inhaler or insufflator containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

Antimalarial compounds can also be in rectal compositions such as suppositories or retention enemas, e.g. containing conventional base for suppository, such as cocoa butter or other glycerides is.

In addition to the preparations described previously, anti-malarial compounds can also be in the form of a depot preparation. These preparations with prolonged action, you can enter by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be injected approximately 1 to approximately 6 months or longer intervals. Thus, for example, anti-malarial compounds can be with suitable polymeric or hydrophobic materials (for example, in the form of emulsions in a suitable oil or ionoobmennymi resins, or as sparingly soluble derivatives, for example, in the form of a sparingly soluble salt.

With transdermal administration of anti-malarial compounds can be applied to the patch, or can be applied using transdermal, therapeutic systems that come later in the body.

Pharmaceutical compositions containing the anti-malarial compounds can also contain suitable solid or gel-like carriers or excipients. Examples of data carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as, for example, glycols.

In another embodiment, undertake the surveillance of antimalarial compounds described in this invention can be transported in vesicles, in particular a liposome (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

In yet another embodiment, anti-malarial compounds described in this invention can be delivered in a system with controlled release. In one embodiment, it is possible to use the pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med., 1989, 321, 574). In another embodiment, it is possible to use polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol, 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, a system for controlled release can be placed near the target of antimalarial compounds described in this invention, for example, liver, thus requiring only a fraction of the total dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). You can use other systems with controlled release discussed in the review Langer, Science, 1990, 249, 1527-1533).

Proteomes the applications connection you can also type in combination with other active ingredients, such as, for example, antibiotics, including, but not limited to, vancomycin, ciprofloxacin, Meropenem, oxacillin and amikacin. Antimalarial compounds can also type in combination with other antimalarial compounds, such as, for example, any one or more of artemisinin, quinine, artesunate, sulfadoxine-pyrimethamine, of hydroxychloroquine, chloroquine, amodiaquine, pyrimethamine, sulfadoxine, proguanil, mefloquine, atovaquone, primaquine, halofantrine, doxycycline, clindamycin.

Thus, the present invention also relates to a method of treating malaria in an animal, including the introduction of the required treatment to the animal an effective amount of anti-malarial compounds or salts thereof. The present invention also relates to a method of treating malaria in an animal, comprising an introduction to the needy in the treatment of animal compositions containing the anti-malarial compound or its salt. The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of anti-malarial compounds or salts thereof. The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumcomprising contacting the composition comprising the anti-Christ. malarine compound or its salt. The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumsensitive to chloroquine or resistant to chloroquine, comprising contacting the species with an effective amount of anti-malarial compounds or salts thereof. The present invention also relates to methods of destroying or inhibiting the growth of a species ofPlasmodiumsensitive to chloroquine or resistant to chloroquine, comprising contacting the species with a composition containing the anti-malarial compound or its salt. The present invention also relates to methods of destruction of food vacuoles species ofPlasmodiumthat includes contacting the species with an effective amount of anti-malarial compounds or salts thereof. The present invention also relates to methods of destruction of food vacuoles species ofPlasmodiumthat includes contacting the species with a composition containing the anti-malarial compound or its salt.

"In need of treatment of an animal" is an animal diagnosed as having malaria, the animal, which is expected to malaria, and/or the animal that is in the environment, or will be traveling in an environment where malaria is transmitted.

The present invention also relates to anti-malarial compounds or their salts, or containing the m their compositions, for use in the treatment of malarial infection in the animal. The present invention also relates to anti-malarial compounds, or their salts, or their containing compositions for application to destroy or inhibit the growth of species ofPlasmodium. The present invention also relates to anti-malarial compounds or their salts, or their containing compositions for use in obtaining drugs for the treatment of malaria infection in the animal. The present invention also relates to anti-malarial compounds or their salts, or their containing compositions, for use in obtaining drugs to destroy or inhibit the growth of species ofPlasmodium.

Antimalarial compounds described in this invention can be mixed with one, two or three other antimalarial compounds described in this invention, to obtain a cocktail. This cocktail can also contain other anti-malarial compounds.

To the present invention described in the present description, could be more successfully understood, the following examples. It should be clear that these examples are given only for illustration and are not considered as limiting the present invention in any way.

EXAMPLES

Example 1: P is receiving connections 142 and 149

Stage 1: the Diamine (0.1 mmol) and ({[(tert-butoxycarbonyl)amino][(tert- butoxycarbonyl)imino]methyl}amino)pentane acid (4 equivalents) was dissolved in 3 ml of pyridine and cooled to 0°C. To the solution was added dropwise POCl3(4 equiv.) and was stirred at 0°C for 1.5 hours. The reaction was suppressed in ice-cold water. The solvent was removed on a rotary vacuum evaporator.

Stage 2: the Product of stage 1 was treated with 50% triperoxonane acid (TFA) in dichloromethane (DCM). The product was purified reversed-phase chromatography.

Example 2: Obtaining compounds 109, 111 and 144

Stage 1: 319,6 mg 4,4-dihydroxyphenyl 4.0 ml of dimethylformamide (DMF), was added to 839,0 mg K2CO3and 1,3166 g of 3,5-dinitrobenzotrifluoride. The reaction mixture was heated at 125°C with stirring overnight. TLC analysis showed the complete disappearance of the parent compounds. The reaction extinguished with water and was extracted twice with ethyl acetate (EtOAc). The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The product was purified column chromatography to yield 865,6 mg (69%).

Stage 2: 312,3 mg of product obtained in stage 1, 5.0 ml of MeOH was sequentially added to 365,3 mg NH4Cl and 400,2 mg of zinc dust. Reactio the ing the mixture was irradiated by microwave at 115°C for 20 minutes. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was filtered and concentrated. The remainder extinguished with water and was extracted with EtOAc twice. The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The crude product was kept at high pressure for 6 hours and used without further purification.

Stage 3: to 44.9 mg of diamine obtained in stage 2, was added to thetert-butyl ether (2-oxoethyl)carbamino acid (2 EQ. to connect 109 and 111, 1 EQ. to connect 144) in 1.5 ml of anhydrous EtOH. To the reaction mixture was sequentially added 3 drops of HOAc and 78.6 mg NaCNBH3. The reaction mixture was stirred at room temperature overnight. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was concentrated, and the residue extinguished with water and was extracted with EtOAc twice. The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The product was purified column chromatography with a yield of 72.3 mg (97%).

Stage 4: 41.3 mg of Boc-protected diamine obtained in stage 3, 1.5 ml of DCM was added 1.5 ml of TFA, and the reaction mixture was stirred at room temperature for 45 minutes. LCMS analysis showed complete ischeznovenie the parent compounds. The reaction mixture was concentrated, and the residue was washed twice with ether. White powder in 2 ml of ether was additionally treated with ultrasound for 10 minutes. Then, the white solid residue was washed twice with ether and kept at high pressure for 12 hours. The output amounted to 39.6 mg

Example 3: Obtaining connections 148 and 147

Stage 1: To 1,1071 g of bis(4,4-dihydroxyphenyl)-bis(trifluoromethyl)methane 4.0 ml DMF was sequentially added 1,36 g K2CO3and 1,2777 g of 4-fluoro-3-triftormetilfullerenov. The reaction mixture was heated at 130°C and was stirred for 6 hours. The reaction extinguished with water and was extracted with EtOAc twice. The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The product was purified column chromatography to yield 400,0 mg.

Stage 2: 71,4 mg dialdehyde obtained in stage 1, in 3.0 ml of dichloromethane was sequentially added 241,8 mgtert-butyl ether piperazine-1-carboxylic acid and 257,8 mg NaBH(OAc)3. The reaction mixture was stirred at room temperature overnight. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was concentrated, and the residue was marked by a solution of Na2CO3and was extracted twice EtOc. The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The product was purified column chromatography to yield 113,7 mg (91%).

Stage 3: 73,0 mg Boc-protected diamine obtained in stage 2, in 2.0 ml of DCM was added 2.0 ml of TFA, and the reaction mixture was stirred at room temperature for 45 minutes. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was concentrated, and the residue was washed twice with ether. White powder in 2 ml of ether was additionally treated with ultrasound for 10 minutes. Then, the white solid residue was washed twice with ether and kept at high pressure for 12 hours. The output was 70,3 mg

Example 4: Obtaining connections 145 and 146

Compound 145 was obtained by applying a technique similar for connection 147. The starting compounds for stage 1 are 4-[(4-hydroxyphenyl)sulfonyl]phenol and 3-fluoro-4 - triftormetilfosfinov.

3-fluoro-5-triftormetilfosfinov3-f the PR-4-triftormetilfosfinov 4-[(4-hydroxyphenyl)sulfonyl]phenol

Compound 146 was obtained by applying a technique similar for connection 147. The starting compounds for stage 1 are 4-[(4-hydroxyphenyl)sulfonyl]phenol and 3-fluoro-5 - triftormetilfosfinov.

Example 5: Receiving connection 143

Stage 1: the Initial connection was received, using the same technique as in stage 1 receive connection 145. To to 60.6 mg of MDA formed in the condensation reaction, 2.0 ml EtOH was sequentially added to 220.3 mg NH2OH·HCl, 0.5 ml water and 0.1 ml of pyridine. The reaction mixture was irradiated with microwaves at 120°C for 30 minutes. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was concentrated, and the residue was suppressed 2 ml of water. The crude product was filtered and used in the next stage without additional purification.

Stage 2: the Crude product obtained in stage 1 above, was dissolved in 4 ml of HOAc. Added two portions of zinc dust (321,3 mg). The resulting mixture was heated at 60°C for 6 hours. The reaction mixture was filtered and concentrated. To the residue was added 5 ml of tetrahydrofuran (THF), 0.3 ml of triethylamine (TEA) and to 100.6 mg of Boc anhydride. The reaction mixture was stirred at room temperature for 4 hours and extinguished concrete is Na 2CO3and was extracted with EtOAc twice. The organic phase is washed with water, with brine and dried over sodium sulfate before concentrating under reduced pressure. The product was purified column chromatography with access and 67.8 mg (82%, two stages).

Stage 3: 42,1 mg Boc-protected diamine obtained in stage 2, in 2.0 ml of DCM was added 2.0 ml of TFA, and the reaction mixture was stirred at room temperature for 45 minutes. LCMS analysis showed complete disappearance of the parent compounds. The reaction mixture was concentrated, and the residue was washed twice with ether. White powder in 2 ml of ether was additionally treated with ultrasound for 10 minutes. Then, the white solid residue was washed twice with ether and kept at high pressure for 12 hours. The output was 30.2 mg

Example 6: obtain the compounds 101, 102, 107, 113, 114, 121, 123 and 124

Stage 1: Dianiline (0.15 mol) and dicarboxylic acid (0,062 mol) was combined with pyridine (121 ml) and a magnetic stirrer, purged in nitrogen 2 l RBF and stirred until the suspension with small pieces for 15 minutes. Then, were added EDCI (0.185 mol)and the mixture was stirred at room temperature for 7.5 hours. The reaction extinguished with water (810 ml). The product was purified column chromatography and the and rubbing, using heptane and ethyl acetate.

Stage 2: the Product of stage 1 (0,179 mol) and ({[(tert-butoxycarbonyl)amino][(tert- butoxycarbonyl)imino]methyl}amino)pentane acid (0,734 mol) was dissolved in 2.1 liters of dry pyridine. The solution was cooled to -20°C-0°C. To the solution was slowly added POCl3(0,716 mol) over 30 minutes. The reaction mixture was stirred for 2 hours at -20°C to 0°C and then heated to room temperature and was stirred for the next 2 hours. In order to stop the reaction was added to ice water (8 l). Precipitated solid precipitate was collected and purified or column chromatography or by rubbing.

Stage 3: the Product of stage 2 (98,4 mmol) was dissolved in 465 ml of formic acid. To the solution was added 246 ml of 4M HCl in dioxane and stirred at room temperature for 10 hours. To this reaction mixture was added 1-butanol (2.5 liters). The resulting precipitate was collected by filtration and was purified reversed-phase column chromatography.

Example 7: the formation of compounds 122 and 126-129

Stage 1: Initial diamine get, applying the same methodology as in stage 1 General synthesis of 2. The diamine was treated with 50% triperoxonane acid in dichloromethane for 2 hours. The resulting R is the target concentrated to an oil and triturated with chilled diethyl ether. The solid residue was collected by filtration.

Stage 2: the Product of stage 1 (1 mmol) and N,N'-bis-Boc-1-guanidinate (2 mmol) was dissolved in 10 ml of methanol, followed by addition of 2 equivalents of diisopropylethylamine. The mixture was stirred over night at room temperature before removal of solvent on a rotary vacuum evaporator. The product was purified column chromatography.

Stage 3: This stage was similar to the stage 2 General synthesis of 2, using the product of stage 2 and Ntert-butoxycarbonylamino acid.

Stage 4: This stage is similar to stage 3 in the total synthesis of 2.

Example 8: Getting connection 108

The connection 108

Receiving is similar to the General synthesis of 2 except that in stage 3 apply ({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)propanoic acid.

Example 9: Getting connection 125

Stage 1 and 2 are similar to stages 1 and 2 receive connection 101.

Stage 3: the Product of step 2 was treated with 20% piperidine in DMF. After dilution with ethyl acetate and washing with 10% citric acid and salt solution, the organic phase was concentrated and triturated with hexane.

Stage 4: Product stage 3 (0.03 mmol) was mixed with 4-nitrophe what informaton (2 EQ.) in 3 ml of DMF, with the subsequent addition of DIEA (4 EQ.). The reaction mixture was stirred for 4 hours before being diluted with ethyl acetate. The organic layer was washed with saturated K2CO3, 10% citric acid and water before concentrating to a solid residue. The solid residue was treated with 50% TFA in DCM and purified reversed-phase column chromatography.

Example 10: the connection 152

The original connection was received at stages 1-2 when the connection 123. The original Boc-protected amide (0,023 mmol) and 3-chloroperoxybenzoic acid (MCPBA, of 42.3 mg) was dissolved in DCM (0.8 ml) and stirred under Ar for 1 hour. The reaction mixture was diluted with DCM and washed with saturated Na2S2O3saturated NaHCO3and water. The organic layer was dried and concentrated to a solid residue. The solid residue was treated with 50% TFA in DCM. The final product was purified reversed-phase column chromatography.

Example 11: the connection 153

Connection 153

Stage 1: Connection 124 (0.29 mmol) was dissolved in 10 ml of water and then added N-methylmorpholine (NMM, 2.7 EQ.) and 5 ml of DMF. Was added to the solution dropwise N-Boc-Gly-Osu (2.2 mmol) in 5 ml of DMF. The reaction mixture was stirred at room temperature for 20 minutes before concentri what Finance to the solid residue.

Stage 2: the Product of stage 1 was treated with 4 n HCl in dioxane and purified reversed-phase column chromatography.

Example 12: the formation of compounds 103-105 and 150

Stage 1: Besanon and carbonyldiimidazole (CDI) were mixed in dry DMSO (with a molar ratio of besanon:CDI=4:1). The reaction mixture was stirred at 100°C for 24 hours. After cooling, was added to the reaction mixture water. The precipitate was filtered and dried in vacuum. The crude product was purified on a column of silica gel with dichloromethane and ethyl acetate as eluents.

Stage 2 and 3 are similar to the stages 2 and 3 synthetic method for compound 101.

Example 13: Getting connection 151

Stage 1: Besanon (4 equiv.) and 1,4-benzodiazelines (1 EQ.) mixed in dry DMSO. The reaction mixture was stirred at 100°C for 24 hours. After cooling, was added to the reaction mixture water. The precipitate was filtered and dried in vacuum. The crude product was purified on a column of silica gel with dichloromethane and ethyl acetate as eluents.

Stage 2 and 3 are similar to the stages 2 and 3 synthetic method for compound 101.

Example 14: the connection 112

The connection 112

2-Chloro-4,6-dimethoxy-1,3,5-triazine was stirred in anhydrous THF. Was added N-methylmorpholine. The resulting mixture was stirred at room temperature for 30 minutes. Then, were added aniline and pyrimidine-4,6-dicarboxylic acid. The mixture was stirred at room temperature for 24 hours. Then, the solvent was completely evaporated in a vacuum. Was added water, and the mixture was stirred for 4 hours. The solid precipitate was collected and purified on a column of silica gel with dichloromethane and ethyl acetate as eluents. Boc-protected compound was unblocked, using 4 n HCl dioxane solution over night at room temperature to obtain the final product.

Example 15: Getting connection 116

Compound 116 was obtained using three schemes of synthesis.

Scheme 1

Stage 1: 8-(dihydroxyaryl)dibenzo[b,d]thiophene-2-Voronovo acid (4 mmol, 1.08 g) and 3-(3-bromophenyl)propanenitrile (8,8 mmol, 1,875 g) was added to a vial for microwave under argon. Added dioxane (10 ml), Pd(PPh3)4(0.4 mmol, 0,46 g) and K2CO3(16 mmol, 4 ml, 4M). The mixture was irradiated with microwave (120°C, 15 minutes) with stirring. Then the reaction was cooled to room temperature and was extracted with EtOAc and the saline solution. The organic layer was dried over NaSO4and evaporated in vacuum. The remainder acidalia column of silica gel (eluent: EtOAc/hexane = 1/2, about/about). The yellow solid residue (1.18 g, 70%) was obtained as product.1H-NMR was acceptable.

Stage 2: 2,8-di(3-phenylpropionitrile)benzothiophen (1,33 mmol, 0,59 g) and the hydrate of oxide of platinum (80 mg) was mixed in a mixture of MeOH (10 ml)/EtOAC (40 ml). Was added HCl (2 mol, 0.5 ml of 4M in dioxane). After removal of air was injected hydrogen at 60 psi. The mixture was shaken over night. Then, hydrogen was removed. The mixture was filtered through a layer of celite. The filtrate was evaporated in vacuum. The residue was purified reversed-phase HPLC. The solid residue (70 mg, 12%) was obtained as product. LC-MS and1H-NMR were acceptable.

Scheme 2

Stage 1, 2 and 3: Getting 2,8-di(tert-butyl 3-phenylpropionate)benzothiophene.tert-Butyl 3-(3-bromophenyl)propylgallate intermediate compound was obtained from 3-(3-bromophenyl)propanenitrile recovery using BH3and subsequent Boc-protection.tert-Butyl 3-(3-bromophenyl)propylgallate (2.2 mmol, 0,69 g), 8-(dihydroxyaryl)dibenzo[b,d]thiophene-2-Voronovo acid (1 mmol, 0,272 g) were mixed in the vial for microwave under argon. Added dioxane (4 ml), Pd(PPh3)4(0.1 mmol, 0,115 g) and K2CO3(2 mmol, 2 ml, 4M). The mixture was irradiated with microwave (120°C, 15 minutes) with stirring. Then the reaction was cooled to room temperature and was extracted with EtOAc and the saline solution. Organic is Loy was dried over Na 2SO4and evaporated in vacuum. The residue was purified on a column of silica gel (eluent: EtOAc/hexane = 1/100-1/2, V/V). The yellow solid residue (1.0 g, 76,9%) was obtained as product.1H-NMR was acceptable.

Stage 4: the Yellow solid residue from the above reaction was stirred in 10 ml of HCl in dioxane (4 M) at room temperature over night. Then, the mixture was filtered, and the filter residue was washed with ether. The solid residue was purified through reversed-phase column chromatography. Got a white precipitate (0,376 g, 46.6 per cent). LC-MS and1H-NMR were acceptable.

Scheme 3

The intermediate connection 2,8-di(tert-butyl 3-phenylpropionate)benzothiophen was obtained by Suzuki reaction of 2.8-dibromobenzoate andtert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylgallate, which was obtained fromtert-butyl 3-(3-bromophenyl)propellerblade. Compound 116 was obtained by following the same reaction conditions of release in scheme 2.

Example 16: the connection 106

Following the same methodology scheme 2 connections 116, compound 106 was obtained with a total yield of 45% in the form of a white solid residue.

Example 17: the formation of compounds 110, 117, 118, 119, 131, and 132

Following the same methodology scheme 3 connections 116, connection 110, 117, 118, 119, 131, and 132 received from the total outputs is 68%, 40%, 20%, 22%, 71 % and 15%, respectively.

Example 18: the connection 130

Following the same methodology diagram 1 connection 116, the connection 130 was obtained with a total yield of 7%.

Example 19: Obtaining connection 120

2,8-dibromobis[b,d]furan was obtained by bromirovanii with 29%. Following the same methodology of scheme 3, compound 120 was obtained with the yield of 69% after two-stage reaction.

Realizing significant therapeutic limitations of peptides, they developed a series of ones mimetics data AMP (SMAMP), which represent a new and effective therapy against many microbes, including, for example, malaria. In the present invention created a number of small molecules, site-specific oligomers and polymers SMAMP, which have a strong in vivo activity againstStaphyococcal aureusin mice, suggesting a new approach to the development of new therapeutic agents. Six of the data SMAMP experienced, and they have shown that is able to kill parasitesP. falciparumin a culture with a range IC50from 50 nm to 3 μm.

This approach has several advantages. Antimicrobial peptides remain an effective means of combating bacterial infection in the process of evolution, by showing that their mechanism of action inhibit bacterial response, which leads to resistance to toxic wishes is you. This premise is supported by direct experimental data, showing that significant resistance to antimicrobial peptides is not observed after multiple serial passages of bacteria in the presence of sublethal concentrations of peptides. Thus, the target-membrane parasites, but not proteins, are very innovative and new approach for the treatment of parasitic diseases and distinguish the present invention from most others in the field.

For a more complete assessment of the effects SMAMP inhibitors on the growth of parasites during the full life cycle, conduct analyses on the growth of cytotoxic and cytostatic conditions. Synchronized populations of parasites can be subjected to pulse with active SMAMP for 8 hours on "the ring", trophozoites or shizentai stages. Then, the inhibitors were removed by washing the parasites, and then the parasites can be allowed to finish its cycle. To assess the successful growth of parasites, it is possible to apply quantitative analysis of growth using parasites expressing the luciferase. Static effect can be distinguished from toxic effects and can determine the time of action of these compounds.

You can define morphological phenotypes resulting from inhibition. All the inhibitors can be assessed usingP. falciparump is rsity in cultural models erythrocytic cycle. Phenotypes for all treated parasites can be analyzed by applying the coating by Gisu and standard light microscope. After determining the time of death of the parasites, it is possible to apply DIC microscope with under time-lapse fluorescence microscope to determine that after you add SMAMP, the plasma membrane becomes disrupted.P. falciparumparasites expressing cytoplasmic GFP, can be applied in order to make possible the visualization of leakage is contained in the cytoplasm of substances after adding SMAMP.

To investigate the possibility of parasites to develop resistance to antiparasitic activity AMP connections,P. falciparumyou can sequentially previati 0.25× EC50and 0.5× EC50and EC50the top three concentrations AMP connections. The resulting EC50values can be defined at each passage for each inhibitor. As a control, parallel cultures can also be subjected to 0.5 EC50concentrations antifolate WR99210 and/or pyrimethamine, two recognized protivoaritmicheskih agents for whom informed about sustainability. If the parasites that are resistant to SMAMP develop, you can use the "tiling" chips (REF) in order to help identify any genes that contribute to the emergence of Usto the stability.

Can be designed SMAMP, which can be used to study mechanisms of action and resistance emergence, and it is possible to obtain compounds that are activein vivo. There was very good correlation between the relative toxicity of mammalian cells and the total hydrophobicity of the molecule. Activity in relation to specific bacteria correlated with the total affilinet molecules, as well as hydrophobicity, since the charge of the molecule is kept constant.

Example 20: Antibacterial activity against malaria parasites

Seven compounds with different structures testedin vitroagainst malarial agentPlasmodium falciparum.P. falciparumis the simplest parasite and is the infectious agent for the most common and deadly forms of malaria. He is the cause of 80% of all malaria infections in humans and 90% of deaths. More than 120 million clinical cases of malaria and 1 to 1.5 million deaths occur worldwide each year. There is no vaccine for malaria, and modernized methods of therapy suffer from rapid emergence of resistance, which has become endemic in some regions of the world. Several antimicrobial peptides have protivorahiticheskimi activities and, apparently, destroy the parasite is in the interaction with the plasma membrane, causing increased permeability, lysis and death. Specificity to cells of parasites compared to host cells, which are mammals, are attributed to the differences in the phospholipid composition and the absence of cholesterol in the membrane protozoa.

Protivodiabeticheskie activity measurein vitroby applying the analysis using the red blood cells of man. OneP. falciparumthe organism usually infects erythrocytes and produces 24 child within 48 hours after infection. The seed is released and rapidly infects neighboring red blood cells. Seven compounds (table 1) were first tested at one concentration and 6 of the 7 compounds destroyedP. falciparumoffspring at 10 μm concentration. Four of the active compounds was further tested to determine the IC50and IC100values, or minimum concentrations resulting in 50% and 100% destruction, respectively. Observations also were conducted during a 48 hour period of incubation to assess the susceptibility of the parasites during the stages of the life cycle inside and outside of the erythrocyte host. Two connections, the connection 116 and the connection 107, have sub-micron destroying activities and connection 116 effectively kills with IC50 of 0.05 μm. The observations performed during the cycle of infection, showed that only the parasitic body the isms inside the erythrocytes were seen in the presence of active compounds, and it was not visible organisms outside the cells. Together, these data show that the compounds quickly destroys protozoa between time of release and before re-infection. One goal of the action on the membranes of parasites, but not to proteins or metabolic pathway, is extremely innovative and a new strategy for the treatment of parasitic diseases and distinguishes this approach from most others in the field.

Table 1
SusceptibilityP. falciparumconnections
Connection% destroyed @ 10 micronsIC50(µm)IC100(µm)
1161000,0500,850
1071000,2000,850
1021001,53,5
1031000,2001,5
101100NT NT
108100NTNT
102<10NTNT

Example 21: Antimalarial activity

Several compounds were tested in cultures ofP. falciparumat a concentration of 1.0 or 1.5 μm, and they showed high efficiency. Of the tested compounds, compound 106 and 107 showed the best results. Compound 106 was IC50in 3D7 cells 150 nm with cytotoxicity approximately 40-50 microns in HepG2 human cells. Compound 107 was IC50in 3D7 cells 275 nm with cytotoxicity approximately 50-100 μm in HepG2 human cells. The destruction of the parasites usually took place between 6 and 9 hours (data not shown). Neither of the two compounds, however, was not hemolytic, as defined by the treatment of uninfected red blood cells using standard analysis of absorption for the release of hemoglobin (data not shown). In addition, both compounds were destroyed food vacuoles, as tested for parasites, expressionwhich marker for food vacuoles (plasmepsin II-YFP), with the integrity of the food vacuoles, measured using a standard fluorescent microscope is.

Example 22: Antimalarial activity

Connections 106 and 107 also experienced in culturesP. falciparum3D7 and DD2 and compared with chloroquine. Flow cytometry was used to quantify the presence of parasites in the blood, using SYOX Green on LSRII. The results are shown in table 2.

Table 2
ConnectionIC50(3D7)IC50(DD2)
chloroquine20 nm80 nm
Connection 107275 nm200 nm
The connection 106150 nm100 nm

DD2 strain ofP. falciparumis 4 times more resistant to chloroquine than the 3D7 strain. Both connections 106 and 107 were effective against strain DD2. Thus, these compounds are effective against sensitive to chloroquine and/or chloroquine resistant strains.

Example 23: Antimalarial activity

Many compounds were initially tested using quantitative analysis of high-throughput, in which remaneat parasites expressing cytoplasmic luciferase Firefly (obtained from Dr. Kirk Deitsch, Cornell Medical College). These parasites transferout vector, containing the gene for Firefly luciferase, using malaria HRPII promoter. For cultivation of parasites, used cups for cultivation, from 96 well plates to 30 ml cups. Originally used 3D7 strain ofP. falciparumfor assays and transfection, because he was sensitive to chloroquine, the standard strain and was used in the draft sequence of the genome. Parasites were cultured in human RBC in an atmosphere of 5% O2/7% CO2/88% N2in RPMI 1640 medium supplied with 25 mm Hepes, 30 mg/l gipoksantina, 0,225% (in/Rev) NaHCO3and 0.5% (V/V) Albumax II (Life Technologies, Grand Island, NY). The growth of parasites is usually synchronized by combining sequential processing D-sorbitol for the selection of parasites on the "ring" stage, followed by selective clearing of Mature schizonts using Super Macs II magnetic separator (Miltenyi Biotec).

The standard device for recording the luminescence was used to measure the growth of parasites. Parasites were grown in normal conditions, literally in the presence of the fluorescent reagents (Bright GIo, Promega), and then measured. For the initial test on the growth of parasites expressing the luciferase synchronized using sequential processing of sorbitol, and then Alicia parasites in the blood, the percentage of RBC infected with parasites, coordinated, using uninfected RBC. 100 μl of complete medium was used in 96-well format. Infected RBC were incubated in 96-well tablets at 37°C and saturated gas with 5% CO25% of O290% of N2. Parasites were grown for approximately 60 hours before they successfully divided out from the cell and infect new PNC. 10-15 hours after infection the cells were literally, and measured the concentration of luciferase using Analyst HT luminometer (Molecular Devices). The results are shown in table 3.

Table 3
ConnectionIC50mcm
Artesunate0,009
The connection 1061,153
The connection 1180,364
Connection 1191,858
The connection 1100,584
Connection 1170,301
The connection 104>10
Connection 111 0,587
Connection 1130,241
The connection 112>10
Connection 1200,604
Connection 1211,505
The connection 114>10
Connection 1025,376
Connection 1030,783
Connection 1070,314
The connection 1160,318
Connection 1010,308
The connection 122is 0.260
Connection 1231,366
The connection 1241,582
Connection 1290,832
Connection 1281,725
Connection 1271,765
Connection 1261,420
Connection 1250,286

The connection 1302,559
Connection 1310,235
Connection 1320,236
Connection 1332,028
Connection 1342,438
Connection 135to 0.108
Connection 1360,958
Connection 1370,604
Connection 1380,213
Connection 1391,169
The connection 1401,674
Connection 1420,063
Connection 1540,200
Connection 1490,357
Connection 1411,344
Connection 13 0,258
Connection 1443,399
Connection 1450,369
Connection 146to 0.127
Connection 1550,535
Connection 1520,783
Connection 1530,925
Connection 1506,608
Connection 1512,784
Connection 1470,221
Connection 1480,704
Connection 1560,107

Various modifications of the present invention, in addition to the modifications described in this invention will be obvious to experts in the art from the preceding description. It is also assumed that the data modification is included in the scope of the attached claims. Each reference (including, but not limited to, articles from journals, patents in the U.S. and other countries, published patent applications, international the derivative of a published patent application, access number of gene banks and the like)cited in the present application, is introduced in the present invention fully by reference.

1. The compound of formula III:

where:
Z represents,or phenyl;
each Q independently represents
or - C(=O)-(CH2)b-NH-C(=NH)-NH2where each b is 4;
each X independently represents O or N;
each R1independently represents H or CF3;
each R3independently represents H, -(CH2)r-NH2, -NH-(CH2)w-NH2orwhere each r independently represents 1 or 2; each w is 2 and each y independently represents 1 or 2;
each R4independently represents H, -NH-C(=O)-(CH2)p-NH-C(=NH)-NH2orwhere each p independently represents 4, and each q independently represents 1 or 2; and
each R5independently represents H or CF3;
or its pharmaceutically acceptable salt;
provided that the compound is not:




2. The compound according to claim 1, chosen from:
,,
,
,
,
,,
and
or its pharmaceutically acceptable salt.

3. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.

4. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of a compound according to claim 1 or claim 2 or a composition according to claim 3.

5. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of a compound according to claim 1 or claim 2 or a composition according to claim 3.

6. The compound of formula VIII:

where:
D representsor;
each B independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;
or;
each X independently represents O or S;
or headlamp is asepticheski acceptable salt.

7. The compound of claim 6 selected from:
,
,
and

or their pharmaceutically acceptable salts.

8. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt according to claim 6 or claim 7 and a pharmaceutically acceptable carrier.

9. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of a compound according to claim 6 or claim 7 or the composition of claim 8.

10. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of a compound according to claim 6 or claim 7, or its pharmaceutically acceptable salt, or a composition of claim 8.

11. The compound of formula I:

where:
X represents N(R9), O, S, S(=O) or S(O)2;
R9represents H or C1-C8alkyl;
R1and R2independently represent H or C1-C8alkoxy;
R3and R4independently represent a phenyl(R5)(R6) or pyridyl(R5)(R6);
each R5and each R6independently represent piperazinil,
-(CH2)n-NH2,or -(CH2)n-NH-(CH2)n-NH2,or -(CH2)n-NH-C(=N)NH 2where each n independently represents 1-8;
or its pharmaceutically acceptable salt.

12. Connection claim 11, selected from:
,,,
,,,,
,,,,,,,and
or their pharmaceutically acceptable salts.

13. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt according to claim 11 or 12 and a pharmaceutically acceptable carrier.

14. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compound according to item 11 or item 12 or the composition according to item 13.

15. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of the compound according to item 11 or item 12 or the composition according to item 13.

16. The compound of formula II:

where:
X represents O;
each Y is independently p is ecstasy an O or S;
each R1independently represents pyrrolidinyl or -(CH2)n-NH2where each n independently represents 1-4; or
each R1independently together with Y represents a 5 piperazinil;
each R2independently represents CF3or C(CH3)3;
each R3independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;
or its pharmaceutically acceptable salt.

17. Connection P16, chosen from:
,
,
and

or their pharmaceutically acceptable salts.

18. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt according to item 16 or 17 and a pharmaceutically acceptable carrier.

19. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compound according to item 16 or 17, or the composition of p.

20. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of a compound according to A16 or 17 or song on p.

21. The compound of formula IV:

where:
G representsthe sludge is ;
each X independently represents O or S;
each R1independently representsor -(CH2)n-NH2where each n independently represents 1-4;
each R2independently represents a C1-C8alkyl or (CH2)n-NH2where each n independently represents 1-4;
each R3is a CF3;
each R4independently represents -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;
or its pharmaceutically acceptable salt;
provided that the compound is not:
.

22. Connection item 21, selected from:
,
and

or their pharmaceutically acceptable salts.

23. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt according to item 21 or article 22 and a pharmaceutically acceptable carrier.

24. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of the compound according to item 21 or article 22 or composition according to item 23.

25. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of travel is in item 21 or article 22 or composition according to item 23.

26. The compound of formula V

where:
each X independently represents O, S or S(=O)2;
each R1independently represents -(CH2)n-NH2, -(CH2)n-NH-C(=NH)NH2or -(CH2)n-NH-C(=O)-R4where each n independently represents 1 to 4, and
each R4independently represents H or -(CH2)p-NH2; where each p independently represents 1 or 2;
each R2independently represents H, halogen, CF3or C(CH3)3;
each V2represents H, and
each V1independently represents a-N-C(=O)-R3where each R3independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1 to 4; or each V1represents H, and for every V2independently represents-S-R5where each R5independently represents -(CH2)n-NH2or -(CH2)n-NH-C(=NH)NH2where each n independently represents 1-4;
or its pharmaceutically acceptable salt;
provided that the compound is not:
a);
b);
c); or
d)

,
,
,
,
,
,
,
,
,
,
,
,
and

or their pharmaceutically acceptable salts.

28. Pharmaceutical composition for the treatment of malaria or destroy or inhibit the growth of species ofPlasmodiumcontaining the compound or salt p or item 27 and a pharmaceutically acceptable carrier.

29. A method of treating malaria in an animal, comprising an introduction to the animal a therapeutically effective amount of a compound according p or item 27 or the composition of p.

30. Method for killing or inhibiting the growth of a species ofPlasmodiumthat includes contacting the species with an effective amount of a compound according p or item 27 or the composition of p.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are racemic- or enantiomer-rich 3-substituted piperidine compounds of formula (I) or pharmaceutically acceptable salts thereof, where A denotes phenyl, naphthyl, optionally substituted, or benzothiophenyl; B denotes an azole selected from a group consisting of triazole, benzotriazole, 5-methyl- or 5-phenyltetrazole; Y-CH2 and X- N-R, where R denotes hydrogen or C1-4alkyl, pharmaceutical compositions containing said compounds, and methods of treating depression, anxiety or pain disorder in mammals.

EFFECT: high efficiency of using compounds.

11 cl, 4 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted indole derivatives of formula , where A and B are independently CH2 or C=O, X is indolyl, unsubstituted or mono- or polysubstituted; T is (CR5a-cR6a-c)n, n=1 or 2. Q is (CR7a-cR8a-c)m, m=0, 1 or 2, the values of the rest of the radicals are given in claim 1, which act on the ORL1 receptor.

EFFECT: improved method.

13 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole compounds of formula I or pharmaceutically acceptable salts thereof: I, where: Ar denotes phenyl, thiophenyl; R1 denotes imidazolyl, imidazolyl substituted with C1-C6alkyl, chlorine, bromine, fluorine, hydroxy group, methoxy group; R2 denotes H, CH3, Cl, F, OH, OCH3, OC2H5, propoxy group, carbamoyl, dimethylamino group, NH2, formamide group, CF3; X denotes CO and SO2. The compounds inhibit S-nitrosoglutathione reductase (GSNOR).

EFFECT: using the compound to produce a pharmaceutical composition and for treating asthma.

17 cl, 1 tbl, 14 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic electroluminescent devices based on compounds of formula

where Y, Z is selected from N, P, P=O, C=O, O, S, S=O and SO2; Ar1, Ar2, Ar3 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene or thiophene, optionally substituted with R1; Ar4, Ar5, Ar6, Ar7 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene, thiophene, triphenylamine, diphenyl-1-naphthylamine, diphenyl-2-naphthylamine, phenyldi(1-naphthyl)amine, phenyldi(2-naphthyl)amine or spirobifluorene, optionally substituted with R1; E is a single bond, N(R1), O, S or C(R1)2; R1 denotes H, F, CN, alkyl, where the CH2 can be substituted with -R2C=CR2 -, -C=C-, -O- or -S-, and H can be substituted with F, optionally substituted aryl or heteroaryl, where R1 can form a ring with each other; R2 denotes H, aliphatic or aromatic hydrocarbon; X1, X4, X2, X3 are selected from C(R1)2, C=O, C=NR1, O, S, S=O, SO2, N(R1), P(R1), P(=O)R1, C(R1)2-C(R1)2, C(R1)2-C(R1)2-C(R1)2, C(R1)2-O and C(R1)2-O-C(R1)2; n, o, p, q, r and t are equal to 0 or 1; s = 1.

EFFECT: obtaining novel compounds - emission layer dopants, and novel electroluminescent devices based on said compounds which emit a blue colour.

18 cl, 91 ex, 6 tbl

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to cocrystalline form of (1S)-1,5-anhydro-1-[3-(1-benzothiene-2-ylmethyl)-4-fluorophenyl]-D-glucitol (compound A) with L-proline. Proposed cocrystalline form is a promising anti-diabetes medicine.

EFFECT: cocrystalline form of compound is characterised with constant composition, improved stability in storage, and also low hygroscopicity, and is suitable for use as crystalline medicinal substance to produce pharmaceutical preparations.

11 cl, 1 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: method includes synthesis of o-phenylenediamine (o-PDA) dihydrochloride first by dissolving o-PDA in hydrochloric acid solution, filtering the obtained solution and vacuum evaporation to a dry residue which is dried at 105-110°C; mixing the dry o-PDA dihydrochloride with urea, heating the obtained mixture on a paraffin bath to 150°C, cooling the obtained melt, grinding and dissolving in a warm diluted sodium hydroxide solution, filtering, adding hydrochloric acid to the filtrate until neutralisation, filtering out the precipitated benzimidazolone-2, purifying by recrystallising from ethanol; adding phosphorus oxychloride to the benzimidazol-2one, adding concentrated hydrochloric acid, heating at 145-150°C for 4 hours, stirring after cooling the mixture and pouring on ice, filtering out the reaction mixture, neutralising the filtrate with 10 ammonia solution to pH 7-8, filtering the 2-chlorobenzimidazole precipitate, drying at 60°C, recrystallising from a mixture of ethanol and water in ratio of 1:1; synthesis of 2-chloromethylthiirane by mixing epichlorohydrin and ethanol, cooling to 0°C, adding ground thiourea, mixing for 60 minutes at 0-5°C, slowly raising temperature to 20°C for 60 minutes and stirring at said temperature for 3 hours, filtering, pouring the filtrate in three portions into a separating funnel containing 3 litres of water, collecting the organic layer, washing with water, filtering, drying the filtrate, adding anhydrous calcium chloride, filtering and vacuum distillation. Further, the method includes synthesis of 1-(thietanyl-3)-2-chlorobenzimidazole by adding 2-chlorobenzimidazole to aqueous potassium hydroxide solution, heating to 70°C and adding 2-chloromethylthiirane, stirring the reaction mixture at said temperature until achieving pH≤7, filtering out the filtrate, washing with diethyl ether, 10% potassium hydroxide solution, water, drying, purifying by crystallisation from a mixture of ethanol and water in ratio of 1:1, separating the organic and aqueous layers, adding hydrochloric acid solution to the aqueous solution to pH 5-6, filtering out the precipitate, washing with water and drying. Further, 2-[1-(1,1-dioxothietanyl-3)benzimidazolyl-2-thio]acetic acid is obtained using thioglycolic acid solution and potassium hydroxide solution in distilled water, boiling for 30 minutes, cooling to room temperature, filtering the solution, acidifying the filtrate with hydrochloric acid to pH 3-4, filtering out the precipitate, washing with water and drying. The end product is obtained by adding potassium hydroxide to a solution of 2-[1-(1,1-dioxothietanyl-3)benzimidazolyl-2-thio]acetic acid in ethanol, boiling the mixture for 45 minutes, cooling, filtering out the filtrate and drying.

EFFECT: novel method of producing a compound, which increases the output of the end product while reducing the time and cost of production.

1 ex

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