Methods of obtaining bicyclic amidinohydrolase (options) and the bicyclic hydroxyamide
(57) Abstract:
The invention concerns a method of obtaining a pharmaceutically active compounds of the formula V< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes a Deputy than hydrogen, selected from methyl and ethyl, And represents -(CH2)nwhere n is 1,2,3 or 4, and R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl, or their tautomers, or salts, which, as described, passes through the compounds of formula I
< / BR>where R1, R2and have the specified values, or their salts, as well as the use of new compounds I as intermediates. 3 S. and 6 C.p. f-crystals. The invention relates to new methods of producing pharmaceutically active bicyclic amidinothiourea of amidinohydrolase, and to new bicyclic to hydroxyamides, which are intermediate compounds for obtaining pharmaceutically active bicyclic amidinothiourea of amidinohydrolase, in the form of various touch">Methods of obtaining pharmaceutically active amidinohydrolase described in EP A (published 13.11.1991). The patent describes, for example, three ways to obtain (4-amidino-1-indanone-2'-amidinopropane) formula Va
< / BR>and its salts.The first way is that 4-cyano-1-indanone formula
< / BR>in pyridine and in the presence of triethylamine at a temperature of approximately 40oC using hydrogen sulfide is transformed into 4-thiocarbamoyl-1-indanone formula
< / BR>The obtained 4-thiocarbamoyl-1-indanone in absolute methylene chloride in the atmosphere of argon at room temperature is treated with triethylorthoformate in ethylthio-iminoethyl formula D
< / BR>which then in absolute ethanol transform using ammonium chloride in boiling and subsequent chromatography on resin-adsorbent converted into the hydrochloride of 4-amidino-1-indanone formula E
< / BR>which is then transformed using aminoguanidine-hydrocarbonate in aqueous metal solution at boiling in the presence of hydrochloric acid into the hydrochloride of the compound of formula Va.The second way is that 4-cyano-1-indanone using hydrogen sulfide is transferred to the connection formula, as described new hydrochloric acid at reflux conditions to obtain 4-thiocarbamoyl-1-indanone-2'-amidinohydrolase formula F
< / BR>in the form of hydrochloride. Last using triethylorthoformate in methylene chloride and in the atmosphere of argon at room temperature is converted into the corresponding dihydrochloride - ethylthio-aminoether formula G
< / BR>which then in absolute ethanol using ammonium chloride and subsequent chromatographic purification on the resin-absorbent turns into the dihydrochloride of the compound of formula Va.It would be desirable to find a method of obtaining compounds of formula Va, which does not require conversion with poisonous, gaseous hydrogen sulfide and where all intermediate and final products after the reaction is provided directly in crystalline form, so that would not require any chromatographic separation.The third method, described in EP A, is that 4-cyano-1-indanone first turn using bicarbonate aminoguanidine in aqueous-methanolic hydrochloric acid at reflux conditions for 4 days in hydrochloride 4-amidino-1-indanone-2'-amidinohydrolase formula N
< / BR>which is treated in absolute methanol with sodium methylate in conditions of reflux and then treated with ammonium chloride to obtain dihydrochloride connection formul, such as, for example, 4-day transformation, and leads to the compound of formula H under conditions of reflux.Was unexpectedly discovered a method using a new type of intermediate products and selective catalytic hydrogenation of N-acetamidino 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone.According to the present invention offers a method of obtaining a pharmaceutically active bicyclic amidinothiourea of amidinohydrolase formula V
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of the two radicals R1and R2denotes Deputy other than hydrogen, selected from methyl and ethyl, And represents -(CH2)nwhere n is 1,2,3 or 4, and R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl, or its tautomers; or its salt.The method consists in the fact that the compound of the formula I
< / BR>where R1, R2and a have the meanings mentioned above,
or its salt is subjected to interaction with aminoguanidine formula III
< / BR>where R3, R4, R5and Rwhat receiving examinination formula IV
< / BR>where R1, R2, R3, R4, R5, R6and a have the meanings specified for compounds of formula V,
or tautomer, or its salt.The resulting examinination formula IV, or its tautomer either in free form in the presence of an acid or as a salt selectively hydronaut in the presence of a catalyst, to obtain the compounds of formula V, where the radicals have the above significance, or its tautomers, or salts, followed, if necessary, transfer salts of the compounds of formula V or its tautomer in free form or another salt, and/or separation of the mixture of isomers of compounds of formula V or its tautomer or its salts of the isomers, and/or converting the compounds of formula V or its tautomer into another compound of formula V or its tautomer.It is preferable in obtaining the compounds of formula V, or its tautomer, or salts thereof, where each of the radicals R1and R2denotes hydrogen, And denotes-CH2- and each of the radicals R3, R4, R5and R6denotes hydrogen, the compounds of formula I, to use the compound of formula I, or salts thereof, and compounds of formulas III and IV, or their tautomers; or their salts, is of oral III and V, or its tautomers, or their salts, where each of the radicals R3, R4, R5and R6denotes hydrogen.It is desirable transformation of compounds of formula I, the compounds of formula IV to carry out when using 1-2-fold molar amount aminoguanidine formula III relative to the molar amount of the compounds of formula I, with aminoguanidine of the formula III are preferably used in the form of a salt halomonadaceae acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or in situ from the corresponding salt readily volatile weak acid by adding a strong acid, in a mixture of water one or more alcohols at temperatures ranging from room temperature up to the boiling temperature under reflux corresponding reaction mixture; and selective hydrogenation to convert gidroksietilirovaniya formula IV to the compound of formula V is preferably carried out in the presence of Nickel as a catalyst, which is used in powdered form or media, in the presence of acid taken in the stoichiometric required for salt formation with both main contractoring organic solvents with water or in the water at temperatures in the range of 0oC to the boiling temperature under reflux suitable solvent by passing hydrogen to its absorption of the calculated amount with obtaining the compounds of formula V in the crystalline form of the salt used acid.Another method according to the invention is a method of obtaining compounds of formula V, where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes Deputy, other than hydrogen, selected from methyl and ethyl, And represents -(CH2)nwhere n is 1,2,3 or 4, and R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl, or its tautomers; or its salt, is that the compound of formula II
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes a Deputy than hydrogen, selected from methyl and ethyl,
And represents -(CH2)nwhere n is 1,< / BR>or its salt,
where R1and R2have the values specified above.The resulting compound of formula I or its salt is treated with aminoguanidine formula III
< / BR>where R3, R4, R5, R6independently of one another denote hydrogen or lower alkyl,
or tautomers, or its salt, the receiving examinination formula IV
< / BR>where R1, R2, R3, R4, R5and R6have the values specified above for compounds of formula V,
or tautomer, or its salt. Examinination formula IV, or its tautomers, in free form in the presence of acid or its salts selectively hydronaut in the presence of a catalyst, obtaining the compound of formula V, where the radicals have the abovementioned meanings, or tautomer, in the form of a salt, and, if necessary, the salt of the compounds of formula V or its tautomer translate into a free form or another salt, and/or the mixture of isomers of compounds of formula V or its tautomer, or its salt, is separated into the isomers, and/or the compound of formula V or its tautomer transferred to another compound of formula V or its tautomer.It is preferable in obtaining the compounds of formula V, or its tauto which each of the radicals R3, R4, R5and R6denotes hydrogen from compounds of formula II, to use the compound of formula II, the compounds of formula I or their salts and compounds of formulas III and IV, or their tautomers, or their salts; where each of the radicals R1and R2represents hydrogen and a represents-CH2- and in the connection of the formula III or their toomelah, or their salts, each of the radicals R3, R4, R5and R6denotes hydrogen.It is desirable in the implementation of this method, the conversion of the compounds II to the compounds of formula I with a parallel transformation of carbonyl - and ceanography to carry out a double-a ten-fold molar amount of hydroxylamine or hydroxylamine salt in relation to the molar amount of the compounds of formula II, with inorganic acids, carboxylic acids or sulfonic acids in water, di-ness.alkynes.alkanolamide or a mixture of water with one or more alcohols at temperatures ranging from -30 to 100oC, at normal pressure and acid neutralizing hydroxide, carbonate or bicarbonate, a salt of a weak organic acid or a secondary or tertiary amine, and the conversion of compounds of formula I to compound of formula IV prepact the Oia to the molar amount of the compounds of formula I, in this case, as a rule, aminoguanidine of the formula III is used in the form of salt kaleidotrope acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or first obtained in situ from the corresponding salt readily volatile weak acid by adding a strong acid, in a mixture of water and one or more alcohols at a temperature ranging from room temperature up to the boiling temperature under reflux corresponding reaction mixture, and selective hydrogenation to convert hydroxyamino the compounds of formula IV to the compound of formula V is carried out in the presence of Nickel as a catalyst, used in micronized form or media, in the presence of acid taken in the stoichiometric required for salt formation with the two main centers of the compounds of formula IV quantity or in excess (weak acid with a magnitude of the PKs>4), in a mixture of water-soluble organic solvents with water or in the water at a temperature of from 0oC to the boiling temperature under reflux suitable solvent feeding hydrogen to its absorption of the calculated amount is ri, the process may also t compounds of the formula II into compounds of the formula I to carry out a step by sequential transformation of the first 1-ketogroup and then ceanography, and initially transformed ketogroup in position 1 of the Central Bicycle with hydroxylamine, and the hydroxylamine is taken in one-, two-times molar excess relative to the compound of formula II and hydroxylamine reacts in the form of salts kaleidotrope acid in alcohol at a temperature of from about 75 to 80oC, to obtain the corresponding lanoxine, which then use the two-, three-fold molar amount of hydroxylamine in the form of a salt kaleidotrope acid in alcohol in the presence of alkaline earth metal alcoholate at temperatures from 60oC to the boiling temperature under reflux, the transformation of ceanography translated into the corresponding compound of formula I, which is further transferred to the compound of formula IV with one-, two-times the molar amount aminoguanidine formula III relative to the molar amount of the compounds of formula I, and aminoguanidine of the formula III is used as a salt kaleidotrope acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or first obtained in situ from the corresponding salt readily volatile weak acid by wnou to the boiling temperature under reflux corresponding reaction mixture, and selective hydrogenation to convert gidroksietilirovaniya formula IV to the compound of formula V is carried out in the presence of Nickel as a catalyst, which is used in powdered form or media, in the presence of acid taken in the stoichiometric required for salt formation with the two main centers of the compounds of formula IV quantity or in excess (weak acid with a magnitude of the PKs>4), in a mixture of water-soluble organic solvents with water or in the water at temperatures in the range of 0oC to the boiling temperature under reflux suitable solvent feeding hydrogen to its absorption of the calculated amount with obtaining the compounds of formula V in crystalline form as a salt of the appropriate acid.The object of the present invention are also the compounds of formula I
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of the two radicals R1and R2denotes Deputy, other than hydrogen, selected from methyl and ethyl,
And represents -(CH2)nSUB>2denote hydrogen, And denotes-CH2or its salt.The compounds of formula I are valuable intermediates in organic synthesis, in particular, to obtain drugs. They are, in particular, intermediate products to obtain pharmaceutically active examinination of amidinohydrolase above formula IV and, in particular, bicyclic amidinothiourea of amidinohydrolase above formula V, which are described, for example, in EP A as inhibitors of S-adenosylmethionine (SAMDC) and thus are inhibitors of the growth of both eukaryotic and prokaryotic cells. This inhibitory effect of the compounds of formula V can be used for therapy of malignant diseases and for the treatment of infectious diseases caused by protozoa organisms.One unexpected aspect of the present invention deserves attention. Catalytic hydrogenation amidoxime salts in amidinov salt is already known (published application Germany 1568144, which describes the recovery only in non-aqueous media). However, in the literature there are references to the fact that the hydrogenation Asimov possible in such conditions, as, aprilutskiy Nickel catalysts within 1 to 2 hours in nonaqueous solvents [Winans F. C. and Adkins, H. J. Am. Chem. Soc.55, 2051 (1933)] . This acetonemia formed Isopropylamine, from phenylhydrazone of Butyraldehyde - n-butylamine, di-n-butylamine and aniline. Thus there is also a splitting-N-N-bond hydrazones. However, it is unexpected that the catalytic hydrogenation of the compounds of formula IV selectively on amidoximes the group is carried out without simultaneous cleavage or recovery group =N-NR3-(C=NR6)-NR4R5.General concepts used previously and hereinafter, are within the present invention, preferably, the following values.Depending on the structure of the compounds of formulas I,II,III,IV and/or V may be in the form of mixtures of isomers or pure isomers. For example, if R1and/or R2indicate other substituents than hydrogen, then the corresponding compounds of formula I can be in the form of racemates or pure enantiomers. In the compounds of formulas I and IV oxyiminegroups may have the configuration of the E - and/or Z [formula (E) or (Z)], in addition, there may be tautomeric forms T
< / BR>in which the radical X represents one of the radicals of the formula
< / BR>where Y represents one of the divalent radicals =NOH (in the formula (I) Il the e values.Preferred is Z-configuration (Z), however, it is also possible in the equilibrium solution or in solid form, the presence of E-form (E) or tautomer (T), in particular, their small quantities. Since we are talking about the compounds of formula I or IV, it is always covered by all existing in equilibrium isomers and/or tautomers.In the compounds of formula I oxyimino in 1st position Bicycle can be in configuration "sin" or "anti" or both configurations.The term "lower" means the content of the radical up to and including 7, preferably up to and including 4, carbon atoms.Typically, the radicals R1and R2located on the bicyclic core (or first stage) instead of hydrogen atoms of this Bicycle.When mentioned "connection, tautomer or its salts or compounds, tautomers or salts", it means "one or more" unless specified otherwise. When it says "connections", then under this you should understand a single compound, salt, or salt, if you have soleobrazutaya group, isomer or isomers as possible isomerism and/or tautomer or tautomers as possible tautomerism; if not specified.Lower alkyl PR is n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl.The tautomers can be formed, for example, if in the compounds of formulas III or VR3, R4and/or R5denote hydrogen. The corresponding guanidine moiety in the formulae III, IV and V in the form of-N(R3)-C(=NR6)-NR4R5may be in tautomeric forms, in particular-N=C(NR6)-NR4R5, -N(R3)- (- NR6)= NR5or-N(R3)- (- NR6)= NR4. Specialist known such and such tautomers. Compounds of General formulas I,III,IV and V cover all relevant tautomers.If a denotes the group -(CH2)nand R1and R2not represent hydrogen, the corresponding substituent R1and/or R2may also be on the carbon atom of the group -(CH2)n-.Radical And denotes a divalent linear radical of the formula -(CH2)n-, where n is 1,2,3 or 4, preferably 1 or 2, in particular, is 1.Salts of compounds of formula V are primarily used pharmaceutically non-toxic salt accession acids with acid [PA], which denotes a mono - or polycarboxylic kislotnyh acids, which can be unsubstituted or substituted, cycloalkylcarbonyl acids, arylcarboxylic acids, aryl-lower alkylcarboxylic acids, geterotsiklicheskikh acids, alkanesulfonyl, which can be unsubstituted or substituted, arylsulfonyl (aryl-SO2-), alkylene acids, N-substituted sulfamic acids, organic acids bases carboxy, sulfo-, sulfate - or hostgroup, and inorganic acids, such as carbonic acid, kaleidotrope acid, such as hydrochloric acid, sulfuric acid, or phosphoric pyrophosphoryl acid.The following definitions relate to the acid [PA] (PA] denotes a proton acid):
Alcamovia acids are primarily C1-C20-alcamovia acid, preferably C1-C7-alcamovia acid, such as formic acid, acetic acid, propionic acid, butyric acid, somalina acid, pentane acid, hexanoic acid or heptane acid, or, alternatively, octanoic acid, cekanova acid or dodekanisa acid, preferably acetic acid, propionic acid or octanoic acid, and these acids are unsubstituted or one - and the th, such as glycolic acid, lactic acid or 2-hydroxybutyric acid or multiply substituted, in particular, to have up to five hydroxyl groups, as, for example, gluconic acid or glukozaminoglicanov acid ("glucoheptonate acid"); a carboxyl group, for example, C1-C20-ascendicate primarily C1-C7-alcantarilla, such as succinic acid and adipic acid, Emelyanova acid, subernova acid or azelaic acid; hydroxyl and carboxyl group, for example, malic acid, tartaric acid, citric acid, glogarova or galactosemia acid; amino - or amino - and carboxyl group and/or have one or two radicals independently selected from mercapto, methylmercapto, hydroxyl group, phenyl, 4-oxyphenyl, cyclohexyl, imidazolyl or indolyl, such as, for example, amino acids, in particular, glutamic acid or aspartic acid (D), (L)- or (D,L)-, preferably (D)- or (L)-form; substituted amino - or amino - and carboxyl group and/or with one or two radicals independently selected from mercapto (in oxidized form, such as an appropriate disulfide of two molecules correspond to the and or indolyl, as, for example, amino acids, for example, N-mono - or N,N-di-lower alkylaminocarbonyl, such as, for example, N-methylglycine, or N-lower alkanolamines, such as, for example, N-methylglycine, or N-lower alkanolamines (for example, N-acetylglycine), N-acetylaspartate or N-acetylcystein, exography, such as pyruvic acid or acetoacetic acid, phospho - amino group, such as, for example, phosphoserine, or phospho - and hydroxyl group, such as 2 - or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid or fructose-1,6-Biosfera acid. Amino acids are primarily amino acids, which can be in (D), (L)- or (D,L)-form, preferably (L)- or (D) the form and in the presence of other asymmetric centers may be in the form of other isomers, for example, selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), Norvaline (-aminosalicilova acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (-aminohexanoic acid, (H-Nle-OH), serine (H-Ser-OH), homoserine (- amino--hydroxybutyric acid), threonine (H-Thr-OH), methionine (D-Met-OH), cysteine (H-Cys-OH) (which may also be in the oxidized form as cystine), phenylalanine (N-Ph Is (N-Cha-OH), cyclohexylglycine, tryptophan (L-Trp-OH), aspartic acid (H-Asn-OH), asparagine (H-Asn-OH), aminomalonate acid, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), -oxidizing, ornithine ((,-diaminopurine acid),- diaminoalkanes acid ,-diaminopropionic acid, arginine (H-Arg-OH) and lysine (H-Lys-OH). Particularly preferred amino acids are glycine, serine, cystine, aspartic acid and glutamic acid, especially aspartic and glutamic acid.Alkenone acids are, for example, C2-C10-eccenticity, which are unsubstituted, such as maleic acid or fumaric acid, or substituted, preferably a hydroxyl group, such as, for example, ximalayasha acid (tautomer: salewoman acid), or lower alkyl, for example, stands, such as, for example, methylmaleimide acid.Cycloalkylcarbonyl acid are preferably C4-C12-cycloalkylcarbonyl acid, where cycloalkenyl radical is mono-, bi - or tricyclic, preferably monocyclic or tricyclic, for example, cyclopentyl, cyclohexyl, cyclopentyl and what about acid.The aryl radical in arylcarboxylic acids is, for example, from 6 to 20, preferably from 6 to 14 carbon atoms, and selected from, for example, phenyl, 1 - or 2-naphthyl and Indiana, and is unsubstituted, such as, for example, benzoic acid or substituted, preferably by 1 to 3 radicals independently selected from lower alkyl, such as methyl, halogen, such as fluorine, chlorine or bromine, hydroxyl group, lower alkoxygroup, for example, metoxygroup, phenoxy-, lower alkanoyloxy-such as, for example, acetoxy, amino or carboxyl group. An example of such acids may be salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid or phthalic acid.In aryl-lower alkylcarboxylic acid aryl has the value specified for arylcarboxylic acids, and may be unsubstituted or substituted, and the lower alkyl is preferably stands or ethyl, and the lower alkyl may be unsubstituted as, for example, phenylacetic acid, or substituted, for example, a hydroxyl group, such as, for example, mandelic acid.In Ari is kenil is preferably from 2 to 5 carbon atoms, such as, for example, cinnamic acid.Heterocalixarenes acids may contain, for example, heterocyclyl from one to three rings, preferably one or two rings, which is saturated or partially or fully unsaturated, preferably saturated or unsaturated, having from 5 to 12 atoms in the ring, preferably from 5 to 7 atoms selected from carbon and up to three heteroatoms, preferably from one to two heteroatoms selected from oxygen, nitrogen and/or sulfur, primarily oxygen and nitrogen, and heterocyclyl, for example, is pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, pyrazinyl, pyrimidinyl, indolyl, hinely, ethanolic, honokalani or fully or partially saturated derivatives of these groups or pyranyl, or furanyl, and unsubstituted, such as, for example, nicotinic acid or isonicotinoyl acid, or one-, five-substituted, preferably a hydroxyl group and/or ossenisse-alkyl, in particular, a hydroxyl group or oxymethylene group, for example, glucuronic or galacturonic acid.Alkanesulfonyl are primarily C1-C20-alkanesulphonic the PTA, which can be unsubstituted or substituted, preferably by one or two radicals chosen from hydroxyl groups and sulfopropyl, such as, for example, 2-oxetanemethanol or alkanesulfonyl, for example, the lowest alkanesulfonyl, in particular, ethane-1,2-disulfonate.In arylsulfonate aryl has the value specified for arylcarboxylic acids and is unsubstituted, such as, for example, benzosulfimide, or substituted as indicated above, in particular, lower alkyl, for example, stands, for example, 2-, 3 - or 4-methylbenzenesulfonate, or other sulfonylation, such as, for example, 1,3-benzylisothiocyanate or naphthalene-1,5-disulfonate, especially 1,5-naphthalenedisulfonate.Alkylene acids are primarily C1-C20-alkylene acid, in particular, the lower alkylene acid, in particular, methylsergide acid or atillery acid, or modellserie acid.N-substituted sulfamic acids are, for example, N-cycloalkylcarbonyl acid, where cycloalkyl means preferably C4-C12-cycloalkyl and cycloalkenyl radical is mono-, bi - or tricycle the like, for example, N-cyclohexylsulfamic acid, or N-alkylsulfonate acid, preferably N-lower alkylsulfonyl acid, such as methyl-, ethyl - or propylsulfonyl acid.To organic acids without carboxyl, sulfo-, sulfate - or hostgroup include, for example, compounds containing an acidic hydroxyl group, for example, ascorbic acid.The main acids are hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, cekanova acid, dodekanisa acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glukozaminoglicanov acid, succinic acid, adipic acid, Emelyanova acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, glogarova acid, galactosemia acid, glutamic acid, aspartic acid, N-methylglycine, azetildigoxina acid, N-acetylaspartate, N-acetylcystein, pyruvic acid, acetoacetic acid, phosphoserine, 2 - or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-beta acid, adamantanecarbonyl acid, benzoic acid, salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinamide acid, glucuronic acid, galacturonic acid, methanesulfonate, econsultation, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, 2-, 3 - or 4-methylbenzenesulfonate, mmelserna acid, atisara acid, modellerna acid, N-cyclohexylsulfamic acid, methyl-, ethyl - or propylsulfonyl acid, or ascorbic acid.Very important are hydrogen chloride, sulfuric acid, acetic acid, octanoic acid, fumaric acid, succinic acid, adipic acid, lactic acid, salicylic acid, methanesulfonate, benzosulfimide, 1,5-naphthalenedisulfonate or N-cyclohexylsulfamic acid, especially hydrogen chloride, lactic acid, acetic acid, methanesulfonate or benzosulfimide.
Salt of the compounds of formula V or its tautomer can translate if desired, in free form or another salt, and/or the mixture of isomers of compounds of formula V or its tautomer; or its salt can be divided into isomers, and/or the compound of formula V or its tautomer can be translated into another compound of formula V or its tautomer.Transfer salts of the compounds of formula V or its tautomer into another salt, preferably in salt using one of the above acids [PA] carry out usually in a solvent, in particular, in organic solvents, especially in esters, such as, for example, a complex low alkanoyl lowest alkilany ether, in particular, complex ethyl ester acetic acid, amido, such as, for example, N,N-di-lower alkanolamide, in particular, dimethylformamide, alcohols, such as, for example, Nissi the R, phenols, in particular, phenol, or in dimethyl sulfoxide, in the absence or presence of water, preferably in the presence of water or in the water. Especially preferred is the transformation of alcohols, as, for example, in the above-mentioned lower oxyamino, in mixtures of these alcohols and water, or in the water.The reaction is carried out, for example, in solution, but can be done also on chromatographic columns, for example, using gel filtration, ion exchangers or by osmotic processes through prunaprismia membrane, for example by dialysis.The reaction is carried out at a temperature within the freezing temperature and the boiling temperature of the respective solutions, preferably in the range from 0 to 50oC, in particular in the range from 20 to 40oC, for example, at room temperature, in the presence or absence of an inert gas, such as nitrogen or argon.The compounds of formula V and acid [PA] are applied in the appropriate molar ratios, or acid [PA] is used to excess. The individual components are used preferably in a molar ratio corresponding to the ratio of polyarnosti the base of the formula V and sour is whether after the addition of solvents, in particular, non-polar solvents, for example ethers, such as, for example, a simple diethyl ether, or out of the water and/or by partial or complete evaporation.The reaction can be carried out using the free base of the formula V, which receive, for example, by treatment with a base salt of the acid base formula V obtained using as a starting compound, the acid, which does not fall under the definition of [PA]. As such a base may be, for example, a hydroxide, such as, for example, a hydroxide of an alkali metal, in particular NaOH or KOH in aqueous solution and in the presence or absence of an organic solvent specified above, to obtain the free base; subsequent conversion of the free base is, for example, as described above.Obtaining a free bases of the formula V or their tautomers carried out mainly as described above, followed by chromatography, in particular, gel filtration or ion exchangers.These transformations salts and free bases of the compounds of formula V can be similarly carried out using intermediate compounds, castaldelli isomers in a known manner, the racemates, for example by formation of salts with optically pure salt-forming reagents and separation of the thus obtained mixture of diastereoisomers, for example by means of fractional crystallization or by chromatography on optically active column materials.The compound of formula V or its tautomer in free form or its salt, can be converted into another compound according to the formula V.For example, in the compound of formula V where one, several or all of the radicals R3, R4, R5or R6denote hydrogen, one or more or all of the hydrogen atoms may be converted by alkylation, for example, the lower alkylhalogenide, such as lower alkylchloride, the lowest were synthesized or lower alkilinity, with the introduction of a lower alkyl radical; however, the reaction is carried out in the conventional alkylation conditions and is carried out in solvents, in particular organic solvents, especially polar organic solvents, primarily in esters, for example, in complex lower alkanoyloxy alilovic esters, as, for example, a complex ethyl ester acetic acid, amido, for example, in N,N-di-lower alkyl-lower emer, methanol, ethanol, ethylene glycol or glycerol, or arolovich alcohols, such as, for example, phenols, in particular, phenol, or in dimethyl sulfoxide, in the absence or in the presence of water, preferably in the absence of water, at a temperature ranging from -80oC and the boiling point of the reaction mixture, preferably between 20 and 100oC.As indicated above, preferred is the above method of obtaining the formula V, or its tautomer; or salts thereof, where each of the radicals R3, R4, R5and R6denotes hydrogen, the compounds of formula I. preferably obtaining salts of the compounds of formula V using hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoas acid, dodecanol acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glukozaminoglicanov acid, succinic acid, adipic acid, pipelinewall acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, glucurono acid, galacturonic acid, glutamic acid, aspartic acid, N-methylglycine, acetyl is speerin, 2 - or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-biosfernoi acid, maleic acid, oximino acid, methylmaleimide acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimetoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, almond acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, methanesulfonate, econsultancy, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, 2-, 3 - or 4-methylbenzenesulfonate, metallernas acid, atillery acid, modellserie acid, N-cyclohexylsulfamic acid, methyl-, ethyl - or propylsulfonyl acid, or ascorbic acid, in particular, salts, obtained with hydrogen chloride, sulfuric acid, acetic acid, octanoic acid, fumaric acid, succinic acid, adipic acid, lactic acid, salicylic is inovas acid, especially with hydrogen chloride, lactic acid, acetic acid, methanesulfonate or benzosulfimide.In the preferred method of using the compounds of formula I, or salts thereof, to obtain the compounds of formula V, tautomers, or salts thereof; where each of the radicals R1and R2denotes hydrogen, And denotes-CH2and each of the radicals R3, R4, R5and R6denotes hydrogen, is used as a compound of formula I, or salts thereof, and compounds of formulas III and IV, or their tautomers, or salts; each of the radicals R1and R2represents hydrogen and a represents-CH2- and that the connection of the formula III or their tautomers; or their salts; each of the radicals R3, R4, R5and R6denotes hydrogen, and are obtained mainly salts of the compounds of formula V, preferably salts derived from hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoas acid, dodecanol acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glukozaminoglicanov acid, succinic acid, adipinate, citric acid, glucurono acid, galacturonic acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminobenzoic acid, N-acetyllactosamine, N-acetylcystine, pyruvic acid, acetoacetic acid, phosphoserine, 2 - or 3-glycerophosphoric acid, glucose-6-phosphoric acid, fructose-1,6-biosfernoi acid, maleic acid, oximino acid, methylmaleimide acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, almond acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, methanesulfonate, econsultation, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, 2-, 3 - or 4-methylbenzenesulfonate, metallernas acid, atillery acid, modellserie acid, N-cyclohexylsulfamic acid, restim hydrogen, sulfuric acid, acetic acid, lactic acid, octanoic acid, fumaric acid, succinic acid, adipic acid, salicylic acid, methanesulfonate, benzosulfimide, 1,5-naphthalenedisulfonate or N-cyclohexylsulfamic acid, especially hydrogen chloride, lactic acid, acetic acid, methanesulfonate or benzosulfimide.Especially preferred is a method of obtaining the compounds of formula V, or its tautomer; or salts thereof; where each of the radicals R1and R2denotes hydrogen, And denotes-CH2- and each of the radicals R3, R4, R5and R6denotes hydrogen, the compounds of formula II. Mainly receive salts of the compounds of formula V, preferably salts derived from hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoas acid, dodecanol acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glukozaminoglicanov acid, succinic acid, adipic acid, pipelinewall acid, subernova acid, azelaic acid, Apple withdraws the acid, aspartic acid, N-methylglycine, acetylaminobenzoic acid, N-acetyllactosamine, N-acetylcystine, pyruvic acid, acetoacetic acid, phosphoserine, 2 - or 3-glycerophosphoric acid, glucose-1-phosphoric acid, fructose-1,6-biosfernoi acid, maleic acid, oximino acid, methylmaleimide acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, almond acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, methanesulfonate, econsultation, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, 2-, 3 - or 4-methylbenzenesulfonate, metallernas acid, atillery acid, modellserie acid, N-cyclohexylsulfamic acid, methyl-, ethyl - or propylsulfonyl acid, or ascorbic acid, in particular, salts, obtained with chloris, nternal acid, adipic acid, salicylic acid, methanesulfonate, benzosulfimide, 1,5-naphthalenedisulfonate or N-cyclohexylsulfamic acid, especially preferred salts with hydrogen chloride, acetic acid, lactic acid, methanesulfonate or benzosulfimide.Reaction conditions of the above methods and applications, preferably are selected as follows, and more General guidance on the introduction above for the respective stages of the method, special and preferred definitions can be replaced.The conversion of compounds of formula II into compounds of the formula I is preferably in a parallel transformation of the carbonyl and ceanography with double-a ten-fold molar amount, in particular, a double or threefold molar amount of hydroxylamine or hydroxylamine salt in relation to the molar amount of the compounds of formula II with inorganic acids, carboxylic acids or sulfonic acids, in water di-lower alkyl-lower alkanolamide, as, for example, dimethylformamide, or a mixture of water with one or more alcohols at a temperature of from -30 to 100oC, in particular, when the tempo is her acid hydroxide, carbonate or bicarbonate, a salt of a weak organic acid or a secondary or tertiary amine, the compounds of formula I preferably receive directly in crystalline form or, respectively, after recrystallization from, for example, alcohols, such as methanol or ethanol, or ethers, for example, a complex ester of the lower alkyl-lower alanovoy acid, such as, for example, a complex ethyl ester of acetic acid.Alternatively, you can perform the transformation Paladino when turning the first 1-ketogroup, and then ceanography. The sequential transformation reacts first, preferably, ketogroup in position I of the Central Bicycle with hydroxylamine, and use one-, two-times molar excess of hydroxylamine in comparison with the compound of the formula II, preferably in the absence of base. Hydroxylamine in the form of a salt kaleidotrope acid, such as HCl, reacts, in particular, in alcohol, for example methanol or ethanol, preferably at a temperature in the range of about 75 and 80oC, and get the corresponding cyano-1-oxime, which can be purified or used directly in the subsequent the native acid, for example, HCl, in alcohol, for example methanol, ethanol or tertbutanol, in the presence of alkali metal alcoholate, for example, lithium methylate, sodium or potassium, ethylate or trebuchet lithium, sodium or potassium, and first at lower temperatures, to turn ceanography, for example, at room temperature, the precipitated salt of the cation of an alkali metal optionally filtered using anion of a halide salt of hydroxylamine at a temperature in the range between 60oC and the reflux temperature, converting ceanography into the corresponding compound of formula I.The conversion of compounds of formula I, the compounds of formula IV is carried out preferably by using one-, two-times the molar amount aminoguanidine formula III relative to the molar amount of the compounds of formula I, and aminoguanidine of the formula III is used in the form of salt kaleidotrope acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or receive, in particular, the first in situ from the corresponding salts of volatile weak acids, such as carbonic acid or bicarbonate by adding strong the acid, or methansulfonate, in a mixture of water and one or more alcohols, such as methanol, ethanol or isopropanol, or, in particular, in alcohol, such as methanol, ethanol or isopropanol, at a temperature between room temperature and the reflux temperature of the corresponding reaction mixture. The compound of formula IV is obtained directly in the form of free or usually in the form of a salt, preferably a salt of the acid present in the reaction, in particular in crystalline form, from which the compound of formula IV in a free form, for example, by treatment with base, in particular, hydroxide, for example, alkali metal hydroxide, e.g. potassium hydroxide or sodium in aqueous solution in the presence or preferably in the absence of organic solvents, as described above, at a temperature ranging from -20 to 80oC, in particular from 0 to 40oC, for example, at room temperature, or then by using the anion exchange resin in the HE-form, and after recrystallization, for example, from a mixture of water and organic solvents, for example, alcohols, in particular methanol or especially ethanol.Selective hydrogenation of examinination formula IV, which is introduced as a catalyst, used in micronized form, for example, such as a Raney catalyst, or, alternatively, on carriers such as alumina, pumice, alumina, silica gel or activated carbon, in the presence of acid, which is used in the stoichiometric amount required for salt formation with the two main centers of the compounds of formula IV, for example, in equimolar amounts, primarily for divalent acids, or double the molar quantity, primarily for monovalent acids, or in excess (especially weak acids with the magnitude of the PKs>4, such as, for example, lower alcamovia acid, in particular acetic acid. Used acid can be, in particular, one of the above acids [PA], primarily selected from hydrochloric acid, sulfuric acid, carbonic acid, acetic acid, propionic acid, octanoic acid, decanoas acid, dodecanol acid, fumaric acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glukozaminoglicanov acid, succinic acid, adipic acid, pipelinewall acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, guanoxan acid, N-acetyllactosamine, N-acetylcystine, pyruvic acid, acetoacetic acid, phosphoserine, 2 - or 3-glycerophosphoric acid, glucose-1-phosphoric acid, glucose-6-phosphoric acid, fructose-1,6-biosfernoi acid, maleic acid, oximino acid, methylmaleimide acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1 - or 3-axiatel-2-carboxylic acid, 3,4,5-trimetoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, almond acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, methanesulfonate, econsultancy, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, 2-, 3 - or 4-methylbenzenesulfonate, metallernas acid, atillery acid, modellserie acid, N-cyclohexylsulfamic acid, methyl-, ethyl-, or propylsulfonyl acid, or ascorbic acid, primarily hydrogen chloride, sulfuric acid, acetic acid, lactic acid, octane benzolsulphonate, 1,5-naphthalenedisulfonate or N-cyclohexylsulfamic acid, especially hydrogen chloride, acetic acid, lactic acid, methanesulfonate or benzosulfimide. Hydrogenation of lead in a mixture of water-soluble organic solvents, such as, for example, alcohols, in particular methanol, ethanol or isopropanol, water or in the water, at a temperature in the range of 0oC and the reflux temperature of the respective solvent, in particular in the range from room temperature to approximately the 50oC, with the introduction of hydrogen until the uptake of the calculated amount of hydrogen, usually before the final spontaneous absorption of hydrogen, and the compound of formula V is obtained directly after filtering off the catalyst, for example, using filter paper or filter excipients, for example, kieselguhr or cellulose-based, crystalline, in the form of a salt of the corresponding acid used, which precrystallization, for example, from an organic solvent, such as alcohol, in particular methanol or ethanol, or a simple ester, for example diethyl ether, dioxane, tetrahydrofuran (THF) or Anis the e R1and R2independently from each other selected from hydrogen and lower Alila, in particular from hydrogen, methyl and ethyl, and in position 2 the Central Bicycle none or at least one of both of the radicals R1and R2designate a Deputy than hydrogen, selected from methyl and ethyl, and especially preferred are such compounds where in position 2 of the Central Bicycle are two hydrogen atoms, and a represents -(CH2)nwhere n is 1,2,3 or 4, in particular 1 or 2, and their salts, especially preferred is the above method of obtaining the compounds of formula I, when using the compounds of formula II, where R1and R2independently of one another denote hydrogen or lower alkyl, and in position 2 the Central Bicycle none or at least one of both of the radicals R1and R2denote Deputy than hydrogen, selected from methyl and ethyl, and especially preferred are such compounds where in position 2 of the Central Bicycle are two hydrogen atoms, and a represents -(CH2)nwhere n is 1,2,3 or 4, in particular 1 or 2.To obtain the compounds of formula I, where R1and R21and R2denote hydrogen and a represents-CH2-.In this reaction preferably the conditions are the conditions described above as preferred.The present invention also includes embodiments of a method and/or application of compounds of the formula I, in which proceed from any step of the method and/or reactions, which plays a role in the application of the compounds of formula I, and perform the subsequent steps or reactions. This applies in particular to the reactions presented in the examples.The most preferred methods for obtaining the compounds of formula I and their use is described in the following examples.The source connection
The above starting compound of formula II and formula III and hydroxylamine or their salts may be purchased, known and/or produced by known methods. Particularly preferred are the reaction conditions specified in EP A.The compounds of formula II can be obtained, for example, by intramolecular acylation of the Friedel-Crafts - vanillasky alkanovykh acids of the formula VI
< / BR>where W denotes cyano or its predecessor and the remaining radicals have the above which of Satarov when using the free acid can be used, for example, polyphosphoric acid, and the use of acid chloride or acid anhydride, for example AlCl3. In this reaction are used the preferred compounds of formula IV, where W denotes not cyano, and the predecessor of ceanography, for example, halogen, in particular bromine, or a protected amino group, for example, acetylamino. After cyclization these groups can be converted to the cyano in a known manner, for example, if W is bromine by treatment with copper cyanide (I), or if W-acetylamino by removal of acetyl protective group, diazotization and treatment with copper cyanide (I).The compounds of formula II can be obtained, for example, by oxidation with chromium trioxide (SGAs3relevant decarbonising compounds of formula VII
< / BR>where W denotes, as above, cyano or her predecessor, and the remaining radicals have the above values. If W denotes the predecessor of ceanography it after oxidation is transferred to cyano, for example, as indicated above.Another method of preparing compounds of the formula II is that emanate from compounds of formula II, where instead of ceanography is hydrogen, cyano enter, for example, by conducting the placenta is azotirovannye and then processing the copper cyanide (I) (reaction of Sandmeyer).Aminoguanidine formula III, where the radicals have the abovementioned meanings, can be obtained, for example, from the corresponding thiosemicarbazides, the latter by alkylation, for example, alkyllithium or alkylhalogenide, translated into the corresponding salt of S-alkyldimethylammonium and treated with the amine of the formula with other4R5.These thiosemicarbazide (the precursor compounds of the formula (III) are obtained, for example, by processing the hydrazines of the formula H2N-OTHER3where R3has the meaning specified above, isothiocyanato formula R6N=C=S or thiocarbamoylation formula R6NH=CSCl, or by processing one of these hydrazines of alligatorinae, for example, acetylsalicylate, and subsequent acidic hydrolysis.The hydroxylamine or its salts can be obtained, for example, from sales of hydroxylamine hydrochloride by treatment with base, such as an alcoholate of an alkali metal, such as, for example, ethoxide sodium or piperonyl sodium, carbonate of alkali metals, such as, for example, sodium carbonate or potassium, and, if necessary, distillation, or an excess of the appropriate acid, for example, in crystalline form, or in situ.The following abbreviations are used: a simple broadcast - simple diethyl ether; DMF is dimethylformamide; h - hour(s); end. - concentrated; min - minutes; NMR laternamagica resonance spectroscopy; TA is the temperature of melting; decomp. - decomposition.Example 1: the oxime of 4-(N-oximino)of 1-indanone
Option 1:
A mixture of 20,43 g (0.13 mol) of 4-cyano-1-indanone [Coll. Czecholov. Chem. Commun. 43, 3227 (1978)] 18.07 g (0.26 mol) of hydroxylamine hydrochloride, 13,46 g (to 0.127 mol) of sodium carbonate and 650 ml of 50% aqueous ethanol is stirred for 3.5 hours at a temperature of 80oC. Then the reaction mixture was added again 9,035 g (0.13 mol) of hydroxylamine hydrochloride and of 6.73 g (0,06535 mol) of sodium carbonate, stirred for further 5 hours at 80oC and then leave for slow cooling to room temperature. Then the reaction mixture is cooled to 10oC, filtered and the precipitated product is washed with 20 ml of 50% aqueous ethanol and a small amount of simple diethyl ether. Then crystallized placed in 900 ml of methanol, stirred for 1 hour at room temperature, filtered off the insoluble component is filtrowa, washed with a small amount of methanol and simple diethyl ether and dried. Thus obtained reaction of 4-(N-oxyamino)-1-indanone is melted at a temperature 192-194oC (decomp). Option 2:
The solution of 7,86 g (50 mmol) 4-cyano-1-indanone [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] in 75 ml of N,N-dimethylformamide is mixed with 10.4 g (150 mmol) of hydroxylamine hydrochloride and 37.5 ml of a 2M solution of Na2CO3and heated for 3.75 hours before the 75oC. warm the reaction mixture is diluted with 25 ml of water and filtered warm. Then the filtrate is mixed with 88 ml of water and cooled to 0-5oC. Bicrystalline product is pulled, washed with DMF/water 1:3 and, finally, washed with EtOH, dried and recrystallized from a threefold amount of DMF. Thus obtained compound of the oxime of 4-(N-oxyamino)-1-indanone which melts at a temperature 192-194oC(decomp. ); MS (FAB) : (M+H)+=206;1H-NMR (DMSO) : 10,87 (s, 1H); for 9.64 (s, 1H); 7,56 (d,1H); 7,30 (t,1H); USD 5.76 (s,2H); 3.15 in (t,2H); to 2.74 (t,2H).Option 3:
A mixture of 157 (1.0 mmol) 4-cyano-1-indanone [Coll. Czechoslov. Chem. Commun.43, 3227 (1978)] and 139 mg (2.0 mmol) of hydroxylamine hydrochloride in 4 ml of ethanol is stirred for 1.5 hours at 80oC and cooled in a bath of ice water. Bicrystalline product: if you want the hydrated reaction of 4-cyano-1-indanone which melts at a temperature 200-202oC decomp. ;1H-NMR (DMSO) : 11,22 (s, 1H); to 7.84 (d, 1H); 7,81 (d,1H); was 7.45 (t, 1H); 3.15 in (t,2H); 2,84 (t,2H).A mixture of 360 mg (of 2.06 mmol) of the intermediate product of the reaction of 4-cyano-1-indanone and 355 mg (5.1 mmol) of hydroxylamine hydrochloride in 10 ml of methanol is mixed with 920 mg (5.1 mmol) of sodium methylate and stirred for 10 min at room temperature. Then the reaction mixture is filtered and the filtrate is boiled for 2 hours under conditions of reflux. After cooling, the precipitated product is filtered off, washed with a small amount of methanol and dried. So get the oxime of 4-(N-oxyamino)-1-indanone which melts at a temperature 192-194oC(decomp.);1H-NMR (DMSO) : 10,87 (s, 1H); for 9.64 (s, 1H); 7,56 (d,1H); 7,49 (d,1H); 7,30 (t,1H); USD 5.76 (s,2H); 3.15 in (t,2H); to 2.74 (t,2H).Similarly, a specified example of turn: a) 5-cyano-1-tetralone in the reaction of 5-(N-acetamidino)1-tetralone;1H-NMR (DMSO) : 10,75 (s, 1H); 8,23 (q, 1H); 7,84 (q,1H); 7,40 (t,1H); 5,6 (s,2H); 3,26 (t,2H); to 2.75 (t,2H); of 2.21 (m,2H); b) 4-cyano-2-methyl-1-indanone in the oxime of 4-(N-oxyamino)-2-methyl-1-indanone.Similarly to the above example (option 3) a mixture of 0,85 (5.0 mmol) 4-cyano-2-methyl-1-indanone and 0.52 g (7.5 mmol) of hydroxylamine hydrochloride in 20 ml of ethanol is stirred for 1.5 hours at 80oC. After ocheskey phase washed with diluted sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Thus obtained mixture of intermediate SYN/anti oxime 4-cyano-2-methylindene, which melts at a temperature 136-139oC;1H-NMR (DMSO) : is 11.39 11,16 and (2s,1H); 8,56 and 7,81 and 7,46 (d and 2m, 3H); 2,5-of 3.46 (m, 3H); of 1.23 (2d,3H). 180 mg (1 mmol) of this intermediate product are dissolved in 4 ml of DMF, mixed with 140 mg (2 mmol) of hydroxylamine hydrochloride and 0.5 ml of a 2M solution of Na2CO3and heated for 1.5 hours to 80oC. After cooling, the reaction mixture was mixed with 20 ml of water. Bicrystalline the product is separated, washed with water and dried. So get the above compound in the form of a mixture Asimov;1H-NMR (DMSO) : 11,05 and 10,81 (2s,1H); 9.6 9,63 (2s,1H); 8,33-7,28 (m, 3H); 5,73 (s,2H); 2,5-of 3.46 (m,3H); of 1.20 (2d,3H); C) 4-cyano-2-ethyl-1-indanone 4-(N-oxyamino)-2-ethyl-1-indanone;1H-NMR (DMSO) : 10,83 (1s, 1H); 9,65 (s, 1H); a 7.85-of 7.23 (m,3H); 5,8 (s,2H); 3,55 is 2.55 (m,3H); 1,95-of 1.33 (m, 2H); 0,9 (m,3H); d) 4-cyano-3-methyl-1-indanone in the oxime of 4-(N-oxyamino)-3-methyl-1-indanone;1H-NMR (DMSO) : 10,69 (s,1H); to 7.95 (m,2H); at 7.55 (t, 1H); 5,71 (s,2H); 3,71 (m,1H); to 3.06 (q,1H); of 2.45 (q,1H); 1.57 in (d, 3H); d) 4-cyano-6-methyl-1-indanone in the oxime of 4-(N-oxyamino)-6-methyl-1-indanone, and/or (e) 4-cyano-6,7-dimethyl-1-indanone - oxime of 4-(N-oxyamino)-6,7-dimethyl-1-indanone.The products of example 1 and 1A) to 1E) could the A mixture of 14,22 g (69,3 mmol) of the oxime of 4-(N-oxyamino)-1-indanone 10,37 g (76,2 mmol) of hydrogen aminoguanidine and 170 ml of isopropanol is mixed with the 15.4 ml conc. hydrochloric acid and then heated for 75 minutes to reflux. Then the reaction mixture is cooled to 10oC, filtered and the filter residue is washed with isopropanol and a small amount of simple diethyl ether. Dried at 100oC, obtained as crude product, dihydrochloride specified in the title compound melts at 269-271oC (decomp.); 1H-NMR (D2O) : 8,03 (d,1H); to 7.67 (d, H); 7,52 (t,1H); 3,29 (m,2H); 2.91 in (m,2H).For converting a free base a mixture of 20,63 g (about a 64.6 mmol) of the dihydrochloride of 4-(N-oxyamino)-1-indanone-2'-amidinohydrolase, in the form of a crude product and 136 ml of 1 N. sodium liquor is stirred for 30 min at room temperature. After filtering and washing the filter residue with a small amount of water, ethanol and simple diethyl ether, the crude product is recrystallized from water/ethanol. The result is the connection specified in the header, in the form of the dihydrate, melting point 208oC (decomp.). If instead recrystallization from water/ethanol crude product muddle in 5-10-fold amount of ethanol for 15 min at maintened at, specified in the header, in the form of a dehydrated product, melting point 235oC (decomp.).Similarly to the above example, get:
a) From the reaction of 5-(N-oxyamino)-1-tetralone with 5-(N-oxyamino)-1-tetralone-2'-amidinohydrolase;
b) of the oxime of 4-(N-oxyamino)-2-methyl-1-indanone - 2'-amidinohydrolase 4-(N-oxyamino)-2-methylindene;
From the oxime of 4-(N-oxyamino)-2-ethyl-1-indanone - 2'-amidinohydrolase 4-(N-oxyamino)-2-ethyl-1-indanone;
g) of the oxime of 4-(N-oxyamino)-3-methyl-1-indanone - 2'-amidinohydrolase 4-(N-oxyamino)-3-methyl-1-indanone;
d) of the oxime of 4-(N-oxyamino)-6-methyl-1-indanone - 2'-amidinohydrolase 4-(N-oxyamino)-6-methyl-1-indanone; and/or
e) of the oxime of 4-(N-oxyamino)-6,7-dimethyl-1-indanone - 2'-amidinohydrolase 4-(N-oxyamino)-6,7-dimethyl-1-indanone.The products of examples 2 and 2A - 2E) can be used as follows:
Example 3: a) 2'-amidinohydrolase 4-amidino-1-indanone-dihydrochloride
A solution of 4.0 g (14,17 mmol) dihydrate 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone in 240 ml of water and 14.3 ml of 2 N. hydrochloric acid is mixed with 1.3 g of Raney Nickel and hydronaut at room temperature until the absorption of hydrogen. The reaction mixture is heated to 55ovacaria) and the filtrate is evaporated to a volume of approximately 150 ml Fallen upon concentration of the filtrate, the product is again dissolved by heating. Then the solution is cooled to 10oC, filtered and the resulting crystallized washed with a small amount of water, ethanol and simple diethyl ether. After drying at a temperature of 100oC get the connection specified in the header, with a water content of 6.26%, melting point >280oC. By evaporating the mother liquor to a volume of about 50 ml and further processing to receive the second portion of the connection specified in the header, with a water content 5,98%, melting point >280oC.For translation in the free base solution of 9,63 g (30 mmol) of 1-amidinohydrolase 4-amidinohydrolase-dihydrochloride hydrate in 900 ml of distilled water with stirring dropwise at a temperature of 10-20oC is mixed with 30 ml of 2 N. sodium lye. The precipitated product is sucked off, washed with a small amount of ice-cold water and dried. Get the connection specified in the header, in the form of the free base, melting point 250oC (decomp.).Example 4: 2'-amidinohydrolase 4-amidino-1-indanone-dimethanesulfonate
A solution of 4.0 g (14,17 mmol) dihydrate 2'-amidinohydrolase 4-(N-acetamidate temperature until the absorption of hydrogen. Then filter throughHyflo Super Cel (Fluka, Switzerland), the filtrate is evaporated in vacuum and the residue is recrystallized from methanol. Thus obtained compound indicated in the title, has a water content of 3,68% and melts at a temperature 263-265oC (decomp. ). By concentrating the mother liquor to receive a second portion with a water content of 4.5%, with a melting point 261-263oC (decomp.).For translation in the free base solution to 5.93 g (25 mmol) of 1-amidinohydrolase 4-amidinohydrolase-dimethanesulfonate-hydrate in 37 ml of distilled water with stirring dropwise at a temperature of 10-20oC mix 13 ml 2 N. sodium lye. The precipitated product is sucked off, washed with a small amount of ice water and ethanol and dried. Get 2'-amidinohydrolase 4-amidino-1-indanone with a melting point 250oC (decomp.).Alternative: 2'-amidinohydrolase 4-amidino-1-indanone-dimethanesulfonate-monohydrate
The solution of 15,04 g (0,043 mmol) 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone-dimethanesulfonate in 43 ml of water is mixed with 3.0 g of Raney Nickel and hydronaut at room temperature until the absorption of hydrogen. Then filter throughoC (decomp.).The original connection of this method are as follows: a) 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone-dimethanesulfonate
Suspension from 40,2 g (0,163 mmol) of anhydrous 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone (example 2) in 96 ml of water with stirring dropwise mixed with of 31.4 g (21.2 ml) methansulfonate. Get unsustainable clear solution, from which vykristallizovyvalas the connection specified in the header. The suspension of crystals diluted with 127 ml of ethanol and filtered. The obtained product is washed with water/EtOH 1:1 and dried in vacuum to obtain a constant weight, melting point 237-239oC (decomp.);1H-NMR (D2) : Of 8.04 (d,1H); to 7.67 (d,1H); 7,53 (t,1H); with 3.27 (m,2H); 2.95 and (m,2H); 2,77 (s,6H).Example 5: 2'-amidinohydrolase 4-amidino-1-indanone-dihydrochloride
A solution of 4.0 g (14,17 mmol) dihydrate 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone in 60 ml of water and ml of 28.34 1 N. methansulfonate mixed with 1.2 g of Raney Nickel and hydronaut at room temperature until the end of my absorption is mixed with 14,17 ml of 2 N. of hydrochloric acid. Bicrystalline the product is sucked off, washed with small amount of water, ethanol and simple diethyl ether and dried. Thus obtained compound indicated in the title, has a water content of 7.1%, melting point >280oC.Example 6: 2'-amidinohydrolase 4-amidino-1-indanone-diacetate
A solution of 980 mg (4 mmol) 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone in 30 ml of 10% acetic acid hydronaut in the presence of 0.3 g of Raney Nickel at normal pressure and a temperature of 50oC. After absorption of the calculated amount of hydrogen and filtering off the catalyst as in example 5, the filtrate is evaporated. The residue is crystallized from ethanol/plain diethyl ether and receive the connection specified in the header, in the form of a hemihydrate, melting point 218-220oC (decomp.).Example 7: 2'-amidinohydrolase 4-amidino-1-indanone-dibenzalacetone
A solution of 980 mg (4 mmol) 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone and 1.26 g (8 mmol) benzosulfimide in 50 ml of methanol hydronaut in the presence of 0.3 g of Raney Nickel at normal pressure and a temperature of 50oC. After absorption of the calculated amount in the ethanol. So get the connection specified in the header, melting point >250oC (decomp.).1H-NMR (D2) : 7,38-to 7.95 (m, 16H); is 3.21 (m,2H); 2,78 (m,2H).Example 8: Similar to one of the above examples dehydrate 2'-amidinohydrolase 4-(N-oxyamino)-1-indanone translated using salicylic acid, succinic acid, adipic acid, lactic acid, 1,5-naphthalenedisulfonate, or 1,2-identicality to the corresponding salt:
a) 2'-amidinohydrolase 4-amidino-1-indanone-disalicylate;
b) 2'-amidinohydrolase 4-amidino-1-indanone-succinate;
C) 2'-amidinohydrolase 4-amidino-1-indanone-atipat;
g), 2'-amidinohydrolase 4-amidino-1-indanone-dilactate;
d) 2'-amidinohydrolase 4-amidino-1-indanone-1,5-naphthalenedisulfonate; and/or
e) 2'-amidinohydrolase 4-amidino-1-indanone-etandisulfonat.Example 9:
Similar to one of these examples:
a) 2'-amidinohydrolase 5-(N-oxyamino)-1-tetralone was transferred to the 2'-amidinohydrolase 5-amidino-1-tetralone,
b) 2'-amidinohydrolase 4-(N-oxyamino)-2-methyl-1-indanone was transferred to the 2'-amidinohydrolase 4-amidino-2-methyl-1-indanone
C) 2'-amidinohydrolase 4-(N-oxyamino)-2-ethyl-1-indanone was transferred to the 2'-amidinohydrolase 4-Razon 4-amidino-3-methyl-1-indanone
d) 2'-amidinohydrolase 4-(N-oxyamino)-6-methyl-1-indanone was transferred to the 2'-amidinohydrolase 4-amidino-6-methyl-1-indanone and/or
e) 2'-amidinohydrolase 4-(N-oxyamino)-6,7-dimethyl-1-indanone was transferred to the 2'-amidinohydrolase 4-amidino-6,7-dimethyl-1-indanone.The products are allocated directly in the form of a salt in the presence of acids (in the form of dihydrochloride in the presence of hydrochloric acid, in the form of dimethanesulfonate in the presence of methansulfonate, in the form of a diacetate in the presence of acetic acid, in the form of dilactate in the presence of lactic acid, in the form of dibenzoylmethanato in the presence of benzosulfimide, in the form of disalicylate in the presence of salicylic acid, succinate in the presence of succinic acid in the form of adipate in the presence of adipic acid, in the form of 1,5-naphthalenesulfonate in the presence of 1,5-naphthalenesulfonate, or atendimento in the presence of ethicality). 1. A method of obtaining a bicyclic amidinohydrolase formula V
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2describes 2 ,3,or 4;
R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl,
or their tautomers, or their salts, characterized in that the compound of the formula I
< / BR>where R1, R2and a have the meanings specified for compounds of formula V,
or its salt is subjected to interaction with aminoguanidine formula III
< / BR>where R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl,
or tautomers, or its salt, getting gidroksietilirovaniya formula IV
< / BR>where R1, R2, R3, R4, R5, R6and a have the meanings specified for compounds of formula V,
or tautomer, or its salt, and then gidroksietilirovaniya formula IV, or its tautomer, either in free form in the presence of an acid or as a salt, selectively hydronaut in the presence of a catalyst, to obtain the compounds of formula V, where the radicals have the stated meanings, or its tautomers, or salts, followed, if necessary, converting a salt obtained the compounds of formula V or its tautomer in free form or another salt, and/or separation of the mixture of isomers of swedencamera into another compound of the formula V or its tautomer.2. The method according to p. 1, obtaining the compounds of formula V, or its tautomer, or salts thereof, where each of the radicals R1and R2denotes hydrogen, And denotes - CH2and each of the radicals R3, R4, R5and R6denotes hydrogen, of compounds of the formula I, characterized in that the compound of formula I, or salts thereof, and compounds of formulas III and IV, or their tautomers, or salts, each of the radicals R1and R2represents hydrogen and a represents - CH2- and in the compounds of formulas III and V, or their tautomers, or salts of each of the radicals R3, R4, R5and R6denotes hydrogen.3. The method according to p. 1 or 2, characterized in that the transformation of compounds of formula I to the compound of formula IV is carried out with the use of 1 - to 2 - fold molar amount aminoguanidine formula III relative to the molar amount of the compounds of formula I, and aminoguanidine of the formula III used in the form of salt halomonadaceae acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or in situ from the corresponding salt readily volatile weak acid by adding a strong acid, in a mixture of water Hladilnika corresponding reaction mixture, and selective hydrogenation to convert gidroksietilirovaniya formula IV and compounds of formula V is carried out in the presence of Nickel as a catalyst, which is used in finely powdered form or media, in the presence of acid taken in the stoichiometric required for salt formation with the two main centers of the compounds of formula IV quantity or in excess (weak acid with a pK values>4), in a mixture of water-soluble organic solvents with water or in the water at temperatures in the range of 0oC to the boiling temperature under reflux suitable solvent by passing hydrogen to its absorption of the calculated amount with obtaining the compounds of formula V in the crystalline form of the salt used acid.4. The method of obtaining the compounds of formula V, where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes Deputy, other than hydrogen, selected from methyl and ethyl, And represents - (CH2)nwhere n = 1,2,3 or 4, and R3, R4, R notable the compound of formula II
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes a Deputy than hydrogen, selected from methyl and ethyl;
And represents - (CH2)nwhere n is 1,2,3 or 4,
subjected to interaction with hydroxylamine or its salt to obtain the compounds of formula I,
< / BR>or its salts,
where R1, R2and a have the meanings specified in paragraph 1,
and then, the resulting compound of formula I or its salt is treated with aminoguanidine formula III
< / BR>where R3, R4, R5and R6independently of one another denote hydrogen or lower alkyl,
or tautomers, or its salt with obtaining gidroksietilirovaniya formula IV
< / BR>where R1, R2, R3, R4, R5, R6and a have the meanings specified for compounds of formula V,
or tautomer, or its salt, and then gidroksietilirovaniya formula IV or its tautomers, in free form in the presence of acid or its salts selectively hydronaut in the presence of Ki, and, if necessary, the salt of the compounds of formula V or its tautomer translate into a free form or another salt, and/or the mixture of isomers of compounds of formula V, or its tautomer or its salt is separated into the isomers and/or a compound of formula V or its tautomer transferred to another compound of formula V or its tautomer.5. The method according to p. 4, obtaining the compounds of formula V, or its tautomer, or salts thereof, where each of the radicals R1and R2denotes hydrogen, And denotes - CH2and each of the radicals R3, R4, R5and R6denotes hydrogen, the compounds of formula II, wherein in the compound of formula II, the compounds of the formula I or their salts and the compounds of formulas III and IV or their tautomers, or salts of each of the radicals R1and R2represents hydrogen and a represents - CH2- Oh, and that compound of formula III, or tetrameric or their salts, each of the radicals R3, R4, R5and R6denotes hydrogen.6. The method according to p. 4 or 5, characterized in that the conversion of compounds of formula II into compounds of the formula I with a parallel transformation of carbonyl - and ceanography perform double - a ten-fold molar amount of the hydroxyl is Oh acid, carboxylic acids or sulfonic acids in water, di-ness. alkyl-ness. alkanolamide or a mixture of water with one or more alcohols at temperatures ranging from -30 to 100oC, at normal pressure and acid neutralizing hydroxide, carbonate or bicarbonate, a salt of a weak organic acid or a secondary or tertiary amine, the transformation of compounds of formula I, the compounds of formula IV is carried out using one-, two-times the molar amount aminoguanidine formula III relative to the molar amount of the compounds of formula I, and aminoguanidine of the formula III is used as a salt kaleidotrope acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or first obtained in situ from the corresponding salt readily volatile weak acid by adding a strong acid, in a mixture of water and one or more alcohols at a temperature of from room temperature up to the boiling temperature under reflux corresponding reaction mixture, and selective hydrogenation to convert hydroxyamino the compounds of formula IV to the compound of formula V is carried out in the presence of Nickel as katalimetricheskom required for salt formation with the two main centers of the compounds of formula IV quantity or in excess (weak acid with a pK values>4), in a mixture of water-soluble organic solvents with water or in the water at a temperature of from 0oC to the boiling temperature under reflux suitable solvent feeding hydrogen to its absorption of the calculated amount, obtaining the compounds of formula V in crystalline form as a salt of the appropriate acid.7. The method according to p. 4 or 5, characterized in that the conversion of compounds of formula II to the compound of formula I is carried out stepwise sequential transformation of the first 1-ketogroup and then ceanography, and initially transformed ketogroup in position 1 of the Central Bicycle with hydroxylamine, and the hydroxylamine is taken in one-, two-times molar excess relative to the compound of formula II and hydroxylamine reacts in the form of a salt kaleidotrope acid in alcohol at a temperature of from about 75 to 80oC, to obtain the corresponding lanoxine, which then use the two-, three-fold molar amount of hydroxylamine in the form of kaleidotrope acid in alcohol in the presence of alkaline earth metal alcoholate at temperatures from 60oC to the boiling point with the reverse was built in the compounds of formula IV using a single, double molar quantity aminoguanidine formula III relative to the molar amount of the compounds of formula I, and aminoguanidine of the formula III is used as a salt kaleidotrope acid, sulfuric acid or hydrosulfate, phosphoric acid, hydrogen phosphate or dihydrophosphate, carboxylic acids or sulfonic acids, or first obtained in situ from the corresponding salt readily volatile weak acid by introducing a strong acid, in a mixture of water and one or more alcohols at temperatures from room temperature up to the boiling temperature under reflux corresponding reaction mixture, and selective hydrogenation to convert hydroxyamino the compounds of formula IV to the compound of formula V is carried out in the presence of Nickel as a catalyst, which is used in finely powdered form or media, in the presence of acid, which is taken in the stoichiometric required for salt formation with the two main centers of the compounds of formula V the amount or the excess (if weak acid with a pK values>4), in a mixture of water-soluble organic solvents with water or in the water at a temperature of from 0oC to the boiling point with a reflux is eating the compounds of formula V in the crystalline form of the salt used acid.8. The bicyclic hydroxyamide formula I
< / BR>where R1and R2independently of one another denote hydrogen or lower alkyl, provided that at position 2 of the Central Bicycle none or at least one of both of the radicals R1and R2denotes Deputy, other than hydrogen, selected from methyl and ethyl;
And represents - (CH2)nwhere n is 1,2,3 or 4,
or its salt.9. The compound of formula I on p. 8, where R1and R2denote hydrogen, And denotes - CH2or its salt.
Same patents:
Phenylhydrazine derivatives, method of pest control and insecticidenematicides composition // 2109730
The invention relates to compounds having the structural formula I, where X, Y, R and Z are defined in the description of the application
The invention relates to organic synthesis and relates to a method (variants) obtain derivatives amidoxime O-(2-hydroxy-3-piperidino-1-propyl)-nicotinic acid and their salts
Method of producing ketazine compound // 2425028
FIELD: chemistry.
SUBSTANCE: invention relates to a method of producing a ketazine compound of formula (1) from a ketone compound of formula (2), ammonia and an oxidising agent, where a solution containing a ketone compound of formula (2) and ammonia is brought into contact with aqueous solution of sodium hypochlorite or hydrogen peroxide in a tubular reactor, having flow channel width between 2 and 10000 mcm where R1 and R2 are identical or different and each denotes a C1-6 alkyl group, or R1 and R2 are bonded to form a C2-7alkylene group with a straight chain
where R1 and R2 are as described above and each of the liquids is in laminar flow state.
EFFECT: obtaining ketazine compounds with high output and with inhibition of by-products.
4 cl, 1 tbl, 2 ex, 2 dwg
FIELD: chemistry.
SUBSTANCE: filler used is chromogenic ion-exchange dispersed silica with covalently grafted hydrazones or formazans.
EFFECT: high sensitivity and selectivity of detecting metals.
3 tbl, 4 dwg, 14 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of phenylglycine of the formula (I) , to their hydrates or solvates, and/or to physiologically acceptable salts and/or physiologically acceptable esters possessing inhibitory effect on amidolytic activity of the complex factor VIIa/tissue factor that can be used for therapeutic and/or prophylactic treatment of diseases, for example, thrombosis. In the formula (I) R1 means (C1-C6)-alkyl; R2 means hydrogen atom, hydroxy-(C1-C6)-alkoxy-, (C1-C6)-alkoxycarbonyloxy-, (C1-C6)-alkoxy-group or halogen-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-group; R3 means hydrogen atom, (C1-C6)-alkoxy- or heterocycloalkyloxy-group wherein heterocycloalkyl group means 5-6-membered ring comprising a heteroatom taken among nitrogen and oxygen atom; R4 means hydrogen atom or ester residue that is cleaved off under physiological conditions. R5 means hydrogen atom, hydroxy-group, (C1-C6)-alkoxycarbonyl, halogen-(C1-C6)-alkoxycarbonyl, (C6)-aryloxycarbonyl,(C6)-arylalkoxycarbonyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy(C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkyloxycarbonyl, (C2-C6)-alkynyloxycarbonyl, 5-methyl-2-oxo[1,3]dioxol-4-yl-methoxycarbonyl, (C6)-arylcarbonyloxy-, (C1-C6)-alkylaminocarbonyloxy-group, (C1-C6)-alkylcarbonyl, arylcarbonyl, arylaminocarbonyl or heteroarylcarbonyl wherein heteroaryl represents 5-6-membered ring comprising nitrogen atom the cycle; X means atom F, Cl or Br. Also, invention relates to a method for preparing compounds, intermediates substances and pharmaceutical composition and a method for treatment.
EFFECT: improved preparing method, valuable medicinal properties of agents and composition.
29 cl, 5 ex
Esters of pentamidine-amidoxime acids as prodrugs and their application as medicinal agents // 2608388
FIELD: chemistry.
SUBSTANCE: invention relates to pentamidine prodrugs, namely to compound of formula given below, where n equals to 2, as well as to its pharmaceutically acceptable salts, solvates, salts of solvates, which have improved properties, such as solubility and bioavailability, compared to existing prodrugs.
EFFECT: invention also relates to method of producing said compound, various versions of therapeutic agents for treating and/or preventing diseases, selected from oncological and tumor diseases, leishmaniasis, trypanosomiasis, pneumocystis pneumonia and malaria, including this compound, and methods of treating above diseases.
13 cl, 7 dwg, 5 tbl
Method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity grade // 2335497
FIELD: chemistry.
SUBSTANCE: invention claims a new method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity degree by reaction of 2,3-dichlorbenzoylcyanide with 1-2 mol equivalents of dimethylase aminoguanidine salt in the presence of 3-6 mol equivalents of methanesulfoacid, with further addition of 2-5 mol equivalents of magnesium oxide to the reaction mix. The process is performed at 50-80°C, and target product is recrystallised from acetone.
EFFECT: improved efficiency of compounds.
5 cl, 3 ex
FIELD: chemistry.
SUBSTANCE: invention relates to compounds of general formula III and their pharmaceutically acceptable salts, A represents (C1-C6)alkyl-O-, phenyl-(C1-C6)alkyl-O-; aryl, selected from phenyl, naphthyl,
and
which is possibly substituted by 1-3 substituents, given in the invention formula; or heteroaryl, which has four or five carbon atoms and one heteroatom, selected from oxygen, nitrogen and sulphur, which is possibly substituted by 1-3 substituents, given in the invention formula; B represents phenyl, possibly substituted by 1-3 substituents, where substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halogeno; and R1 and R2 independently represent (C1-C6)alkyl, phenyl-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl, (C3-C7)cycloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; on condition that R1 is different from R2; where absolute configuration of asymmetric R1 and R2 -carrying carbon atom is mainly R-configuration. Invention also relates to pharmaceutical composition, possessing ability to modulate gene expression, methods of modulation of gene expression in host cell, method of regulating expression of endogenous or heterologous gene in transgenic subject, method of regulating transgenic expression in transgenic subject, method of polypeptide production and to method of obtaining formula IV
compound. Method includes stages: a) interaction of formula V compound with formula IV compound with obtaining formula VII compound; b) reduction of formula VII compound with obtaining formula VIII compound, b) interaction of formula VIII compound with formula B-CO-LG compound, where B has values, given above, and LG is leaving group representing -F, -Cl or -Br, with formation of formula IX compound, d) removal of group R7CO2- from formula IX compound with obtaining formula X compound, e) interaction of formula X compound with formula A-CO-LG compound, where A has values, given above, and LG is leaving group, representing -F, -Cl or -Br, with obtaining formula IV compound ( compounds of formulas V, VI, VII, VIII, IX, X are given in the invention formula).
EFFECT: obtaining formula III compounds, possessing ability to modulate gene expression.
19 cl, 4 ex, 2 tbl, 78 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound presented by formula
,
wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula
,
wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.
EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.
13 cl, 25 tbl, 125 ex
FIELD: chemistry.
SUBSTANCE: invention relates to agriculture. The compound is selected from a group including formula 1, formula 2, formula 3, formula 4, formula 5 and formula 6. Formula 1 is , where R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H; n=0-25. Formula 2 is
, where R1 = sec-butyl or tert-butyl-CH2; R2=H. Formula 3 is
, where R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H. Formula 4 is
, where R1 = isobutyl; R2=H; R3 = n-alkyl containing 2-25 carbon atoms, except n-heptyl and n-undecyl, branched alkyl containing 4-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 12-26 carbon atoms; or R1 = sec-butyl or tert-butyl-CH2; R2=H; R3 = n-alkyl containing 1-25 carbon atoms, branched alkyl containing 3-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 7-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 7-25 carbon atoms; or R1 = isobutyl; R2 = methyl; R3 = n-alkyl, containing 2, 3, 6 and 12-25 carbon atoms, branched alkyl containing 3-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 7-25 carbon atoms. Formula 5 is
, where R4=H, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy or haloalkythio, each containing 1-4 carbon atoms, or halogen, hydroxyl group, nitro group, carboxylic acid group or cyano group; an either R1 = sec-butyl or tert-butyl-CH2; and R2=H; or R1 = isobutyl; and R2 = methyl; and formula 6 is
, where R4 = H, alkyl, haloalkyl, alkoxy, alkythio, haloalkoxy, haloalkylthio, each containing 1-4 carbon atoms, or halogen, hydroxyl group, nitro group; carboxylic acid group or cyano group; and either R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H; or R1 = isobutyl; and R2 = methyl. Said compounds are used to attract zoospores of plant pathogenic oomycetes of fungi or control plant diseases.
EFFECT: invention increases treatment efficiency.
17 cl, 2 dwg
Neprilysin inhibitors // 2605557
FIELD: chemistry.
SUBSTANCE: invention relates to a compound of formula I, where R1 is -OR7; R2 is H; X is selected from a pyrazole, triazole, benzotriazole, tetrazole, oxazole, isoxazole, thiazole, pyridazine, pyrimidine and pyridyl triazole; R3 is absent or is selected from H; halogen; -C0-5alkylene-OH; -C1-6alkyl; -C3-7cycloalkyl; -C0-2alkylene-O-C1-6alkyl; -C(O)R20; -C0-1alkylene-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; phenyl, optionally substituted with one or two groups independently selected from halogen, -OCH3, -NHC(O)CH3 and phenyl; naphthalenyl; pyridinyl; pyrazinyl; and R3, when present, is bonded to carbon atom; R4 is selected from H; -OH; -C1-2alkylene-COOR35; -pyridinyl; and phenyl or benzyl, optionally substituted by one or more groups selected from halogen and -OCH3; and R4, when present, is bonded to carbon atom or a nitrogen atom; a equals 0 or a equals 1; and R5 is selected from halogen and -CN; b is equal to 0 or 1, and R6 is selected from Cl, F, -OH, -CH3, -OCH3 and -CF3; or b is equal to 2, and R6 each is independently selected from halogen, -OH, -CH3, or -OCH3, or b is equal to 3, and R6 each is independently selected from halogen or -CH3; R7 is selected from H, -C1-8alkyl, -C1-3alkylene-C6-10aryl, -C0-6alkylene morpholinyl or dioxol-2-one methyl, of formula (a); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) are obtained by condensation of compound of formula 1 with a compound of formula 2, where P1 is H or tert-butoxycarbonyl; and wherein method further includes removal of protective group of compound of formula 1, when P1 is tert-butoxycarbonyl. Also compound of formula (I) is obtained by removing protective group of compound of formula (6) or salt thereof; where R1P is -O-P3, where P3 is methyl. Invention also relates to intermediate compounds of formulae (1) and (6). Compounds of formula (I) are intended for inhibiting neprilysin activity.
EFFECT: compounds having neprilysin inhibiting activity.
19 cl, 9 ex
,
(а),
,
FIELD: biotechnology.
SUBSTANCE: invention relates to a method for preparation of an enantiomerically enriched compound with Formula III , wherein A is (C1-C6)alkyl-O-, phenyl- C1-C6)alkyl-O-; aryl selected from phenyl, naphthyl, benzo 1,3]dioxole, 2,3-benzo[1,4]dioxin which is optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; or heteroaryl having four or five carbon atoms and one heteroatom selected from oxygen, nitrogen and sulfur, which is optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; B is phenyl optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; and R1 and R2 independently represent (C1-C6)alkyl, phenyl-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl, (C3-C7)cycloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; provided that R1 differs from R2; where the absolute configuration of the asymmetric carbon atom carrying R1 and R2, is an R-configuration; including (a) reaction of Formula XI
acylhydrazine with Formula XII
ketone to form a compound of Formula XIII
, where R1 differs from R2, (b) reduction of the Formula XIII compound in the presence of a chiral catalyst to form a Formula R-XIV compound and (c) reaction of the Formula R-XIV
compound with the Formula B-CO-LG compound, wherein LG is a leaving group, forming a compound with Formula III.
EFFECT: chiral diacylhydrazine ligands for genome modulation.
6 cl, 25 dwg, 11 tbl
