Bisamidate phosphonate compounds as inhibitors of fructose 1,6-bisphosphatase

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

 

The technical field

This invention relates to novel prodrugs, their reception, their use for oral delivery of inhibitors of fructose-1,6-bisphosphatase (Fbpase, FBPase) and their use for the treatment of diabetes and other diseases where the inhibition of gluconeogenesis, regulation of glucose levels in the blood, reducing the deposition of glycogen or reduction of insulin levels is useful.

Prior art

Organic compounds, which are charged at physiological pH, are often limited oral bioavailability, cell permeability and tissue distribution (e.g., CNS). These properties are attributed to the inability of ionic compounds to penetrate through the cell membrane by passive diffusion. One strategy to overcome this problem, is to obtain lipophilic prodrugs, which are able to penetrate the cell membrane and subsequently to undergo the transformation, followed by the generation of a charged connection. The transformation may be the result of either chemical instability, or is the result of the reaction catalyzed by an enzyme.

A large number of structurally different prodrugs described for phosphonic acids. Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997). The largest class is typically used is rilecart represents the number aryloxyalkyl esters, who first used as a strategy prodrugs for carboxylic acids, and then in 1983, was used for phosphate Farquhar et al. J.Pharm. Sci, 72: 324 (1983). Subsequently aryloxyalkanoic ester was used for delivery of phosphonic acids across cell membranes and increase oral bioavailability. It is also reported about alkoxycarbonylmethyl complex ether, as a close variant of the strategy aryloxyalkyl of ester, which is used to increase oral bioavailability.

Much less progress has been made in the use of other classes phosphonate prodrugs. In several cases reported using arolovich esters, particularly phenyl ethers, to improve bioavailability. DeLambert et al. J.Med. Chem. 37: 498 (1994). In addition, there are reports of phenyl esters containing an ester of carboxylic acid in the ortho-position to the phosphate. Khamnei and Torrence, J.Med. Chem. 39: 4109-4115 (1996). Reported benzyl esters for the formation of the source phosphonic acid. In some cases, you can accelerate the hydrolysis, using the substituents in the ortho - or para-position. Benzyl analogues with acylated phenol or alkilirovanny phenol can form a phenolic compound under the action of enzymes such as esterase, oxidase, etc. which, in turn, is subjected to the splitting of the structure on the benzyl C-O bonds, forming phosphoric acid and quinonmethydic intermediate connection. Examples of this class of prodrugs are Mitchell et al., J.Chem. Soc. Perkin Trans. 12345 (1992); Brook et al. WO 91/19721. Were described and other benzyladenine prodrugs, including a group containing an ester of carboxylic acid, is associated with benzoylmethylene. Glazier et al. WO 91/19721. Reported testarray the prodrugs used for intracellular delivery phosphonate drugs. These ProFire contain ethylthiourea in which Tolna group or etherification acyl group, or connected to another Tilney group with the formation of disulfide. Deesterification or restore disulfide leads to the formation of intermediate compounds, free of tio, which then splits into phosphoric acid and epauleted. Puech et al., Antiviral Res., 22: 155-174 (1993); Benzaria et al. J.Med. Chem. 39: 4958 (1996). In addition, there are reports of cyclic phosphonate esters as prodrugs of compounds containing phosphorus.

In addition, some phosphoramidate are known prodrugs of phosphonates, however, they showed poor oral bioavailability. In some cases, phosphoramidate were very unstable in acidic conditions, which is discussed as a possible explanation for their poor oral bioavailability (J.Med. Chem., 37: 1857-1864 (1994)). Similarly, have I message about insufficient oral bioavailability of miamidade of similar RMEA (J.Med. Chem., 38: 1372-1379 (1995)). Another prodrug of RMAA consists of amidate of monoether glycine and phenyl ether complex (WO 95/07920).

Although there are reports of a variety of methodologies for developing prodrugs of phosphoric acid whose aim is to achieve a high degree of delivery of phosphoric acid into the cells, a few of them, as you know, lead to a good (enough) oral bioavailability. In some cases, prodrugs unstable in the gastrointestinal tract (low pH, the activity of esterases). In other cases, prodrugs too stable and therefore insufficiently converted in vivo into the original drug.

In international publications WO 98/39344, WO 98/39343, WO 98/139342 and WO 00/14095 describes compounds containing phosphoric acid and esters which inhibit fructose-1,6-bisphosphatase.

Full disclosure publications and references referred to above and hereinafter in this specification, are included in this description by reference, and Pets that they may not have a relationship to the prior art.

The invention

This invention relates to new bisamidines the phosphonates, which are potent inhibitors Fbpase. In one aspect, these compounds possess excellent oral bioavailability compared with the corresponding FOC is nowymi acids. In another aspect, the present invention relates to in vitro and in vivo inhibitory activity of these compounds against Fbpase. Another aspect of the present invention refers to the clinical use of these inhibitors Fbpase as a method of treatment or prevention of diseases that are sensitive to inhibition of gluconeogenesis and diseases that are sensitive to low levels of glucose in the blood.

In another aspect, compounds used for the treatment or prevention of diseases associated with excessive deposition of glycogen and diseases, such as cardiovascular diseases, including atherosclerosis, coronary heart disease, and diseases such as metabolic disorders, such as hypercholesterolemia, hyperlipemia, which are reinforced by hyperinsulinemia and hyperglycemia.

In addition, the invention includes novel compounds defined by the following formula I, X and XI, and methods of using these compounds. In the scope of the present invention also includes the usual salts and prodrugs of the compounds of formula I, X and XI.

Since these compounds may have asymmetric centers, the present invention also includes not only racemic mixtures of these compounds, but also the individual who stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formula I, X and XI, including additive salts of acids. In addition, the present invention covers the usual prodrugs of compounds of formula I, X and XI.

A detailed description of the invention

Definition

In accordance with the present invention used therein, the following terms are defined below, unless noted otherwise.

The nomenclature of the groups X, X', X2and X3used here in formulas I and XI, describes the group associated with the phosphonate, and ends with a group associated with a heteroaromatic ring. For example, when X represents alkylamino, refers to the following structure:

(heteroaromatic ring)-NR-ALK-P(O)(NR15R16) (NR18-(CR12R13)n-(C(O)-R14)

Similarly, a, b, C, D, E, a", B", C", D", E", A2L2E2I , J2And3L3E3and J3groups and other substituents heteroaromatic ring described in such a way that the term ends with the group attached to the heteroaromatic ring. In General, the substituents are named so that the term ends with the group at the point of connection. The hyphen before or after a term indicates the point of attachment. For example, "alkyl" refers to a bivalent alkyl and the and alkylene.

The term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted. Suitable aryl groups include phenyl and furan-2,5-diyl.

Carbocyclic aryl groups are groups where the ring atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl group and a polycyclic or condensed compounds such as optionally substituted raftiline group.

Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the other ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower acylpyrrole, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.

The term "annelation" or "annelirovannymi" refers to the formation of additional circular part on the existing aryl or heteroaryl group. This is a form optional substitution on the aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated and contains 2-9 new atoms, 0-3 of which can be heteroatoms taken from the group N, O and S. Annelation may include atoms from group X as part of the newly formed ring. For example, the expression "together L2and E2form anilinophenol cyclic group" includes

The term "biaryl" represents an aryl group containing more than one aromatic ring, including a condensed ring system, and aryl groups, aryl substituted by other groups. Such groups can be optionally substituted. Suitable burilnye groups include naphthyl and biphenyl.

The term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds. Such cyclic compounds include, but are not limited to, aromatic, cycloalkyl and the United bridging communication cycloalkyl connection. Cyclic compound includes heterocycles. Cyclohexenylmethyl and cyclohexylethyl are suitable alicyclic group. Such groups can be optionally substituted.

The term "optionally substituted" or "substituted" includes groups substituted by one who mirima substituents, optional selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhalogenated, Alcoxy, heteroaryl, geterotsiklicheskie, heteroaromatic, heteroallyl, heteroaromatic, azido, amino, guanidino, amidino, halogen, lower alkylthio, oxo, arylalkyl, carboxyethyl, carboxyl, carboxamido, nitro, acyloxy, aminoacyl, acylaminoacyl, alkylaryl, acylaminoalkyl, alkoxyaryl, arylamino, aralkylamines, phosphono, sulfonyl-carboxymethylcellulose-carboxamidine, hydroxyalkyl, haloalkyl, alkylaminocarbonyl-aminocarbonylmethyl-, cyano the bottom alkoxyalkyl, lower pergolide and arylalkylamine. "Substituted aryl" and "substituted heteroaryl" refers to aryl and heteroaryl groups, substituted 1-2; 1-3 or 1-4 substituents. In one aspect, suitable substituents of aryl groups include lower alkyl, lower alkoxy, lower perhalocarbon, halogen, hydroxy and amino. "Substituted" in the description of R5the group does not include annelation.

The term "aralkyl" refers to an alkyl group, substituted aryl group. Suitable kalkilya groups include benzyl, picolyl, etc. and can be optionally substituted. The term "aralkyl-" refers to the divalent group-aryl-alkylene "Heteroaromatic" refers to alkalinous group, substituted heteroaryl group.

The term "alkylaryl-" refers to the group-ALK-aryl-, where "ALK" is alkylenes group. "Lower-alkylaryl-" refers to such groups, where alkylene is lower alkylene.

The term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms. Such groups can be straight chain, branched or cyclic.

The terms "arylamino" and "aralkylamines" (b) respectively belong to the group-NRR', where (a) R is aryl and R' is hydrogen, alkyl, aralkyl or aryl, and (b) R represents aralkyl and R' represents hydrogen or aralkyl, aryl, alkyl.

The term "acyl" refers to-C(O)R, where R represents the alkyl and aryl.

The term "carboxy ester" refers to-C(O)OR where R is alkyl, aryl, aralkyl and alicyclic group, all optionally substituted.

The term "carboxyl" refers to-C(O)HE.

The term "oxo" refers to =O in the alkyl group.

The term "amino" refers to-NRR1where R and R1independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic groups, all except H, are optionally substituted, and R and R1may form a cyclic ring system.

The term "carbonylation the" and "-carbylamine-" refers to RCONR - and-CONR -, respectively, where each R is independently hydrogen or alkyl.

The term "halogen" or "halogen" refers to-F, -Cl, -Br, and-I.

The term "oxyalkylene-" refers to-O-ALK-NR-, where "ALK" is alkylenes group and R represents H or alkyl.

The term "alkylaminocarbonyl-" refers to the group-ALK-NR-ALK-C(O)-Oh, where "ALK" is alkylenes group and R represents H or lower alkyl.

The term "alkylaminocarbonyl-" refers to the group-ALK-NR-C(O)-, where "ALK" is alkylenes group and R represents H or lower alkyl.

The term "oxaalkyl-" refers to the group-O-ALK-, where "ALK" is alkylenes group.

The term "alkylcarboxylic-" refers to the group-ALK-C(O)-O-ALK-, where each "ALK" is an independently alkylenes group.

The term "alkyl" refers to saturated aliphatic groups, including straight chain, branched chain and cyclic groups. Alkyl groups can be optionally substituted. Suitable alkyl groups include methyl, isopropyl and cyclopropyl.

The term "cyclic alkyl" or "cycloalkyl" refers to alkyl groups that are cyclic group with 3-6 or 3-10 atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups can be substituted.

The term "heterocyclyl" and "heterocyclic alkyl" relation is seeking to cyclic groups 3-6 or 3-10 atoms, containing at least one heteroatom. In one aspect, these groups contain 1-3 heteroatoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. Heterocyclic group may be attached via a nitrogen or via a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl and pyridyl. Such groups can be substituted.

The term "phosphono" refers to RHO3R2where R is selected from the group consisting of-H, alkyl, aryl, aralkyl and alicyclic groups.

The term "sulfonyl" refers to-SO3R, where R is H, alkyl, aryl, aralkyl and alicyclic group.

The term "alkenyl" refers to unsaturated groups which contain at least one carbon-carbon double bond, and includes group with a straight chain, branched chain and cyclic groups. Alkeneamine groups can be optionally substituted. Suitable alkeneamine groups include allyl. "1 Alkenyl" refers to alkenyl groups, where the double bond is between the first and second carbon atom. If 1-Alchemilla group is associated with another group, for example, it is W Deputy associated with cyclic FOSFA(aramid)atom, then it is attached to the first carbon.

The term "quinil" refers to unsaturated groups which contain, on ENISA least one carbon-carbon triple bond, and includes group with a straight chain, branched chain and cyclic groups. Alkyline groups can be optionally substituted. Suitable alkyline group include ethinyl. "1-Quinil" refers to alkynylaryl groups, where the triple bond is between the first and second carbon atom. If 1-Alchemilla group is associated with another group, then it is attached to the first carbon.

The term "alkylene" refers to divalent straight chain, branched chain or cyclic saturated aliphatic group.

The term "cycloalkyl-COOR3" refers to divalent cycloalkyl group or heterocyclic group containing 4-6 atoms in the ring, with the 0-1 heteroatom selected from O, N and S. Cycloalkyl or heterocyclic group substituted-COOR3.

The term "acyloxy" refers to the ester group-O-C(O)R, where R is H, alkyl, alkenyl, quinil, aryl, aralkyl or alicyclic group.

The term "aminoalkyl-" refers to the group NR2-ALK-, where "ALK" is alkylenes group and R is selected from H, alkyl, aryl, aralkyl and alicyclic.

The term "alkyl(hydroxy)-" indicates the position in relation to the alkyl chain. When the specified term is X group, HE is in position α to the phosphorus atom.

The term "alkyl is isoalkyl-" refers to the group alkyl-NR-ALK-, where each "ALK" is an independently selected alkylene and R represents H or lower alkyl. "Lower acylaminoalkyl-" refers to the groups, where each Allenova group represents the lowest alkylen.

The term "alluminati-" refers to the group aryl-NR-ALK-, where "ALK" is alkylenes group and R represents H, alkyl, aryl, aralkyl and alicyclic. In the "lower alluminare-" Allenova group represents the lowest alkylen.

The term "acylaminoacyl-" refers to the group alkyl-NR-aryl-, where "aryl" represents a divalent group, and R represents H, alkyl, aralkyl and alicyclic. In the "lower acylaminoacyl-" Allenova group is lower alkyl.

The term "alkyloxyaryl-" refers to an aryl group substituted by alkyloxy. In "lower "alkyloxyaryl-" alkyl group is lower alkyl.

The term "aryloxyalkyl-" refers to an alkyl group substituted by arroceros.

The term "aralkylamines-" refers to the group aryl-ALK-O-ALK-, where "ALK" is alkylenes group. "Lower aralkylamines-" refers to such groups, where alkylene groups represent lower alkylene.

The term "alkoxy" or "-alkyloxy-" refers to the group-ALK-O-, where "ALK" is alkylenes group. The term "alkoxy" refers to the group alkyl-O-.

The term "alkoxyalkyl-" or "-alkyloxyalkyl the l-" refers to the group-ALK-O-ALK-, where each "ALK" is an independently selected alkalinous group. In "lower-alkoxyalkyl-every alkylene is lower alkylene.

The terms "alkylthio-and-alkylthio-" refers to the groups alkyl-S - and-ALK-S -, respectively, where "ALK" is alkylenes group.

The term "alkylthiomethyl-" refers to the group-ALK-S-ALK-, where each "ALK" is an independently selected alkylenes group. In "lower-alkylthiomethyl" every alkylene is lower alkylene.

The term "alkoxycarbonyl-" refers to alkyl-O-C(O)-O-.

The term "aryloxypropanolamine-" refers to aryl-O-C(O)-O-.

The term "alkyldiethanolamine-" refers to alkyl-S-C(O)-O-.

The term "alkoxycarbonyl-" refers to-ALK-O-C(O)-NR1-where "ALK" represents alkylene and R1include-H, alkyl, aryl, alicyclic and aralkyl.

The term "alkylaminocarbonyl" refers to an-ALK-NR1-C(O)-NR1-where "ALK" represents alkylene and R1independently selected from H, alkyl, aryl, aralkyl and alicyclic groups.

The terms "amido" or "carboxamido" refer to NR2-C(O) -, RC(O)-NR1-where R and R1include H, alkyl, aryl, aralkyl and alicyclic. The terms do not include urea, -NR-C(O)-NR.

The terms "carboxymethylchitin and carboxamide" refers to aryl-ALK-NR'-C(O) -, and ap-NRl-C(O)-ALK -, respectively, where "ar" is the Rila and "ALK" represents alkylene, R1and R include H, alkyl, aryl, aralkyl and alicyclic.

The term "alkylcarboxylic-" or "-alkylcarboxylic-" refers to the group-ALK-C(O)N(R)-, where "ALK" is alkylenes group, and R represents H or lower alkyl.

The term "alkylaminocarbonyl-" refers to the group-ALK-NR-C(O)-, where "ALK" is alkylenes group and R represents H or lower alkyl.

The term "aminocarboxylate-" refers to the group NR2-C(O)-N(R)-ALK-, where R represents an alkyl group or H, and "ALK" represents alkylenes group. "Lower aminocarboxylate-" refers to such groups, where "ALK" is lower alkylene.

The term "thiocarbonyl" refers to-O-C(S)-O-, or an acyclic or cyclic group.

The term "hydroxyalkyl" refers to an alkyl group substituted by one HE.

The term "haloalkyl" refers to an alkyl group substituted with one halogen selected from the group of I, Cl, Br, F.

The term "cyano" refers to-C≡N.

The term "nitro" refers to-NO2.

The term "arylalkyl" refers to alkyl-S(O)-ALK-, where "ALK" represents alkylene.

The term "heteroaromatic" refers to an alkyl group, substituted heteroaryl group.

The term "-1,1-dialogical-" refers to the X group, where 1 indicates the location and therefore the halides are α position in relation to the atom phospho is A.

The term "paraloid" refers to the groups, where each C-H bond is replaced With a halogen bond in an aliphatic or aryl group. Suitable perhelomille groups include-CF3and-CFCl2.

The term "guanidino" refers to-NR-C(NR)-NR2and-N=C(NR2)2where each R group is independently selected from the group of-H, alkyl, alkenyl, quinil,- aryl and alicyclic, all except-H, optionally are substituted.

The term "bidentate" refers to an alkyl group that is attached by their ends to the same atom, form a cyclic group. For example, propylenimine contains a bidentate propylene group.

The term "amino acid of natural origin" refers to alpha-amino acids, containing at least one hydrogen at the alpha carbon, and in the case where the alpha carbon is chiral, he has an absolute configuration s

The term "amidino" refers to-C(NR)-NR2where each R group is independently selected from the group of-H, alkyl, alkenyl, quinil, aryl and an alicyclic group, all except-H, optionally substituted.

The term "pharmaceutically acceptable salt " includes salts of compounds of the formula IA and their prodrugs, obtained by combination of the compounds of the present invention and an organic or inorganic acids or bases. Suitable acids which include hydrochloric acid, Hydrobromic acid, acetic acid, triperoxonane acid, methanesulfonate, p-toluensulfonate and maleic acid.

Used herein, the term "prodrug" refers to any compound that when introduced into a biological system generates the substance - "medicine" (the biologically active compound) as a result of spontaneous chemical reaction(s), chemical reaction(s)catalyzed by the enzyme, and/or metabolic chemical reaction(s). Standard prodrugs receive using group attached to the functional group, for example BUT-, HS-, noos-, R2N-related inhibitor Fbpase that hatshepsuts in vivo. Normal prodrugs include, but are not limited to, carboxylate esters, where the group is alkyl, aryl, aralkyl, aryloxyalkyl, alkoxycarbonylmethyl, and esters of hydroxyl, thiol, and amines, where the attached group 'represents an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The above groups are illustrative, but not exhaustive number of groups, and a qualified person skilled in the art can obtain other known varieties of prodrugs. Such prodrugs of compounds of formula I, X and XI are included in the scope of the present invention. Prodrugs have to undergo n is which form chemical conversion, to obtain a compound that is biologically active or represents a precursor of biologically active compounds. In some cases, the prodrug is biologically active, but usually to a lesser extent than the drug itself, and in this case, the specified prodrug is used to improve the efficiency or safety through improved oral bioavailability, pharmacodynamic half-life, etc.

Phosphoroamidite derivatives were investigated as phosphate prodrugs (e.g., McGuigan et al., J.Med. Chem., 1999, 42:393, and references cited in this publication) and how phosphonate prodrugs (Bischofberger et al., U.S. patent 5798340, and references cited therein), represented by the formulas G and H.

In addition, cyclic phosphoramidate were investigated as phosphonate prodrugs due to their perceived higher stability in comparison with non-cyclic phosphoramidate (for example, Starrett et al., J.Med. Chem., 1994, 37:1857).

There are reports of another type of nucleotide prodrugs as a combination of S-acyl-2-dietrologia ether and phosphoroamidite (Egron et al., Nucleosides & Nucleotlde, 1999, 18, 981)represented by the formula J.

The term "enhancing" refers to an increase or improvement to Kratovo properties.

The term "enhanced oral bioavailability" refers to an increase of at least 50% of absorption (suction) of the dose of the original drug or prodrug (not of the invention) from the gastrointestinal tract. In one aspect of this increase is at least 100%. Determination of oral bioavailability generally refers to the definitions of prodrugs, drug or metabolite of the drug in the blood, tissues or urine after oral administration, compared with the definitions after systemic injection.

The term "source drug" refers to any compound that delivers the same biologically active compound. The original form of the medicinal product is M-P(O)(OH)2and the usual prodrugs, such as esters.

The term "metabolite drug" refers to any compound obtained in vivo or in vitro from the original medicinal product, which may include biologically active drug.

The term "pharmacodynamic half-life" refers to the time after administration of a drug or prodrug, when there is a reduction half-defined pharmacological response. In one aspect, the half-life increases when per the od of the half-life increases at least 50%.

The term "biologically active drug or agent" refers to a chemical substance that provides biological action. Thus, the active medication or tools include compounds that are biologically active in the form M-P(O)(OH)2.

The term "inhibitor of fructose-1,6-bisphosphatase" refers to chemical M-P(O)(OH)2that has value IR50(IC50), is equal to or less than 50 μm, in relation to Fbpase human liver.

The term "therapeutically effective amount" refers to the number of (drug), which has a beneficial effect in the treatment of disease or condition.

Connection

Suitable alkyl groups include groups containing from 1 to about 20 carbon atoms. Suitable aryl groups include groups containing from 1 to about 20 carbon atoms. Suitable kalkilya groups include groups containing from 2 to about 21 carbon atoms. Suitable alloctype include groups containing from 1 to about 20 carbon atoms. Suitable alkylene groups include groups containing from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups containing from 3 to about 20 carbon atoms. Suitable heteroaryl groups include GRU is dust, containing from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. Suitable heteroalicyclic groups include groups containing from 2 to about 20 carbon atoms and 1 to 5 heteroatoms, independently selected from nitrogen, oxygen, phosphorus and sulphur.

One aspect of the invention relates to the compound of formula IA

where the compounds of formula IA are converted in vivo or in vitro in M-RO3H2that is an inhibitor of fructose-1,6-bisphosphatase,

n is an integer from 1 to 3;

R2selected from the group of-H and-R3;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, with the formation of a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other17, -NR2OR9and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optional the tion containing 1 heteroatom, selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atoms with the formation of a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

and its pharmaceutically acceptable salts.

Such compounds into the M-RHO3H2include compounds that have a value IR50in respect of the enzyme, Fbpase isolated from human liver, less than or equal to 10 μm. Alternative value IR50less than or equal to 1 μm. Such compounds can contact the website of the AMF (AMR) Fbpase.

In one aspect, M is R5-X-, where the R 5selected from the group consisting of

where each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may represent O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G' groups are N;

And selected from the group consisting of-H, -NR42, -CONR42, -CO2R3, halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, ne is haloalkyl and halogen, optionally substituted;

J is selected from the group consisting of N, or absent;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with the phosphorus is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-, -carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted, provided that X is not substituted -COOR2, -SO3N or RHO3R22;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or R4and R4together form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aryl, aralkyl and alicyclic, or R9and R9in the natural form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

and provided that

1) when G' is N, then the respective a, b, D or E is missing;

2) at least one of a and b or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

and its pharmaceutically acceptable salts.

In one aspect, you can use the following additional conditions:

4) when R5represents a six-membered ring, then X is a bridging group of 2 atoms, optionally substituted-alkyloxy - or optionally substituted-alkylthio-;

5) when X is-heteroaryl - group, then R5not substituted with two or more aryl groups.

In one aspect of the present invention the compounds of formula IA have IR50≤50 μm in relation to the production of glucose in a dedicated hepatic cells of rat liver.

In one aspect, the compounds of formula IA can be selected from those compounds where M is attached to

or

where R17selected from the group consisting of ethyl, isopropyl, n-propyl and neopentyl, and where* electrohome S.

In thiazolo, in the case where A" represents-NH2, X is furan-2,5-diyl," is-S(CH2)2CH3or in the case where A" represents-NH2D represents furan-2,5-diyl," is-CH2-CH(CH3)2then M can be attached to

or

where R17selected from the group consisting of ethyl, isopropyl, n-propyl and neopentyl, and where* is the stereochemistry S.

In one aspect, the compounds of formula IA can be selected from

Within this group of compounds of formula IA can provide compounds of formulas II or IV

In one aspect, the compounds have the formula IA, where M is

where G is selected from the group consisting of-O - and-S-;

And2selected from the group consisting of-H, -NR42, -NHAc, -OR2, -SR2, -C(O)NR42, halogen, -COR11, -CN, pergolide, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil;

L2E2and J2selected from the group consisting of-NR42, -NHA, -NO2, -H, -OR2, -SR2, -C(O)NR42, halogen, -COR11, SO2R3, guanidine, amidine, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHSO2R3, -SO2NR42, -CN, -S(O)R3, pergolide, pergolide, perhalogenated, C1-C6alkyl(OH)-, C1-C6alkyl(SH), C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, heteroaryl and lower alicyclic, or L2and E2or E2and J2together form anilinophenol cyclic group;

X2selected from the group consisting of CR22-, -CF2-, -CR22-O-, -CR22-S-, -C (O)-O-, -C(O)-S-, -C(S)-O-, -CH2-C(O)-O -, and-CR22-NR20-and where the atom is related to the phosphorus is a carbon atom, provided that X2not replaced by a-COOR2, -SO3N or RHO3R22;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or R4and R4together form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

R20selected from the group consisting of Nissel is the alkyl, -H,- COR2,

and their pharmaceutically acceptable salts.

In one aspect bispectrality part of the compounds of the invention

can be selected from the group consisting of

and

where R17selected from the group consisting of ethyl, isopropyl, n-propyl, n-butyl and neopentyl. In another aspect* has the stereochemistry S.

Alternative such compounds may have the formula

In one aspect of the invention M is

where a3E3and L3selected from the group consisting of-NR82, -NO2, -H, -OR7, -SR7, -C(O)NR42, halogen, -COR11, -SO2R3, guanidine, amidine, -NHSO2R3, -SO2NR42-CN, sulfoxide, pergolide, nargological, perhalogenated, C1-C5of alkyl, C2-C5alkenyl, C2-C5the quinil and lower alicyclic, or And3and L3together form a cyclic group, or L3and E3together form a cyclic group, or E3and J3together form a cyclic group including aryl, cycloalkyl and heterocyclic group;

J3selected from the group consisting of the NR 82, -NO2, -H, -OR7, -SR7, -C(O)NR42, halogen, -COR11, -CN, sulfonyl, sulfoxide, pergolide, hydroxyalkyl, perhalogenated, alkyl, haloalkyl, aminoalkyl, alkenyl, quinil; alicyclic, aryl and aralkyl, or together with Y3forms a cyclic group including aryl, cycloalkyl and heteroseksualci;

X3selected from the group consisting of-alkyl(hydroxy)-, -alkyl-, -quinil-, -aryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X3not replaced by a-COOR2, -SO3N or-PO3R22;

Y3selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R3, -S(O)2R3, -C(O)-R11, -CONHR3, -NR22and-OR3all, except H, are optionally substituted;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and Alki is a, or R4and R4together form cycloalkyl group;

R7independently selected from the group consisting of-H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and-C(O)R10;

R8independently selected from the group consisting of-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R10or together they form a bidentate alkyl;

each R9independently selected from the group consisting of-H, -alkyl, aralkyl and alicyclic, or R9and R9together form cycloalkyl group;

R10selected from the group consisting of-H, lower alkyl, -NH2, lower aryl, and lower pergolide;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2,

and their pharmaceutically acceptable salts.

In one aspect, you can use the following conditions:

a) when X3represents an alkyl or alkene, And then3represents-N(R82);

b) X3is not alkylamino and acylaminoalkyl, substituted esters of phosphonic acids and phosphonic acids, and

c) A3L3E3I , J3and Y3together can form only 0-2 cyclic group.

In the table below, the applicants considered any possible combination of the following groups is of Arcos and groups see above for the different variables.

The compounds of formula IA can have an oral bioavailability of at least 5%, and some (of them) may have an oral bioavailability of at least 10%.

Prodrugs of the present invention may have two isomeric forms in relation to phosphorus. In one aspect, compounds of the invention are chiral at phosphorus. In another aspect there is no chiral center in the amino groups attached to phosphorus. Prodrugs of the present invention may have isomers at carbon, substituted R12and R13. The invention considers a mixture of isomers, as well as individual stereoisomers. For example, when n is 1 and R12represents H, carbon, associated with R12and R13can have the stereochemistry of R. In another aspect, when n is 1 and R12 is-H, the carbon associated with R12and R13can have the stereochemistry S.

The present invention includes compounds defined by the following formula: formula i, formula ii and formula iii, and they are presented in Table 1 in coded form.

In the above formulas i, ii and iii, R55may be substituted by a and B. the Compounds of formulas i, ii and iii are listed in Table 1 with numbers attributed to R55And, In, Q1and Q2in the above formulas i, ii and iii in accordance with the following condition;

Q1.Q2.R55.VA For each part of the structure, attributed to the figure presented in the following tables for R55And, In, Q1and Q2.

The variable R55divided into two groups, each represented by four different structures.

Compounds of formulas i, ii and iii are encoded in Table 1, where the parts R55attributed to the following figures.

Group 1:

1234
R55=

Group 2:

1234
R55=

Parts And assigned the following numbers:

1234
A=NH2HMeCl

The parts are assigned the following numbers:

12345678
B=-SCH3-isawi-ceclor-S-NWG-SEt-isorg-NWG-CH2ceclor

Variables Q1and Q2divided into three groups, each represented by eight different substituents. Parts Q1and Q2attributed to the following figures.

Group 1:

Q1and Q2

1. -NH-CH2-C(O)R14

2. -NH(CH 3)-C(O)R14

3. -NH-C(CH3)2-C(O)R14

4. -NH-C(CH3)2CH2-C(O)R14

5. -NH-CH(CH(CH3)2))-C(O)R14

6. -NH-CH(CH2(CH(CH3)2)))-C(O)R14

7. -NH-CH(CH2CH2SCH3)-C(O)R14

8. -NH-CH(CH2SCH2Ph)-C(O)R14

Group 2:

Q1and Q2

1. -NH-CH2CH2-C(O)R14

2. -NH-CH(CH2CH2COR14)-C(O)R14

3. -NH-CH(CH2COR14)-C(O)R14

4. -NH-CH(CH2CONH2)-C(O)R14

5. -NH-CH(COR14)CH2-C(O)R14

6. -NH-CH(CH2OR21)-C(O)R14

7. -NH-CH(CH2CH2COR14)-C(O)R14

8. NH-CH(CH2OH)-C(O)R14

Group 3:

Q1and Q2

1. -NH-CH(CH2-C6H5OH)-C(O)R14

2. -NH-C(cyclopropyl)-C(O)R14

3. -NH-C(cyclopentyl)-C(O)R14

4. -NH-(cyclohexyl)-C(O)R14

5. -NH-CH(CH2Ph)-C(O)R14

6. -N(CH3)-CH2-C(O)R14

7.

8. -NR22R23

where R14selected from the group consisting of OMe, OEt, OBn, O-isorg, O-neopentyl, O-Twi, O-NWG, OPh, -N(Me)2the oksietilenom-N-morpholino, SMe, SEt; R21represents methyl, ethyl, benzyl, and propyl; R22represents H, Me, Et, Bn, Pr and Ph; R23represents Me, Et, Bn, Pr and Ph or R22and R23are morpholinyl and pyrrolidin the L.

Thus, the connection 3.3.1.2.1 in group 1 corresponds to the structure below for the formula i:

and when R14is ethoxy, the connection must have the following structure:

The numbers indicated in Table 1, also apply to compounds of benzothiazole and benzoxazole formula X. these compounds represented by formulas iv and v.

Compounds of formulas iv and v are listed in Table 1 with numbers attributed to a, b, D, Q1and Q2in the above formulas iv and v in accordance with the following condition:

Q1.Q2.A.B.D. For each part of the structure, attributed to the figure presented in the following tables for a, b, D, Q1and Q2.

Variables Q1and Q2divided into three groups, each represented by eight different substituents.

Group 1:

Parts Q1and Q2assigned the following numbers:

Q1and Q2

1. -NH-CH2-C(O)R14

2. -NH-CH(CH3)-C(O)R14

3. -NH-C(CH3)2-C(O)R14

4. -NH-C(CH3)2CH2-C(O)R14

5. -NH-CH(CH(CH3)2))-C(O)R14

6. -NH-CH(CH2(CH(CH3)2)))-C(O)R14

7. -NH-CH(CH2CH2SCH3)-C(O)Rsup> 14

8. -NH-CH(CH2SCH2Ph)-C(O)R14

Group 2:

Q1and Q2

1. -NH-CH2CH2-C(O)R14

2. -NH-CH(CH2CH2COR14)-C(O)R14

3. -NH-CH(CH2COR14)-C(O)R14

4. -NH-CH(CH2CONH2)-C(O)R14

5. -NH-OH(COR14)CH2-C(O)R14

6. -NH-CH(CH2OR21)-C(O)R14

7. -NH-CH(CH2CH2COR14)-C(O)R14

8. -NH-CH(CH2OH)-C(O)R14

Group 3:

Q1and Q2

1. -NH-CH(CH2-CH5OH)-C(O)R14

2. -NH-C(cyclopropyl)-C(O)R14

3. -NH-C(cyclopentyl)-C(O)R14

4. -NH-(cyclohexyl)-C(O)R14

5. -NH-CH(CH2Ph)-C(O)R14

6. -N(CH3)-CH2-C(O)R14

7.

8. -NR22R23

Variable is divided into three groups, each represented by eight different substituents.

Group 1:

The parts are assigned the following numbers:

12345678
In=HMeEtNWGBr-isorgSCNzikang

Group 2:

12345678
In=CNFOMeOEtSMeSEt2-furanylC(O)OEt

Group 3:

12345678
In=B and D are connected, forming tsiklogeksilnogo groupB and D are connected, form a phenyl ringB and D are connected, forming fernilee ring (O-joined In)B and D are connected, forming fernilee ring (O attached to D)B and D are connected, forming tsiklogeksilnogo ringB and D are connected, forming, phenyl ringB and D are connected, forming fernilee ring (O-joined In)B and D are connected, forming fernilee ring (O attached to D)

Group 3 for the variable can only be merged with variable Group 3 D.

The variable D is divided into nine groups, each represented by four different substituents.

Group 1:

1234
D=NMeEtSON

Group 2:

The variable D is replaced with the parts attributed to the following figures:

1234
D=SMeSEtCH2OMeOMe

Group 3:

1234
D=nononono

Group 4:

1234
D=PrO-EtO-PrO-isopropyl

Group 5:

1234
D=O-BuO-isobutylO-cyclopropylO-pentyl

Group 6:

1234
D=O-neopentylO-cyclopentylO-sikorksyO-benzyl

Group 7:

1234
D=S-PrS-isopropyS-BuS-isobutyl

Group 8:

1234
D=S-cyclopropylS-pentylS-neopentylS-cyclopentyl

Group 9:

1234
D=cyclohexylS-benzylOch2OCH3Och2SCH3

Compounds of formulas iv and v are encoded in Table 1, where the parts And assigned the following numbers:

1234
And=NH2NMeC

where R14selected from the group consisting of OMe, OEt, OBn, O-Twi, O-NWG, OPh, O-neopentyl, -N(Me)2the oksietilenom-N-morpholino, SMe, SEt; R21represents methyl, ethyl, benzyl, and propyl; R22represents H, Me, Et, Bn, Pr and Ph and R23represents Me, Et, Bn, Pr and Ph or R22and R23are morpholinyl and pyrrolidinyl.

Thus, the connection 2.2.1.7.4 from Group 1 for b, D, Q1and Q2corresponds to the structure below for formula iv

and when R14is ethoxy, the structure should be of the form

Similarly in group 3 for the variable In the connection 2.2.1.7.4 corresponds to the structure below for formula iv

and when R14is ethoxy, the structure should be of the form

The best way of carrying out the invention relates to compounds numbered examples 50.6, 50.9, 50.15 and 50.20.

Section 1. The synthesis of compounds of formula I.

The synthesis of compounds covered by the present invention typically includes some or all of the following General stages: (1) preparation of phosphonate prodrugs; (2) removing protection from a phosphonate complex ester; (3) modification of the heterocycle; (4) the interaction of the heterocycle with the phosphonate component; (5) the formation of the heterocycle; (6) ring closure to form a heterocycle with the present phosphonate part and (7) obtaining useful intermediates. These stages are presented on the following scheme for compounds of formula I, where R5represents a 5-membered heteroaromatic ring. The compounds of formula I, where R5represents a 6-membered heteroaromatic ring or other heteroaromatic ring, get in the same way.

(1) Obtaining bisamidines fo fonate

General synthesis of bis-phosphoramidate prodrugs

In General, the bis-phosphoramidate formula I, where as-NR15R16and-N(R18)-(CR12R13)n-C(O)-R14are residues of the same amino acids, can be obtained from activated phosphonates, for example dichlorophosphate through a combination of ester amino acids, for example ethyl ester of glycine, in the presence or in the absence of a base, such as N-methylimidazole. The reactive dichloride can be obtained from the corresponding phosphonic acid and gloriouse agent, for example thionyl chloride (Starrett et al., J.Med. Chem., 1994, 1857), oxalicacid (Stowell et al., Tetrahedron Lett., 1990, 31, 3261) or pentachloride phosphorus (Quast et al., Synthesis, 1974, 450). In addition, data dichloride can be obtained from their respective disallowed esters (Bhongle et al., Synth. Commun., 1987, 7, 1071) and dialkylamino esters (Still et al., Tetrahedron Lett., 1983, 24, 4405; Patois et al., Bull. Soc. Chim, Fr., 1993, 130, 485).

Alternative these bis-phosphoramidate can be obtained by reacting the corresponding phosphonic acid complex ester of the amino acids, for example ethyl ester, glycine, in the presence of PPh3and 2,2'-dipyridamole in pyridine, as described in international publication WO 95/07920 or Mukaiyama, T., et al., J. Am. Chem. Soc., 1972, 94, 8528.

Synthesis of mixed bis-phosphoramidates formula I, where-NR15R16 and-N(R18)-(CR12R13)nC(O)-R14are esters of various amino acids, or a combination of ester amino acids and substituted amine, it is possible to obtain the actual transformation through dichloride as described above (coherent addition), followed by purification of the desired product (e.g., column chromatography). Alternative these unsymmetrical bis-phosphoramidate can be derived from the corresponding phosphonate of monoether, such as phenyl ester or benzyl ester, receiving mixed phosphonomethyl ester through chloridate, with subsequent hydrolysis of ester under conditions where the amide bond is stable. Received monoamide can be turned into a mixed basamid condensation with a second complex aminoethanol or substituted amine through chloridate, as described above. The synthesis of such complex monoamino can be performed using a published method (EP 481214).

(2) removing protection from a phosphonate of ester

The compounds of formula 2 can be obtained from phosphonate esters using known conditions for the cleavage of phosphate and phosphonate esters. Silicalite usually used for splitting different phosphonate esters and subsequent hydrolysis under mild conditions received killfast atnah esters gives the desired phosphonic acid. If necessary for the synthesis of acid-labile compounds can be used, the acid acceptors (for example, 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, and so on). Such silicalite include chlorotrimethylsilane (Rabinowitz, J.Qrg. Chem., 1963, 28: 2975), bromotrimethylsilane (McKenna et al., Tetrahedron Lett., 1977, 155) and attributively (Blackburn et al., J.Chem. Soc., Chem. Commun., 1978, 870). Alternative phosphonate esters can be cleaved in strongly acidic conditions (for example, HBr or HCl: Moffatt et al. U.S. patent 3524846, 1970). In addition, these esters can be cleaved through dichlorophosphate obtained by treatment of esters of halogenation agents (for example, pentachloride phosphorus, thionyl chloride, BBr3: Pelchowicz et al., J.Chem. Soc., 1961, 238), followed by hydrolysis in water to obtain phosphonic acids. Arrowie and benzyl phosphonate esters can be broken down in the conditions of hydrogenolysis (Lejczak et al., Synthesis, 1982, 412; Elliott et al., J.Med. Chem., 1985, 28: 1208; Baddiley et al., Nature, 1953, 171: 76) or in terms of recovery in the presence of metal (Shafer et al., J.Am. Chem. Soc., 1977, 99: 5118). In addition, cleavage of various phosphonate esters were used electrochemical conditions (Shono et al., J.Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta et al., Synth. Commun., 1980, 20: 299).

(3) modification of the present heterocycle

Synthesis of heterocyclic compounds included in the composition disclosed in the description of the compounds baltmarine investigated and described in numerous reviews (see section 4). Despite the advantage in the presence of the desired substituents in these compounds to the synthesis of compounds of formula 4, in some cases, the desired substituents are incompatible with subsequent reactions, and therefore require modification of the existing heterocycle at the end of the synthetic schemes using conventional chemistry (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991). For example, the compounds of formula I, where And And or are halogen or cyano, can be obtained from the corresponding amino group by becoming a diazonium group and reaction with various salts of copper (I) (e.g., CuI, CuBr, CuCl, CuCN). In addition, the halides can be entered directly halogenoalkanes various heterocycles. For example, 5-unsubstituted-2-aminothiazole can be converted into 2-amino-5-haloethanol using various reagents (e.g., NIS, NBS, NCS). In addition, heteroarylboronic are useful intermediate compounds and often easily converted into other substituents (such as a, a", B", C", D, D', E and E') by reaction of the combination in the presence of a transition metal, such as the Suzuki reaction, or Heck Stille (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck, Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). The compounds of formula I, where a represents carbamoyl is inuu group, can be formed from their respective alilovic carboxylate esters through aminals various amines, as for the synthesis of compounds of formula I, where a represents-CH2OH group or-CH2-halogroup use a normal reaction for modifying the functional group alilovic carboxylate esters. Substitution reactions of galinhatrololo (for example, 2-bromothiazole, 5-bromothiazole) various nucleophiles (for example, HSMe, C etc) are another way to introduce substituents, such as a, a"and B". For example, the substitution of 2-chlorothiazole the methanethiol leads to the corresponding 2-methylthiazole.

It is assumed that, if necessary, you can easily carry out the alkylation of the nitrogen atoms in the heterocycle (for example, imidazoles, 1,2,4-triazole and 1,2,3,4-tetrazolo), using, for example, standard alkylation reaction (alkylhalogenide, aralkylamines, alkylsulfonates Ali aralkylamines) or Mitsunobu reaction (alcohol).

(4) the interaction of the heterocycle with the phosphonate component (when the compounds disclosed in the present invention are produced by synthetic transformations, calling the combination of the heterocycle with the phosphonate component of diapir).

In particular, for the synthesis of compounds of formula I are suitable of combination reaction catalyzed PE echogram metal, such as reaction Stille or Suzuki. Of combination reaction between heteroarylboronic or triflate (for example, 2-bromopyridine) and M-RO3R', where M is 2-(5-tributylstannyl)fornillo or 2-(5-defended)fornillo group, under the reaction conditions, catalyzed by palladium (Farina et al., Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419), give the compounds of formula I, where X is furan-2,5-dialnow group. It is assumed that the nature of the participants combinations for these reactions can be reversearray (for example, a combination of trialkylsilyl or bornilsalicilova with halogen-X-P(O) (O-alkyl)2). In addition, the reported reactions combination between organomanganese and alkenylphenol or alkylacrylate, which can be used to obtain the compounds of formula I, where X is alkenylphenol group. The Heck reaction can be used to obtain compounds of the formula I, where X is alkenylphenol group (Heck, Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). In particular, these reactions are suitable for the synthesis of various heteroaromatic, as R5for compounds of formula I, subject to the availability of various halogenated heterocycles, and the above reaction, in particular, suitable for parallel synthesis (e.g., combinatorial synthesis on solid phase (Bunin, VA, The Combinatorial Index; Academic Press: San Diego, 1998) or in soluble phase (Flynn, D.L. et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to create large-scale combinatorial libraries. For example, ethyl-5-iodine-2-turningstone can be associated with the polymer Wang under conditions suitable for the reaction combinations. Then associated with the polymer 5-iodine-2-[5-(O-ethyl-O-Wang's polymer)phosphono]furan can be subjected to reactions Suzuki and Stille catalyzed by transition metal (as described above) with organoborane and organohalogen parallel way, with the aim of obtaining libraries of compounds of formula 3, where X is furan-2,5-diyl.

Substitution reactions suitable for a combination of the heterocycle with the phosphonate component of diapir. For example, the acid chloride cyanuric acid can be substituted dialkyldithiophosphate or dialkylaminoalkyl obtaining compounds of formula I, where R5is 1,3,5-triazine, X represents alkylthio or alkylamino. In addition, for a combination of the heterocycle with the phosphonate component of diapir you can use the alkylation reaction. For example, heteroaromatic thiol (e.g., 1,3,4-thiadiazole-2-thiol) can be alkilirovanii derived dialkyldithiophosphate (e.g., ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) to obtain the compounds of formula I, where X represents allylthiourea. In another aspect of the reaction alkylidenemalononitrile carboxylic acid (for example, the thiazole-4-carboxylic acid) derivative dialkyldithiophosphate (e.g., ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to the formation of compounds of formula I, where X is alkoxycarbonyl group, while the alkylation reaction heteroaromatic thiocarbonic acid (for example, thiazole-4-thiocarbonic acid) derived dialkyldithiophosphate (e.g., ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to the formation of compounds of formula I, where X is alkylthiomethyl group. Substitution guidancearticle (for example, 4-haloalkylthio) nucleophiles containing a phosphonate group (diethylhydroxylamine), is used to produce compounds of formula I, where X is alkoxyalkyl or alkylthiomethyl group. For example, the compounds of formula I where X is-CH2OCH2group, can be obtained from 2-chloromethylpyridine or 4-chloromethylthiazole using dialkyldithiophosphate and a suitable base (e.g. sodium hydride). You may address the nature of the nucleophiles and electrophiles for substitution reactions, i.e. haloalkyl and/or sulfonylacetonitrile esters can be subjected to substitution reaction heterocycles containing nucleophile (for example, 2-hidroxi Celerity, 2-mercaptopyridine or 4-hydroxyalkyloxy).

In addition, you can use the well-known formation of the amide bond (for example, a method using allhelgona, the method of mixed anhydrides, carbodiimide method) for a combination of heteroaromatic carboxylic acids with phosphonate component of diapir, which leads to the formation of compounds of formula I, where X is alkylaminocarbonyl or alkoxycarbonyl group. For example, the reaction of the combination of thiazole-4-carboxylic acid with dialkylaminoalkyl or dialkylhydroxylamines lead to the formation of compounds of formula I, where R5represents a thiazole and X represents alkylaminocarbonyl or alkoxycarbonyl group. Alternatively, you can reverse the interactive nature of the reagents, to obtain the compounds of formula I, where X represents alkylcarboxylic. For example, in the above reaction conditions, 2-aminothiazole can be combined with (RO)2P(O)-alkyl-CO2N (for example, diethylphosphonate acid) to give the compounds of formula I, where R5represents a thiazole and X represents alkylcarboxylic. The above reaction can also be used for parallel synthesis of libraries of compounds by combinatorial chemistry on solid phase is whether the soluble phase. For example,

HOCH2P(O)(OEt) (O-polymer),

H2NCH2P(O)(OEt) (O-polymer) and

NOESN2P(O)(OEt) (O-polymer) (obtained using known methods) can be combined with various heterocycles using the above reaction to obtain a library of compounds of formula 3, where X represents-C(O)och2-, or-C(O)NHCH2-or NHC(O)CH2-.

You can also use a rearrangement reaction to produce compounds of the present invention. For example, the rearrangement of Curtius the thiazole-4-carboxylic acid in the presence of dialkyldithiophosphate or dialkylaminoalkyl leads to the formation of compounds of formula I, where X represents alkylaminocarbonyl or alkoxycarbonylmethyl. The above reaction can also be adapted for combinatorial synthesis of libraries of compounds of formula 3. For example, reactions rearrangements Curtius between heterocyclic carboxylic acid and HOCH2P(O)(OEt) (O-polymer)ω and H2NCH2P(O)(OEt) (O-polymer)ω can lead to libraries of compounds of formula I where X is-NHC(O)OCH2or NHC(O)NHCH2-.

In the case of compounds of formula I, where X represents an alkyl group, phosphonate group can be entered using other conventional methods of education phosphonate, still is as a reaction Michaelis-Arbuzov (Bhattacharya et al., Chem. Rev., 1981, 81: 415), the reaction Michaelis-Becker (Blackburn et al., J.Organomet. Chem., 1988, 348: 55), and the reactions of addition of phosphorus to the electrophile (such as aldehydes, ketones, acylhomoserine, Emini and other carbonyl derivatives).

Phosphonate component can also be introduced through reaction injection lithium. For example, the introduction of lithium 2-ethynylpyridine using a suitable base, with subsequent removal of the educated thus the anion dialkylphosphinate leads to the formation of compounds of formula I, where R5is pyridyl, X is 1-(2-phosphono)etinilnoy group.

(5) the formation of the heterocycle

Although for the synthesis of compounds of formula I are using heterocycles, optionally, you can also create heterocycles as a result of interaction, which will provide compounds of the invention. In the literature was described getting heterocycles using a range of reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology In Organic Synthesis; Academic press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddltlon Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry: Syntheses, Reaction and Applications; Wiley, New York, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York). Some of the methods used to obtain the compounds of the present invention, given as examples in the following the discussion.

(i) Education teisaldamisel ring system

Thiazole used for the present invention, it is easy to get using a number of thoroughly described reactions with the formation of rings (Metzger, Thiazole and Its derivatives, part 1 and part 2; Wiley & Sons, New York, 1979). In particular, to create teisaldamisel ring system use cyclization reaction thioamides (such as thioacetamide, thiourea) and alpha-haloalkaliphilic compounds (such as alpha haloalkene, alpha Halogaland). For example, the cyclization reaction between thiourea and 5-diethylphosphino-2-[(2-bromo-1-oxo)alkyl]furans are used for the synthesis of compounds of formula I, where R5represents a thiazole, And represents the amino group and X is a furan-2,5-dialnow group; the cyclization reaction between thiourea and bronirovochnoy ether gives 2-amino-4-alkoxycarbonylmethyl, which is used to obtain the compounds of formula I, where R5represents a thiazole and X represents alkylaminocarbonyl, amoxicillinno, alkylaminocarbonyl or alkoxycarbonylmethyl. Thioamides can be obtained by using the reactions described in the literature (Trost, Comprehensive organic synthesis. Vol. 6; Pergamon press, New York, 1991, pages 419-434), a alpha haloalkaline connections are easily accessible using conventional reactions (Larock, Comprehensive organic transformations, VCH, New York, 1989). For example, amides of monoprinting in thioamides, using the reagent of Lawesson or P2S5and ketones can be perhalogenated using various halogenation reagents (e.g., NBS, CuBr2).

(ii) Education oxazolidine ring system

The oksazolov used for the present invention can be obtained using various methods described in the literature (Turchi, Oxazoles; Wiley & Sons, New York, 1986). To create oxazolidones ring systems can use the reaction between isocyanide (for example, toiletrieschoice) and carbonyl compounds (such as aldehydes and carboxylic acid anhydrides) (van Leusen et al., Tetrahedron Lett., 1972, 2369). Alternative reactions cyclization of amides (for example, urea, carboxamido) and alpha-haloalkaliphilic compounds usually used for education oxazolidine ring system. For example, the reaction of urea and 5-diethylphosphino-2-[(-2-bromo-1-oxo)alkyl]furans are used for the synthesis of compounds of formula I, where R5is oxazol, And represents the amino group and furan-2,5-dialnow group. For education oxazolidine ring system also uses the reaction between amines and imidate (Meyers et al., J.Org. Chem., 1986, 51 (26), 5111).

(iii) Formation of pyridine containing ring system

Pyridine used for the synthesis of compounds of formula I, can be obtained by using different the e well-known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). 1,5-Dicarbonyl compounds or their equivalents may be subjected to interaction with ammonia or compounds that can form ammonia, to obtain the 1,4-dihydropyridines, which are easily dehidrirana to pyridines. When unsaturated 1,5-dicarbonyl compounds or their equivalents (for example, ions pyrilia) use to communicate with ammonia, pyridine can be obtained directly. 1,5-Dicarbonyl compounds or their equivalents can be obtained using conventional chemistry. For example, 1,5-diketones are available through a number of ways, such as joining the Michael enolate to the northward (or predecessor Mannich bases (Gill et al., J.Am. Chem. Soc., 1952, 74, 4923)), ozonolysis predecessor of cyclopentene or reaction siliconebased enol ethers with 3-methoxyethylamine alcohols (Duhamel et al., Tetrahedron, 1986, 42, 4777). When one of the carbonyl carbon is in a state acid oxidation, then this type of reaction provides 2-pyridone, which can be easily converted to 2-kalaidjian (Isler et al., Helv. Chim. Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et al., Chem. Ber., 1984, 117, 1523). Alternative pyridine can be obtained from the aldehyde, 1,3-dicarbonyl compounds and ammonia by classical synthesis Ganch (Bossart et al., Angew. Chem. Int. Ed. Engl., 1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or the x equivalents) with 3-aminoadenine or 3-aminonitriles were used to produce pyridines (such as synthesis Guareschi, Mariella, Org. Synth., Coll, Vol. IV, 1963, 210). 1,3-Dicarbonyl compounds can be obtained by the oxidation reactions of the corresponding 1,3-diols or products of the aldol condensation (Mukaiyama, Org. Reactions, 1982, 28, 203). For the synthesis of pyridines were also used cycloaddition reaction, for example cycloaddition reaction between oksazolov and alkenes (Naito et al., Chem. Pharm. Bull, 1965, 13, 869) and the Diels-alder reaction between 1,2,4-triazine and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).

(iv) the Formation of these compounds ring system

These compounds ring system, used for the synthesis of compounds of formula I, readily available (Brown, The pyrimidines; Wiley, New York, 1994). One method of synthesis of pyrimidine includes a combination of 1,-3-dicarbonyl component (or its equivalent) with a fragment of the N-C-n component Selection N-C-N - urea (Sherman et al., Org. Synth., Coll. Vol. IV, 1963, 247), amidine (Kenner et al., J.Chem. Soc., 1943, 125) or guanidine (Burgess, J.Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coll. Vol. IV, 1963, 245) determines the substitution at C-2 in the products of pyrimidine. This method, in particular, used for the synthesis of compounds of formula I with various groups. In another way pyrimidines can be obtained by cycloaddition reactions, such as reactions of Aza-Diels-alder reaction between 1,3,5-triazine and enamine or enamino (Boger et al., J.Org. Chem., 1992, 57, 4331 and are there links).

(v) Education imidazolidine ring the new system

The imidazoles used for the synthesis of compounds of formula I, easy to get using a number of different synthetic methods. To synthesize the imidazoles, use different cyclization reaction, such as reaction between amidine and alpha haloalkaline (Mallick et al., J.Am. Chem. Soc., 1984, 106 (23), 7252) or alpha hydroxyketone (Shi et al., Synthetic Comm., 1993, 23 (18), 2623), the reaction between urea and alpha haloalkaline and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.

(vi) Education isoxazolidine ring system

Isoxazoles used for the synthesis of compounds of formula I, easy to synthesize, using various methods (such as, for example, the cycloaddition reaction between nitricoxide and alkynes or active methylene compounds, oxymorphine 1,3-dicarbonyl compounds or alpha,beta-acetylenic carbonyl compounds, or of alpha,beta-dihalogenoalkane connections etc), and can be used for the synthesis of oxazolidine ring system (Grunanger et al., Isoxazoles; Wiley & Sons, New York, 1991). For example, the reaction between alkynes and 5-diethylphosphino-2-chlorodibenzofuran in the presence of a base (e.g. triethylamine, base Hunig's, pyridine) is used for the synthesis of compounds of formula I, where R5represents isoxazol and X is furan-2,5-dialnow group.

(vii Education Peratallada ring system

Pyrazoles used for the synthesis of compounds of formula I, easy to get using a number of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidlnes, Jndazoies, and Condensed Rings; Interscience Publishers, New York, 1967), such as the reaction between hydrazine and 1,3-dicarbonyl compounds or 1,3-dicarbonyl equivalents (for example, one of the carbonyl groups blocked as the enamine or ketal, or acetal), and the reactions of addition of hydrazines to Acrylonitrile with subsequent cyclization reactions (Dom et al., Org. Synth., 1973, Coll. Vol. V, 39). The reaction of 2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonate with hydrazines are used for the synthesis of compounds of formula I, where R5is pyrazole, X is furan-2,5-dialnow group and represents the alkyl group.

(viii) Formation of 1,2,4-triazolopyridine ring system

1,2,4-Triazole, used for the synthesis of compounds of formula I, are easily accessible through various methods (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example, for the synthesis of 1,2,4-triazoles using the reaction between hydrazine and imidate or thioimidate (Sui et al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J.Med. Chem., 1995, 38(2), 2196), the reaction between 1,3,5-triazine and hydrazines (Grundmann et al., J.Org. Chem., 1956, 21, 1037) and the reaction between aminoguanidine and esters of carboxylic acids (Ried et al., Chem. Ber., 1968, 101, 2117).

(6) ring Closure to form heterocycle with phosphonate

With the unity of formula 4 can also be obtained, using the reaction ring closure to create a heterocycle from precursors that contain the phosphonate component. For example, the cyclization reaction between thiourea and 5-diethylphosphino-2-[(2-bromo-1-oxo)alkyl]furans are used for the synthesis of compounds of formula I, where R5represents a thiazole, And represents the amino group and X is a furan-2,5-dialnow group. The oksazolov of the present invention can also be obtained using the reaction ring closure. In this case, the reaction of urea and 5-diethylphosphino-2-[(2-bromo-1-oxo)alkyl]furans are used for the synthesis of compounds of formula I, where R5is oxazol, And represents the amino group and X is a furan-2,5-dialnow group. The reaction between 5-diethylphosphino-2-furaldehyde, alkylamino, 1,2-diketone and ammonium acetate is used for the synthesis of compounds of formula I, where R5represents the imidazole and X is furan-2,5-dialnow group. These types of reactions ring closure can also be used for the synthesis of pyridines or pyrimidines used in the present invention. For example, the reaction of 5-diethylphosphino-2-[3-dimethylamino-2-alkyl)acryloyl]furans and cyanoacetamide in the presence of base gives 5-alkyl-3-cyano-6-[2-(5-diethylphosphino)furanyl]-2-pyridone (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion of these 2-Spiridonov in matching the 2-kalaidjian (see references cited in section 3 for modification of heterocycles) can lead to compounds of the formula I, where R5represents pyridine, And represents the group of halogen, X is furan-2,5-dialnow group and represents an alkyl group. The reaction of 5-diethylphosphino-2-[3-dimethylamino-2-alkyl)acryloyl]furans and amidino in the presence of base gives 5-alkyl-6-[2-(5-diethylphosphino)furanyl]pyrimidines, which can lead to compounds of the formula I, where R5represents a pyrimidine, X is furan-2,5-dialnow group and represents an alkyl group.

(7) obtaining the various precursors used for cyclization reactions

Intermediate compounds necessary for the synthesis of compounds of the present invention are usually obtained using either literature method, or a modification of a known method. The synthesis of certain intermediates used for the synthesis of compounds of the present invention described in this specification.

In particular, for the synthesis of compounds of formulas I use different arylphosphonate dialkyl ethers. For example, the compounds of formula I, where X is furan-2,5-dialnow group, can be obtained from a number of predecessors of furanyl. It is assumed that the synthesis of other precursors may flow through some or all of the above with ADI reactions and that for various precursors may be necessary to make changes in these reactions. 5-Dialkylamino-2-furancarboxylic connection (for example, 5-diethylphosphino-2-furaldehyde, 5-diethylphosphino-2-acetylfuran) suitable for the synthesis of compounds of formula I, where X is furan-2,5-dialnow group. Data intermediate compounds derived from furan or derivatives of furan using conventional chemistry, such as reaction injection lithium, protection of carbonyl groups and removing the protection of carbonyl groups. For example, the introduction of lithium in the furan using known methods (Gschwend Org. React., 1979, 26: 1), followed by the introduction fosfauriliruetsa agents (for example, ClPO3R2) provides 2-dialkylphosphinate (for example, 2-diethylphosphonate). This method can also be applied to 2-substituted the furan (for example, 2-frankenboob acid)to obtain 5-dialkylamino-2-substituted furan (for example, 5-diethylphosphino-2-frankenboob acid). It is assumed that other arylphosphate esters can be obtained using this approach or its modification. Alternative to obtain arylphosphonate use other methods, such as reaction of aryl halides or triflates catalyzed by transition metal (Balthazar et al., J.Org. Chem., 1980, 45: 5425; Petrakis et al., J.Am. Chem. Soc., 1987, 109: 2831; Lu et al., Synthesis, 1987, 726). Arylphosphate esters can also be obtained from arylphosphate under the reaction conditions anionic rearrangements (Melin, Tetrahedron Lett., 1981, 22; 3375; Casteel et al., Synthesis, 1991, 691). Salt N alkoxyaryl derivative dialkylphosphinate alkali metal provide other General synthesis heteroaryl-2-phosphonate esters (Redmore J.Org. Chem., 1970, 35: 4114).

The second stage of the introduction of lithium can be used to enable the second group in arylphosphonate diakidoy ester, such as an aldehyde group, trialkylsilyl or halide group, although with the same success for such functionality (e.g., aldehydes) can be assumed and other known methods (for example, the reaction of Vilsmeier-khaak or reaction Rimera-Timan for the synthesis of aldehyde). In the second stage of the introduction of lithium aromatic ring with the lithium treated with reagents that are either directly form the desired functional group (for example, aldehyde using-DMF), HCO2R and so on), or treated with reagents that lead to the formation of a group which is further converted into the desired functional group using known chemistry (e.g., alcohols, esters, NITRILES, alkenes can be converted into aldehydes). For example, the introduction of lithium 2-dialkylphosphinate (for example, 2-diethylphosphonate) in normal conditions (for example, LDA in THF) with subsequent removal of the educated thus anion electrophile is m (for example, chloride or iodine anti) provides 5-functionalized-2-dialkylphosphinate (for example, 5-tributylstannyl-2-diethylphosphonate or 5-iodine-2-diethylphosphonate). In addition, it is assumed that the sequence of these reactions can be reversed, i.e. first, it may be introduced aldehyde part, followed by the reaction of phosphorylation. The procedure of reaction usually depends on the conditions of the reactions and protective groups. It is understood that before the phosphorylation of some of these functional groups can be subjected to a protection using a number of well-known methods (for example, protection of aldehydes to form acetals, Amidala; protection of ketones in the form of ketals). After phosphorylation protected functional group will unlock (Protective groups in Organic Synthesis, Greene, T.W., 1991, Wiley, New York). For example, protection 2-furaldehyde as 1,3-proportionately with the subsequent stage of introduction lithium (using, for example, LDA), sequestering anion dialkylphosphate (for example, diethylphosphate) and subsequent removal of the protection of the aldehyde (acetaldol functional groups) in normal conditions unprotect provides 5-dialkylamino-2-furaldehyde (for example, 5-diethylphosphino-2-furaldehyde). Another example is getting 5-keto-2-dialkylphosphorous, which includes ewusie stage: the acylation of furan in the conditions of the reaction, Friedel-gives 2-californ, subsequent protection of the ketone in the form of ketals (e.g., 1,3-propandiol-circular ketal) with the subsequent stage of the introduction of lithium, described above, gives 5-dialkylamino-2-furanken, and the ketone is protected as 1,3-propertyaccessor Catala, and, finally, removing protection from a ketone (Catala), for example, in acidic conditions gives 2-keto-5-dialkylphosphinate (for example, 2-acetyl-5-diethylphosphonate). Alternative 2-Californi can be synthesized using the reactions catalyzed by palladium, between 2-trialkylborane (for example, 2-tributylstannyl) and acylchlorides (for example, acetylchloride, isobutyramide). Phosphonate part may be present in the 2-trialkylborane (for example, 2-tributylstannyl-5-diethylphosphonate).

2-Keto-5-dialkylphosphorous can also be obtained from 5-dialkylamino-2-frankenboob acid (for example, 5-diethylphosphino-2-frankenboob acid) converting the acid into the corresponding acylchlorides and with the subsequent addition of the Grignard reagent.

In addition, some of the above intermediate compounds can be used for synthesis of other useful intermediates. For example, 2-keto-5-dialkylphosphorous can be further converted into 1,3-dicarbonyl derivative, which is used to produce the pyrazoles, pyridi is s or pyrimidines. The reaction of 2-keto-5-dialkylphosphinate (for example, 2-acetyl-5-diethylphosphonate) dialkylated dialkylamide (for example, dimethylacetal of dimethylformamide) gives the 1,3-dicarbonyl equivalent, as, for example, 2-(3-dialkylamino-2-alkylacrylate)-5-dialkylphosphinate (for example, 2-(3-dimethylaminoacetyl-5-diethylphosphonate).

It is assumed that the above methods of synthesis of derivatives of furan can be either directly or with some modifications applied to the synthesis of various other useful intermediate compounds, such as arylphosphate esters (for example, thienylboronic esters, phenylphosphate esters or pyridylacetonitrile esters).

It is clear that in the case of adaptation of the above synthetic methods for parallel synthesis or solid phase or in solution, to provide a quick study of the relationship CAB (SAR) (the relationship structure-activity) for inhibitors Fbpase covered by the present invention, the improvement of this method for these reactions will be successful.

Section 2. The synthesis of compounds of formula X.

The synthesis of compounds covered by the present invention typically includes some or all of the following General stages: (1) preparation of phosphonate prodrugs; (2) SN is ment protection phosphonate complex ester; (3) the formation of the heterocycle; (4) the introduction of a phosphonate component; (5) synthesis of a derivative of aniline. Stage (1) stage (2) were discussed in section 1, and the consideration stage (3)stage (4) and stage (5) below. These methods are generally applicable to compounds of formula X.

(3) the formation of the heterocycle

(i) Benzothiazolesulfenamide ring system

The compounds of formula 3, where G=S, i.e. benzothiazole, can be obtained by using different synthetic methods described in the literature. Two of these methods are presented as examples below. One method is a modification of the commercially available derivatives of benzothiazole with the aim of obtaining an appropriate functionality on the benzothiazole ring. Another way is to annelation of various anilines (e.g., compounds of formulas 4), to form a thiazole part benzothiazole rings. For example, the compounds of formula 3, where G=S, A2=NH2L2E2I , J2=H, X2=CH2O and R'=Et, can be obtained from commercially available 4-methoxy-2-aminothiazole through a two-stage sequence: conversion of 4-methoxy-2-aminobenzothiazole 4-hydroxy-2-aminobenzothiazole with reagents such as BBr3(Node, M. et al., J.Org. Chem. 45, 2243-2246, 1980) or AlCl3in the presence of a thiol (e.g., EtS) (McOmie, J.F.W. et al., Org. Synth, Collect. Vol. V, 422, 1973) and subsequent alkylation of the phenolic group diethylphosphonoacetate (Phillion, D.P. et al., Tetrahedron Lett. 27, 1477-1484, 1986) in the presence of a suitable base (such as NaH) in polar aprotic solvents (such as DMF) to provide the desired connection.

You can use several methods for the conversion of various anilines in benzothiazole (Sprague, J.M; Land, A.H. Heterocycle. Compel. 5, 506-13, 1957). For example, 2-aminobenzothiazole (formula 3, where A=NH2) can be obtained by annelation of compounds of formula 4, where W2=H, using a variety of common methods. One method includes processing appropriately substituted aniline with a mixture of KSCN and CuSO4in methanol to obtain substituted 2-aminobenzothiazole (Ismail, I.A.; Sharp, D.E; Chedekel, M.R., J.Org. Chem. 45, 2243-2246, (1980). Alternative 2-aminobenzothiazole can also be obtained by processing Br2in the presence of KSCN in acetic acid (Patil, D.G.; Chedekel, M.R., J.Org. Chem. 49, 997-1000, 1984). This reaction can be performed in two stages. For example, treatment of the substituted penultimately Br2in CHCl3gives substituted 2-aminobenzothiazole (Patil, D.G., Chedekel, M.R., J.Org. Chem. 49, 997-1000 (1984). 2-Aminobenzothiazole can also be obtained by condensation of ortho-iodoaniline with thiourea in the presence of Ni catalyst (NiCl2(PPh3)2). (Takagi, K. Chem. Lett. 265-266, 1986).

Benzothiazole mo is but to undergo electrophilic aromatic substitution with obtaining 6-substituted benzothiazoles (Sprague, J.M.; Land, A.H. Heterocycle. Compel. 5, 606-13, 1957). For example, bromination of compounds of formula 3, where G=S, And2=NH2L2E2I , J2=H, X2=CH2O and R'=Et bromine in polar solvents, such as Asón, gives compound of formula 3, where E2=Br.

In addition, the compounds of formula 3, where a is halogen, H, alkoxy, alkylthio or alkyl, can be obtained from the corresponding amino compounds (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press. New York, 1991).

(ii) Benzoxazole

The compounds of formula 3, where G"=O, i.e. benzoxazole, can be obtained by cyclization of an ortho-aminophenols with a suitable reagent, such as galitzianer (A=NH2; Alt, K. O. et al., J. Heterocyclic Chem. 12, 775, 1975) or acetic acid (A=CH3; Saa, J. M.; J. Org. Chem. 57, 589-594, 1992), or trialkylaluminium (A=N; Org. Prep. Proced, Int., 22, 613, 1990)).

(4) the Introduction of a phosphonate component

The compounds of formula 4 (where X2=CH2O and R'=alkyl) can be obtained in various ways, for example by alkylation and reactions of nucleophilic substitution). Usually the compounds of formula 5, where M'=HE, treated with a suitable base (such as NaH in a polar aprotic solvent (such as DMF, DMSO) and the resulting proxeny anion can be alkylated with a suitable electrophile, often present phosphonate component (for example, decisionrelevant, IER is intreportchoosersize, diethyl-p-metilfenoksiftalotsianinato). Method of alkylation can also be applied to compounds predecessor, the compounds of formula 5 where phenolic part, and they can be alkilirovanii component containing phosphonate. Alternative compounds of formula 4 can also be obtained by reaction of nucleophilic substitution in compounds predecessors, the compounds of formula 5, where halide group, such as fluorine or chlorine is present in ortho-position to the nitro-group. For example, the compound of formula 4 (where X2=CH2Oh and R'=Et) can be obtained from the derivative of 2-chloro-1-nitrobenzene processing NaOCH2P(O) (OEt)2in DMF. Similarly, we can obtain the compounds of formula 4 where X2=-alkyl-S -, or-alkyl-N-.

(5) Synthesis of a derivative of aniline

Various synthetic methods published for the synthesis of aniline derivatives, and these methods can be applied for the synthesis of useful intermediates which can lead to the formation of compounds of formula X. for Example, various alkeneamine or aryl group can be introduced in the benzene ring via reactions catalyzed by transition metal (Kasibhatla, S. R. et al., WO 98/39343 and references cited therein); anilines can be obtained from their respective nitro-derivatives by reactions of recovery (for example, hydrogenation reactions in presets is under 10% Pd/C or reaction recovery using SnCl 2in HCl (Patil, D.G.; Chedekel, M. R., J Org. Chem. 49, 997-1000, 1984)).

Section 3. The synthesis of compounds of formula XI.

In international publication WO 98/39343 describes the synthesis of phosphonic acids and esters of benzimidazole of the formula XI.

Bisamidines phosphonates of the present invention can be obtained using the methods described above for compounds of formula I.

Composition

Compounds of the present invention is administered orally at a total daily dose range from about 0.01 mg/kg/dose to about 100 mg/kg/dose from about 0.1 mg/kg/dose to about 10 mg/kg/dose. Discusses the use of drugs with the release depending on time, to regulate the rate of release of the active ingredient. The dose can be administered in several divided doses, repeated after a certain period of time, as convenient. When using other routes of administration (e.g. intravenous), compounds injected into the diseased tissue at a speed of from 0.05 to 10 mg/kg/h and from 0.1 to 1 mg/kg/hour. Such speeds are easily maintained when the compounds are administered intravenously, as discussed below.

For the purposes of this invention, the compounds can be administered in various ways, including oral, parenteral, inhalation spray, topically, or rectally, using compositions containing farmaci is almost acceptable carriers, adjuvants and fillers. Used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, and intraarterial injections using different methods of infusion. Used here intraarterial and intravenous injection involves the introduction through the catheter. Usually preferably oral administration.

Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When using, for example, for oral administration can be obtained tablets, pills, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Composition, intended for oral use can be obtained by any method known in the field of pharmaceutical compositions and such compositions may contain one or more funds, including sweeteners, flavourings, colourings and preservatives, in order to provide a pleasant to use the drug. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which is suitable for receiving the tablets are acceptable. Such excipients can be present, for example, inert diluents, such as carbonat calcium or sodium, lactose, calcium phosphate or sodium; granulating and dezintegriruetsja tools, such as rice starch, or alginic acid; binders, such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated, made using known methods, including microcapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period of time. For example, you can use the substance, providing a slow time allocation, such as glycerylmonostearate or glycerylmonostearate, as such or together with wax.

Compositions for oral use can be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active substance in a mixture with excipients suitable for receiving water suspensions. Such excipients include suspendisse tool such as strikeback metilzellulosa, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum, and dispersing or humectants, such as phosphated of natural origin (e.g., lecithin), a condensation product of alkalinized with a fatty acid (for example, polyoxyethylenated), a condensation product of ethylene oxide with long chain aliphatic alcohol (e.g., heptadecafluorooctyl), a condensation product of ethylene oxide with partial complex ester of fatty acid and lexicalized (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may optionally contain one or more preservatives such as ethyl or n-propyl-p-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweetening agent such as sucrose or saccharin.

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. To obtain enjoyable to use the drug, can be added sweeteners,such as substances, above, and flavoring agents. Such compositions can be conserved by adding an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for obtaining aqueous suspension with the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspendium means and one or more preservatives. Suitable dispersing or moisturizer and suspendresume means are illustrated by relevant substances mentioned above. In addition, there may be additional excipients, for example sweetening, flavorings and dyes.

The pharmaceutical compositions of the invention can be in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, mineral oil such as liquid paraffin, or a mixture of the above. Suitable emulsifying tools include waxes of natural origin, such as the Arabian gum and tragacanth gum, phosphatides of natural origin, such as soybean lecithin, esters or partial esters derived from fatty acids and lexicalized, such as servicemanual, and condensation products partial esters with ethylene oxide is m, such as polyethylenterephthalat. The emulsion may optionally contain sweeteners and flavorings.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such compositions can optionally contain a demulcent, preservative, flavouring or colouring agents.

The pharmaceutical compositions of the invention can be in the form of a sterile injectable preparation, such as sterile injectable aqueous or oily suspension. Suspension may be formulated according to known in this field method using the same of the most suitable dispersing or moisturizing and suspendida funds that have been mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be in the form of liofilizirovannogo powder. Among the acceptable fillers and solvents that can be used, can be called water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment can be used sterile fat (more fat) oils. For this purpose you can use l the fight mild fatty oil, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid, can be similarly used to obtain an injectable drug.

The amount of active ingredient that may be combined with a carrier substance, to obtain a single dosage form will vary depending on the patient to be treated and the particular route of administration. For example, the composition is released over time, intended for insertion through the mouth of humans may contain from about 1 to 1000 mg of the active component, kompaundirovannyh with the appropriate and suitable amount of carrier substances, which may vary from about 5 to about 95% by weight of the total compositions. You can obtain the pharmaceutical composition that provides easily measurable quantities for injection. For example, an aqueous solution intended for intravenous infusion should contain from about 3 to 330 μg active ingredient per milliliter of solution in order that could happen infusion of a suitable volume at a rate of approximately 30 ml/hour.

As noted above, the compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, starch wafers or tablets, ka is the Mae containing a pre-determined quantity of the active component; in the form of a powder or granules; as solution or suspension in water or non-aqueous liquid or in the form of a liquid emulsion oil-in-water, or a liquid emulsion of water-in-oil. The active ingredient may be in the form of a ball, electuary or paste.

The tablet can be obtained by extrusion or molding, optionally with one or more auxiliary components. Molded tablets can be obtained by pressing the active component on a suitable machine in Svobodnaya form, such as powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hypromellose), lubricant, inert diluent, preservative, disintegrant (for example, nachrichtenportal made (intermolecular) povidone, cross-linked sodium carboxymethyl cellulose), surface-active agent or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered compound moistened inert liquid diluent. The tablets may be optionally coated or provided with notches and can be designed in such a way as to provide slow or controlled release of the active ingredient from it using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile of the active component. Tablets can be equipped with optional intersolubility coated to provide release in parts of the intestine, not the stomach, especially when the active ingredient is sensitive to acid hydrolysis.

Compositions suitable for topical application in the mouth include pellet, containing the active ingredient in a flavored basis, usually sucrose and acacia or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia, and liquid for rinsing the mouth, containing the active ingredient in a suitable liquid carrier.

Compositions for rectal injection can be obtained in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Compositions suitable for vaginal administration, may be presented as pessaries, tampons, creams, gels, pastes, foams or formulations for dispersion containing, in addition to the active ingredient such carriers, which are considered in this area are appropriate.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostatic factors and substances that make the composition isotonic with respect to blood predpolagaemoj the recipient; aqueous and non-aqueous sterile suspensions that can include suspendresume tools and thickeners. The compositions can be presented in sealed containers for a single dose or multiple doses, for example, ampoules and vials, and can be stored in dried by freezing (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Solutions and suspensions for injection can be obtained from sterile powders, granules and tablets presented earlier type.

A suitable composition unit dosage include compositions containing a daily dose or unit, daily curioso or the relevant part of this claimed connection, an inhibitor of fructose-1,6-bisphosphatase.

However, it should be borne in mind that the specific dose level for any particular patient will depend upon a number of factors, including the activity of the specific compound; the age, body weight, General health, sex and diet of the individual to be treated; the time and route of administration; rate of excretion; other drugs which had been used previously and severity of the particular disease undergoing therapy, which is obvious for specialists in this field.

Utility

Odie is the aspect of the invention relates to new bis-phosphoramidates the prodrugs of inhibitors Fbpase, which increase the oral bioavailability of the original drug.

Inhibitors Fbpase and their prodrugs can be used to treat diabetes, reduce glucose levels in the blood and inhibition of gluconeogenesis.

Inhibitors Fbpase and their prodrugs can be used to treat diseases associated with excessive deposition of glycogen. Excessive hepatic glycogen found in patients with some diseases associated with the deposition of glycogen. As an indirect way of sharing significantly promotes the synthesis of glycogen (Shulman, G.I., Phys. Rev. 72:1019-1035, 1992), inhibition of indirect pathways (flow gluconeogenesis) reduces overproduction glycogen.

In addition, inhibitors Fbpase and their prodrugs can be used for the treatment or prevention of diseases associated with elevated levels of insulin. Elevated levels of insulin are associated with increased risk of cardiovascular complications and atherosclerosis (Folsom et al., Stroke, 25:66-73, 1994; Howard, G. et al., Circulation, 93:1809-1817, 1996). Suggest that inhibitors Fbpase and their prodrugs reduce afternoon glucose levels by increasing uptake of glucose by the liver. Postulated that this effect occurs in individuals who are not diabetic (or pre-diabetics, i.e. be the increased hepatic release of glucose, "in the future, HSV (HGO), or levels of fasting blood glucose). Increase uptake of glucose by the liver to decrease insulin secretion and thereby reduce the risk of disease or complications that arise from increased levels of insulin.

These aspects are explained in further detail below.

EXAMPLES

1. The synthesis of compounds of formula IA.

Example 1

Getting 5-diethylphosphino-2-furaldehyde (1)

Stage A. the Solution diethylacetal 2-furaldehyde (1 mmol) in THF is treated with n-BuLi (1 mmol) at -78°C. after 1 h, add diethylphosphate (1.2 mmol) and the reaction mixture is stirred for 40 minutes Extraction and evaporation to give a brown oil.

Stage C. the Obtained brown oil is treated with 80% acetic acid at 90°C for 4 h Extraction and chromatography to give compound 1 as a transparent yellow oil. Alternative to the above aldehyde can be obtained from furan, as described below.

Stage C. a Solution of furan (1 mmol) in diethyl ether is treated with TMEDA (N,N,N',N'-tetramethylethylenediamine) (1 mmol) and n-BuLi (2 mmol) at -78°C for 0.5 hours the reaction mixture was added diethylphosphate (1.2 mmol) and stirred for an additional hour. Extraction and distillation to give diethyl-2-furanostanol in the form of a clear oil.

Stage D. a Solution of diethyl-2-parentstate (1 mmol) in TBF education is anywayt LDA (1.12 mmol, N,N-diisopropylamide lithium) at -78°C for 20 minutes Add methylformate (1.5 mmol) and the reaction mixture stirred for 1 h Extraction and chromatography to give compound 1 as a transparent yellow oil. Preferably specified aldehyde can be obtained from 2-furaldehyde, as described below.

Stage E. a Solution of 2-furaldehyde and (1 mmol) and N,N'-dimethylethylenediamine (1 mmol) in toluene is refluxed, while collecting the water formed by the trap Dean-stark. After 2 h the solvent is removed in vacuo and the residue distil, getting furan-2-(N,N'-dimethylimidazolidin) as a clear colorless oil (As 59-61°C/3 mm Hg).

Stage F. a Solution of furan-2- (N,N'-dimethylimidazolidine) (1 mmol) and TMEDA (1 mmol) in THF is treated with n-BuLi (1.3 mmol) at temperatures from -40 to -48°C. the Reaction mixture was stirred at 0°C for 1.5 h, then cooled to -55°and treated With a solution of diethylphosphate (1.1 mmol) in THF. After stirring at 25°C for 12 h, the reaction mixture was evaporated and subjected to extraction, receiving 5-diethylphosphonate-2-(N,N'-dimethylimidazolidin) as a brown oil.

Stage G. a Solution of 5-diethylphosphonate-2-(N,N'-dimethylimidazolidine (1 mmol) in water is treated with concentrated sulfuric acid to achieve a pH of 1. Extraction and chromatography is up connection 1 in the form of a clear yellow oil.

Example 2

Getting 5-diethylphosphino-2-1-[(1-oxo)alkyl]furans and 6-diethylphosphino-2-[(1-oxo)alkyl]pyridines

Stage A. a Solution of furan (1.3 mmol) in toluene is treated with 4-methylpentanoic acid (1 mmol), anhydride triperoxonane acid (1.2 mmol) and efratom of boron TRIFLUORIDE (0.1 mmol) in 56°With over 3.5 hours the Cooled reaction mixture is quenched with aqueous sodium bicarbonate (1.9 mmol), filtered through a layer of celite. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (As 65-77°C/0.1 mm Hg).

Stage C. a Solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmol) in benzene is treated with ethylene glycol (2.1 mmol) and p-toluensulfonate (0.05 mmol) at boiling point under reflux for 60 hours, removing the water through the trap Dean-stark. Add triethylorthoformate (0.6 mmol) and the resulting mixture is refluxed for another hour. Extraction and evaporation gave 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane as an orange liquid.

Stage C. a Solution of 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane (1 mmol) in THF is treated with TMEDA (1 mmol) and n-BuLi (1.1 mmol) at -45°and the resulting reaction mixture is stirred at a temperature of from -5 to 0°C for 1 h the reaction mixture is cooled to -45°and transferred via a cannula in the process is diethylphosphate in THF at -45° C. the Reaction mixture is slowly heated to ambient temperature for 1,25 including Extraction and evaporation gave 2-[(2-(5-diethylphosphino)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane as a dark oil.

Stage D. a Solution of 2-[(2-(5-diethylphosphino)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane (1 mmol) in methanol is treated with 1N hydrochloric acid (0.2 mmol) at 60°C for 18 hours Extraction and distillation to give 5-diethylphosphino-2-[(4-methyl-1-oxo)pentyl]furan (2.1) in the form of a light orange oil (As 152-156°C/0.1 mm Hg).

In accordance with the specified method will receive the following connections.

(2.2) 5-Diethylphosphino-2-acetylfuran. Because 125-136°C/0.1 mm Hg.

(2.3) 5-Diethylphosphino-2-[(1-oxo)butyl]furan. Because 130-145°C/0.1 mm Hg.

Alternative data connection can be obtained using the following methods.

Stage E. a Solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmol), obtained as in stage A) in benzene is treated with N,N-dimethylhydrazine (2.1 mmol) and triperoxonane acid (0.05 mmol) by boiling under reflux for 6 hours Extraction and evaporation to give N,N-dimethylhydrazone 2-[(4-methyl-1-oxo)pentyl]furan as a brown liquid.

Stage F. N,N-Dimethylhydrazone 2-[(4-methyl-1-oxo)pentyl]furan treated in accordance with the stage, receiving N,N-dimethylhydrazone 2-[(4-methyl-1-oxo)pentyl]-5-diethylphosphonate is wound in the form of a brown liquid, which is treated with chloride of copper (II) (1.1 equivalents) in a mixture of ethanol-water at 25°C for 6 hours Extraction and distillation to give the connection 2.1 in the form of a light orange oil.

Some of the 5-diethylphosphino-2-[(1-oxo)alkyl]furans receive, using the following methods.

Stage G. the Solution of compound 1 (1 mmol) and 1,3-propanedithiol (1.1 mmol) in chloroform is treated with efratom of boron TRIFLUORIDE (0.1 mmol) at 25°within 24 hours Evaporation and chromatography yield 2-(2-(5-diethylphosphino)furanyl)-1,3-dithiane in the form of a light yellow oil.

A solution of 2-(2-(5-diethylphosphino)furanyl)-1,3-dithiane (1 mmol) in THF cooled to -78°and treated With n-BuLi (1.2 mmol). After 1 h at -78°the reaction mixture is treated with cyclopropanemethylamine and the reaction mixture stirred at -78°for another hour. Extraction and chromatography gave 2-(2-(5-diethylphosphino)furanyl)-2-cyclopropylmethyl-1,3-dition in the form of oil.

A solution of 2-(2-(5-diethylphosphino)furanyl)-2-cyclopropylmethyl-1,3-dithiane (1 mmol) in a mixture of acetonitrile-water treated with [bis(tripterocalyx)iodo]benzene (2 mmol) at 25°C for 24 h Extraction and chromatography to give 5-diethylphosphino-2-(2-cyclopropylethyl)furan as a light orange oil.

In accordance with the specified method will receive the following connections.

(2.4) 5-Diethylphosphino-2-(2-etox carbonylethyl)furan.

(2.5) 5-Diethylphosphino-2-(2-methylthioethyl)furan.

(2.6) 6-Diethylphosphino-2-acetylpyridine.

Example 3

Getting 4-[2-(5-phosphono)furanyl]thiazolo, 4-[2-(6-phosphono)pyridyl]thiazolo and 4-[2-(5-phosphono)furanyl]selenation

Stage A. a Solution of compound 2.1 (1 mmol) is treated with copper bromide (II) (2.2 mmol) by boiling under reflux for 3 h the Cooled reaction mixture is filtered and the filtrate evaporated to dryness. The obtained dark oil is purified by chromatography, receiving 5-diethylphosphino-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan as an orange oil.

Stage C. a Solution of 5-diethylphosphino-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmol) and thiourea (2 mmol) in ethanol is refluxed for 2 hours the Cooled reaction mixture is evaporated to dryness and the resulting yellow foam suspended in a saturated aqueous solution of sodium bicarbonate (pH=8). The obtained yellow solid is collected by filtration, obtaining 2-amino-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage C. a Solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in methylene chloride is treated with bromotrimethylsilane (10 mmol) at 25°C for 8 h, the Reaction mixture was evaporated to dryness and the residue suspended in water. The obtained solid is collected by filtration, obtaining 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]t is evil (3.1) in the form of not-quite-white solid. TPL > 250°C.

Analysis for C11H15N2O4PS+1,25HBr:

calculated:From:32,75;N:4,06;N:6,94;
found:From:32,39;N:4,33;N;7,18.

In accordance with the above procedures or in some cases with minimal changes using ordinary chemical reaction, given the following connections.

(3.2) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C12H16NO4PS+HBr+0,1CH2Cl2:

calculated:From:37,20;N:of 4.44;N:3,58;
found:From:37,24;N:4,56;N:3,30.

(3.3) 4-[2-(5-Phosphono)furanyl]thiazole.

Analysis for C7H6NO4PS+0,65HBr:

calculated:From:29,63;N:2,36; N:4,94;
found:C;29,92;N:2,66;N:4,57.

(3.4) 2-Methyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 235-236°C.

Analysis for C8H8NO4PS+0,25N2About:

calculated:From:38,48;N:3,43;N:5,61;
found:From:38,68;N:3,33;N:are 5.36.

(3.5) 2-Phenyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C17H18NO4PS+HBr:

calculated:From:45,96;N:or 4.31;N:3,15;
found:From:45,56;N:4.26 deaths;N:was 2.76.

(3.6) 2-Isopropyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 194-197°C.

Analysis for C10H12NO4PS:

calculated:From:43,96;N:4,43;N:5,13;
found: From:43,70;N:4,35;N:4,75.

(3.7) 5-Isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 164-166°C.

Analysis for C11H14NO4PS:

calculated:From:45.99 per;N:4,91;N:4,88;
found:From:45,63;N:5,01;N:4,73.

(3.8) 2-Aminothiazol-4-[2-(5-phosphono)furanyl]thiazole. TPL 189-191°C.

Analysis for C8H7H2O4PS2:

calculated:From:33,10;N:2,43;N:9,65;
found:From:33,14;N:2,50;N:to 9.32.

(3.9) 2-(1-Piperidyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C16H23N2O4PS+1,3HBr:

calculated:From:40,41;N:5,15;N:of 5.89;
found:From:40,46;N: are 5.36;N:of 5.53.

(3.10) 2-(2-Thienyl)-5-isobutyl-4-[2-(5-phosphono)furanyl] thiazole.

Analysis for C15H16NO4PS2+0,N2About:

calculated:From:47,05;N:br4.61;N:3,66;
found:From:47,39;N:4,36;N:3,28.

(3.11) 2-(3-Pyridyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C16H17N2O4PS+3,75HBr:

calculated:From:28,78;N:3,13;N:4,20;
found:From:28,73;N:2,73;N:4,53.

(3.12) 2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 179-181°C.

Analysis for C13H17N2O5PS+0,25N2O:

calculated:From:44,76;N:5,06;N:8,03;
found:From:44,73;N:5,07; N:7,89.

(3.13) 2-Amino-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C7H7N2O4PS:

calculated:From:34,15;N:2,87;N:11,38;
found:From:33,88;N:2,83;N:11,17.

(3.14) 2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 202-205 are°C.

Analysis for C12H17N2O4PS+0,5H2O:

calculated:From:44,30;N:5,58;N:at 8.60;
found:From:of 44.67;N:5,27;N:8,43.

(3.15) 2-(N-Amino-N-methyl)amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 179-181°C.

Analysis for C12H18N3O4PS+1,25HBr:

calculated:From:33,33;N:4,49;N:9,72;
found:From:33,46;N:4,81;N: 9,72.

(3.16) 2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 200-220°C.

Analysis for C8H9N2O4PS+0,65HBr:

calculated:From:30,72;N:3,11;N:8,96;
found:From:30,86;N:3,33;N:cent to 8.85.

(3.17) 2, 5-Dimethyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 195°C (decomp.).

Analysis for C9H10NO4PS+0,7HBr:

calculated:From:34,22;N:3,41;N:4,43;
found:From:to 34.06;N:3,54;N:4,12.

(3.18) 2-Aminothiazol-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C12H15N2O4PS2+0,1HBr+0,3EtOAc:

calculated:From:41,62;N:4,63;N:7,35;
found:From:41,72;N:4,30;N:7,17.

(3.19) 2-Etoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 163-165°C.

Analysis for C10H10NO6PS+0,5H2O:

calculated:From:38,47;N:3,55;N:4,49;
found:From:38,35;N:3,30;N:4,42.

(3.20) 2-Amino-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H13N2O4PS+1HBr:

calculated:From:32,53;N:3,82;N:to 7.59;
found:From:32,90;N:3,78;N:7,65.

(3.21) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. TPL > 250°C.

Analysis for C9H11N2O4PS:

calculated:From:39,42;N:Android 4.04;N:10,22;
found:From:39,02;N:4,15;N:9,92.

(3.22) 2-Cyanomethyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 204-206°C.

Analysis for C9H 7N2O4PS:

calculated:From:40,01;N:2,61;N:10,37;
found:From:39,69;N:2,64;N:there is a 10.03.

(3.23) 2-Aminothiazoline-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 177-182°C.

Analysis for C12H16N3O4PS2+0,2 hexane + 0,3HBr:

calculated:From:39,35;N:4,78;N:10,43;
found:From:39,61;N:4,48;N:10,24.

(3.24) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 235-237°C.

Analysis for C10H13N2O4PS+0,3H2O:

calculated:From:40,90;N:4,67;N:9,54;
found:From:40,91;N:of 4.44;N:9,37.

(3.25) 2-Amino-5-etoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 248-250° C.

Analysis for C10H11N2O6PS+0,1HBr:

calculated:From:36,81;N:3,43;N:8,58;
found:From:36,99;N:3,35;N:8,84.

(3.26) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. TPL 181-184°C.

Analysis for C8H9N2O4PS2+0,4H2O:

calculated:From:32,08;N:3,30;N:9,35;
found:From:32,09;N:3,31;N:9,15.

(3.27) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H11N2O4PS+1H2O+0,75 HBr:

calculated:From:32,91;N:3,80;N:7,68;
found:From:33,10;N:3,80;N:7,34.

(3.28) 2-Amino-5-methanesulfonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL > 20° C.

Analysis for C8H9N2O5PS2+0,35NaCl:

calculated:From:29,23;N:was 2.76;N:charged 8.52;
found:From:29,37;N:2,52;N:8,44.

(3.29) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C15H13N2O6PS+0,2H2O:

calculated:From:46,93;N:3,52;N:7,30;
found:From:46,64;N:3,18;N:7,20.

(3.30) 2-Amino-5-cyclobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H13N2O4PS+0,15HBr+0,15 NM2O:

calculated:From:41,93;N:4,30;N:8,89;
found:From:42,18;N:4,49;N:8,53.

(3.31) the hydrobromide of 2-amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H11N2O4PSBr+0,73HBr+0,mon+0,5H2O:

calculated:From:33,95;N:3,74;N:7,80;S:8,93;Br:
16,24;
found:C:33,72;N:3,79;N:7,65;S:9,26;Br:
16,03.

(3.32) Dihydrobromide 2-amino-5-[(N,N-dimethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H16N3O4Br2PS+0,8CH2Cl2:

calculated:From:24,34;N:3,33;N:7,88;
found:From:24,23;N:3,35;N:of 7.64.

(3.33) 2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 227°C (decomp.).

Analysis for C9H9N2O6PS+0.1 n2O+0,2HBr:

calculated:From:33,55;N:2,94;N:8,69;
found:From:33,46;N:3,02;N:8,49.

(3.34) 2-Amino-5-ethylthiomethyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 245°C (decomp.).

Analysis for C10H11N2O5PS2:

calculated:From:35,93;N:3,32;N:scored 8.38;
found:From:35,98;N:3,13;N:8,17.

(3.35) 2-Amino-5-propylenecarbonate-4-[2-(5-phosphono)furanyl]thiazole. TPL 245°C (decomp.).

Analysis for C11H13N2O6PS:

N:
calculated:From:39,76;N:3,94;N:8,43;
found:From:39,77;N:3,72;8,19.

(3.36) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C14H13N2O4PS+H2O:

calculated:From:to 47.46;N:4,27;N:to $ 7.91;
found:From:is 47.24;N:4,08;N:the 7.85.

(3.37) Dihydrobromide 2-amino-5-[(N,N-diethyl)aminoethyl]-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C12H20N3O4Br2PS+0,1HBr+1,mean:

calculated:From:29,47;N:4,74;N:7,69;
found:From:29,41;N:4,60;N:7,32.

(3.38) 2-Amino-5-[(N,N-dimethyl)carbarnoyl]-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H12N3O5PS+1,3HBr+1,0N2O+0.3 acetone:

calculated:From:28,59;N:3,76;N:9,18;
found:From:28,40;N: 3,88;N:9,01.

(3.39) 2-Amino-5-carboxyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C8H7N2O6PS+0,2HBr+0,1 h2O:

calculated:From:31,18;N:2,42;N:a 9.09;
found:From:31,11;N:2,42;N:8,83.

(3.40) 2-Amino-5-isopropoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 240°C (decomp.).

Analysis for C11H13N2O6PS:

calculated:From:39,76;N:3,94;N:8,43;
found:From:39,42;H:3,67;N:8,09.

(3.41) 2-Methyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H12O4PNS+0,75HBr+0,N2About:

calculated:From:36,02;N:4,13;N:4,06;
found:From:36,34;N:3,86;N: 3,69.

(3.42) 2-Methyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H12NO4PS+0,3HBr+0,5CHCl3:

calculated:From:37,41;N:3,49;N:3,79;
found:From:37,61;N:3,29;N:3,41.

(3.43) 2-Methyl-5-etoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H12NO6PS:

calculated:From:41,64;N:3,81;N:4,40;
found:From:41,61;N:3,78;N:4,39.

(3.44) 2-[(N-Acetyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H13N2About6PS+0,15HBr:

calculated:From:38,36;N:3,85;N:8,13;
found:From:38,74;N:3,44;N:8,13.

(3.45) Dihydro who RAID 2-amino-5-(4-morpholinyl)methyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C12H18Br2N3O5PS+0,25HBr:

calculated:From:27,33;N:3,49;N:7,97;
found:From:27,55;N:3,75;N:a 7.62.

(3.46) 2-Amino-5-cyclopropanecarbonyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 238°C (decomp.).

Analysis for C12H13N2O6PS:

calculated:From:41,86;N:3,81;N:8,14;
found:From:41,69;N:3,70;N:8,01.

(3.47) N,N-Dicyclohexylamine salt of 2-amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. TPL >250°C.

Analysis for C8H9N2O4PS2+1,15C2H23N:

(3.48) 2-[(N-Dansyl)amino]-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C23H26N3About6PS2+0,5HBr:

calculated:From:52,28;N:7,13;N:8,81;
found:From:52,12;N:7,17;N:8,81.
calculated:From:47,96;N:with 4.64;N:7,29;
found:From:48,23;N:4,67;N:7,22.

(3.49) 2-Amino-5-(2,2,2-triptorelin)-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C9H8N2F3O4PS:

calculated:From:32,94;N:2,46;N:8,54;
found:From:32,57;N:2,64;N:8,14.

(3.50) 2-Methyl-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C9H10NO4PS2:

calculated:From:37,11;N:of 3.46;N:4,81;
found:From:36,72;N:3,23;N:4,60.

(3.51) Ammonium salt of 2-amino-5-is ethylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C8H12N3O4PS2:

calculated:From:31,07;N:3,91;N:13,59;
found:From:31,28;N:3,75;N:13,60.

(3.52) 2-Cyano-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H9N2O4PS:

calculated:From:42,26;N:3,19;N:9,86;
found:From:41,96;N:2,95;N:9,76.

(3.53) 2-Amino-5-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C8H9N2O5PS:

calculated:From:34,79;N:3,28;N:10,14;
found:From:34,57;N:3,00;N:10,04.

(3.54) 2-Cyano-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C12H13N2O4SP+0,09HBr:

calculated:From:46,15;N:4,20;N:8,97;
found:C:44,81;N:3,91;N:8,51.

(3.55) the hydrobromide of 2-amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H14BrN2O4PS2:

calculated:From:29,94;N:3,52;N:6,98;
found:From:30,10;N:3,20;N:6,70.

(3.56) 2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C13H11N2O4PS2:

calculated:From:44,07;N:3,13;N:to $ 7.91;
found:From:43,83;N:3,07;N:7,74.

(3.57) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H15N2O4PS2+0,6CH2Cl2:

calculated:From:36,16;N:4,24;N:7,27;
found:From:36,39;N:3,86;N:7,21.

(3.58) the hydrobromide of 2-amino-5-propylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H14BrN2O4PS2:

calculated:From:29,94;N:3,52;N:6,98;
found:From:29,58;N:3,50;N:6,84.

(3.59) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C9H11N2O4PS2+0,25HBr:

calculated:From:33,11;N:3,47;N:8,58;
found:From:33,30;N:3,42;N:at 8.60.

(3.60) 2-[(N-tert-Butyloxycarbonyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C14H19N2O7PS:

calc is but: From:43,08;N:4,91;N:7,18;
found:From:42,69;N:4,58;N:7,39.

(3.61) 2-Hydroxy-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C7H6NO5PS:

calculated:From:34,02;N:2,45;N:5,67;
Found:From:33,69;N:2,42;N:5,39.

(3.62) 2-Hydroxy-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C9H10NO5PS:

calculated:From:39,28;N:3,66;N:5,09;
found:From:39,04;N:3,44;N:4,93.

(3.63) 2-Hydroxy-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H12NO5PS+0,1HBr:

calculated:From:40,39;N:4,10;N:4,71;
found:From:40,44;N:4,11;N:4,68.

(3.64) 2-Hydroxy-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H14NO5PS:

calculated:From:43,57;N:4,65;N:4,62;
found:From:43,45;N:4,66;N:4,46.

(3.65) 5-Etoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H10NO6PS:

calculated:From:39,61;N:3,32;N:4,62;
found:From:39,60;N:3,24;N:4,47.

(3.66) 2-Amino-5-vinyl-4-[2-(5-phosphono)furanyl]thiazole. Analysis for C9H9N2O4PS+0,28HCl:

calculated:From:37,66;N:3,26;N:9,46;
found:From:37,96;N:3,37; N:9,10.

(3.67) the hydrobromide of 2-amino-4-[2-(6-phosphono)pyridyl]thiazole.

(3.68) 2-Methylthio-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Analysis for C12H16NO4PS2:

calculated:From:43,24;N:4,84;N:4,20;
found:From:43,55;N:4,63;N:4,46.

(3.69) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H15N2O4PS+0.1 n2O:

calculated:From:43,45;N:5,04;N:of 9.21;
found:From:43,68;N:5,38;N:8,98.

(3.70) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenate.

Analysis for C11H15N2O4PSe+0,14HBr+0,6EtOAc:

calculated:From:38,93;N:4,86;N:to 6.78;
found:From:39,18;N: 4,53;N:6,61.

(3.71) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]selenate.

Analysis for C8H9N2O4PSSe+0,7HBr+0,2EtOAc:

calculated:From:25,57;N:2,75;N:to 6.78;
found:From:25,46;N:2,49;N:6,74.

(3.72) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenate.

Analysis for C9H11N2O4PSe+HBr:

calculated:From:26,89;N:3,01;N:6,97;
found:C;26,60;N:3,16;N:for 6.81.

Example 4

Getting 5-halogen-4-[2-(5-phosphono)furanyl]thiazolo

Stage A. a Solution of 2-amino-4-[2-(5-diethylphosphino)furanyl]thiazole (obtained as described in stage b of example 3) (1 mmol) in chloroform is treated with N-bromosuccinimide (NBS) (1.5 mmol) at 25°C for 1 h Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5-diethylphosphino)furanyl]thiazole as a brown solid.

Stage C. 2-Amino-5-bromo-4-[2-(5-dieti phosphono)furanyl]thiazole processed, as at the stage of example 3, obtaining 2-amino-5-bromo-4-[2-(5-phosphono)furanyl]thiazole (4.1) in the form of a yellow solid. TPL > 230°C.

Analysis for C7H6N2O4PSBr:

calculated:From:25,86;N:1,86;N:8,62;
found:From:25,93;N:1,64;N:8,53.

By following the above method, you receive the following connections.

(4.2) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C7H6N2O4PSCl:

calculated:From:29,96;N:2,16;N:9,98;
found:From:29.99 is;N:1,97;N:9,75.

(4.3) 2-Amino-5-iodine-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C7H6N2O4PSI:

calculated:From:are 22.42;N:2,28;N:6,70;
found:From:22,32;H:/td> 2,10;N:of 6.31.

(4.4) 2,5-Dibromo-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C7H4NO4PSBr2:

calculated:From:21,62;N:1,04;N:3,60;
found:From:21,88;N:0,83;N:3,66.

Example 5

Getting 2-halogen-4-[2-(5-phosphono)furanyl]thiazolo

Stage A. a Solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (obtained as described in stage b of example 3) (1 mmol) in acetonitrile is treated with copper bromide (II) (1.2 mmol) and solidities (1.2 mmol) at 0°C for 1 h Extraction and chromatography to give 2-bromo-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole as a brown solid.

Stage C. 2-Bromo-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, obtaining 2-bromo-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (5.1) as a yellow hygroscopic solid.

Analysis for C11H13NO4PSBr:

calculated:From:36,08;N:to 3.58; N:3,83;
found:From:36,47;N:3,66;N:3,69.

In accordance with the above methods have the following connections.

(5.2) 2-Chloro-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H13NO4PSCl:

calculated:From:41,07;N:4,07;N:4,35;
found:From:40,77;N:or 4.31;N:of 4.05.

(5.3) 2-Bromo-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C8H7NO4PS2Br:

calculated:From:26,98;N:1,98;N:3,93;
found:From:27,21;N:1,82;N:3,84.

Example 6

For various 2 - and 5-substituted 4-[2-(5-phosphono)furanyl 3 thiazolo

Stage A. a Solution of 2-bromo-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol, obtained as in stage a of example 5) in DMF is treated with tributyl(vinyl)tin (5 mmol) and bis(reperfusion)palladium dichloride (0.05 mmol) at 100° C in nitrogen atmosphere. After 5 h the cooled reaction mixture is evaporated and the residue is subjected to chromatography, obtaining 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole as a yellow solid.

Stage C. 2-Vinyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, obtaining 2-vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (6.1) in the form of a yellow solid.

Analysis for C13H16NO4PS+1HBr+0,1 h2O:

calculated:From:39,43;N:to 4.38;N:3,54;
found:From:39,18;N:to 4.38;N:3,56.

This method can also be used for various 5-substituted 4-[2-(5-phosphono)furanyl]thiazolo of their respective halides.

Stage C. 2-Amino-5-bromo-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with stage A, using 2-tributylstannyl as binding reagent, to obtain 2-amino-5-(2-furanyl)-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage D. 2-Amino-5-(2-furanyl)-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, paragraph is the best 2-amino-5-(2-furanyl)-4-[2-(5-phosphono)furanyl]thiazole (6.2), TPL 190-210°C.

Analysis for C11H9N2O5PS+0,25HBr:

calculated:From:39,74;N:2,80;N:8,43;
found:From:39,83;N:2,92;N:8,46.

The following connection receive in accordance with the above method.

(6.3) 2-Amino-5-(2-thienyl)-4-[2-(5-diethylphosphino)furanyl]thiazole.

Analysis for C11H9N2O4PS2+0,3EtOAc+0,11HBr:

calculated:From:40,77;N:3,40;N:7,79;
found:From:40,87;N:3.04 from;N:7,45.

Example 7

Getting 2-ethyl-4-[2-(5-phosphono)furanyl]thiazolo

Stage A. a Solution of 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol, obtained as in stage a of example 6) in ethanol is treated with palladium on carbon (0.05 mmol) in hydrogen atmosphere (1 ATM) for 12 h, the Reaction mixture is filtered, the filtrate evaporated and the residue purified by chromatography, obtaining 2-ethyl-5-isobutyl-4-[2-(5-diethylphosphino)furane is]thiazole as a yellow foam.

Stage C. 2-Ethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, obtaining 2-ethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (7.1) as a yellow solid.

Analysis for C13H18NO4PS+1HBr:

calculated:From:39,41;N:a 4.83;N:3,53;
found:From:39,65;N:4,79;N:3,61.

Example 8

Getting 4-phosphonomethyliminodiacetic

Stage A. the Solution diethylhydroxylamine (1 mmol) in DMF is treated with sodium hydride (1.2 mmol) followed by treatment of 2-methyl-4-chloromethylthiazole (1 mmol) at 0°C and stirred at 25°C for 12 hours Extraction and chromatography to give 2-methyl-4-diethylphosphonoacetate.

Stage C. 2-Methyl-4-diethylphosphonoacetate processed in accordance with the stage of example 3, obtaining 2-methyl-4-phosphonomethylglycine (8.1).

Analysis for C6H10NO4PS+0,5HBr+0,5H2O:

calculated:From:26,43;N:4,25;N:5,14;
found:From:26,52;N:4,22;N:4,84.

Stage C. 2-Methyl-4-diethylphosphonoacetate processed in accordance with stage a of example 4, and then in accordance with the stage of example 3, receiving 5-bromo-2-methyl-4-phosphonomethylglycine (8.2).

Analysis for C6H9NO4PSBr+0,5HBr:

calculated:From:21,04;N:2,80;N:4.09 to;
found:From:21,13;H:2,69;N:4,01.

Stage D. a Solution of ethyl-2-[(N-Boc)amino]-4-thiazolecarboxamide (1 mmol) in CH2Cl2(10 ml) cooled to -78°and treated With DIBAL-H (1M, 5 ml). The reaction mixture is stirred at -60°C for 3 h and quenched with suspension NaF/H2O (1 g/ml). The resulting mixture was filtered and the filtrate is concentrated, obtaining 2-[(N-Boc)amino]-4-hydroxymethylimidazole in the form of solids.

Stage E. a Solution of 2-[(N-Boc)amino]-4-hydroxymethylimidazole (1 mmol) in DMF (10 ml) cooled to 0°and treated With NaH (1.1 mmol). The mixture is stirred at room temperature for 30 min, then add phosphonomethyliminodiacetic (1,1 IMO is b). After stirring at room temperature for 4 h, the reaction mixture was evaporated to dryness. Chromatography of the residue gives 2-[(N-Boc)amino]-4-diethylphosphonoacetate in the form of solids.

Stage F. 2-[(N-Boc)amino]-4-diethylphosphonoacetate processed in accordance with the stage of example 3, obtaining 2-amino-4-phosphonomethylglycine (8.3) in the form of solids.

Analysis for C5H9N2O4PS+0,16HBr+0,1MeOH:

calculated:From:25,49;N:4,01;N:11,66;
found:From:25,68;N:3,84;N:11,33.

Example 9

Getting 2-carbarnoyl-4-[2-(5-phosphono)furanyl]thiazolo

Stage A. a Solution of 2-etoxycarbonyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in saturated methanolic ammonia solution is heated at 25°C for 12 h of Evaporation and chromatography gave 2-carbarnoyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole as a white solid.

Stage C. 2-Carbarnoyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, obtaining 2-carbarnoyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.1)in the form of solids. TPL 185-186°C.

Analysis for C12H15N2O5PS:

calculated:From:43,64;N:4,58;N:8,48;
found:From:43,88;N:4,70;N:8,17.

Following this procedure, obtain the following connection.

(9.2) 2-Carbarnoyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 195-200°C.

Analysis for C8H7N2O5PS+0,25N2O:

calculated:From:34,48;N:2,71;N:of 10.05;
found:From:34,67;N:2,44;N:9,84.

2-Etoxycarbonyl-4-[2-(5-diethylphosphino)furanyl]thiazole you can also turn to other 2-substituted 4-[2-(5-phosphono)furanyl]thiazole.

Stage C. a Solution of 2-etoxycarbonyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in methanol is treated with sodium borohydride (1.2 mmol) at 25°C for 12 hours Extraction and chromatography to give 2-hydroxymethyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage D. 2-Hydroxymethyl-4-[2-(5-diethylphosphino)furanyl]enous the l processed in accordance with the stage of example 3, getting 2-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole (9.3). TPL 205-207°C.

Analysis for C8H8NO5PS+0,25H2O:

calculated:From:36,16:N:3,22;N:5,27;
found:From:35,98:N:2,84;N:5,15.

Following this procedure, obtain the following connection.

(9.4) 2-Hydroxymethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. TPL 160-170°C.

Analysis for C12H16NO5PS+0,75HBr:

calculated:From:38,13;N:4,47;N:3,71;
found:From:37,90;N:4,08;N:3,60.

Stage E. a Solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in methylene chloride is treated with tribromide phosphorus (1.2 mmol) at 25°C for 2 h Extraction and chromatography to give 2-methyl bromide-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage F. 2-methyl bromide-5-isobutyl-4-[2-(5-diethylphosphino) furanyl]thiazole processed in accordance with article what dia From example 3, getting 2-methyl bromide-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.5). TPL 161-163°C.

Analysis for C12H15BrNO4PS+0,25HBr:

calculated:From:35,99;N:3,84;N:3,50;
found:From:36,01;N:3,52;N:3,37.

Following this procedure, obtain the following connection.

(9.6) 2-methyl bromide-4-[2-(5-phosphono)furanyl]thiazole. TPL > 250°C.

Analysis for C8H7BrNO4PS:

calculated:From:29,65;N:2,18;N:4,32;
found:From:29,47;N:1,99;N:4,16.

Stage G. a Solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in methylene chloride is treated with thionyl chloride (1.2 mmol) at 25°C for 2 h Extraction and chromatography gave 2-chloromethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage N. 2-Chloromethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3 produces the 2-chloromethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.7). TPL 160-162°C.

Analysis for C12H15ClNO4PS+0,45HBr:

calculated:From:38,73;N:4,18;N:3,76;
found:From:38,78;N:4,14;N:to 3.73.

Stage I. a Solution of 2-chloromethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (1 mmol) in DMF is treated with phthalimide potassium (1.2 mmol) at 25°C for 12 hours Extraction and chromatography to give 2-phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage J. 2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole (1 mmol) in ethanol is treated with hydrazine (1.5 mmol) at 25°C for 12 h of Filtration, evaporation and chromatography gave 2-aminomethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole.

Stage K. 2-Aminomethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with the stage of example 3, obtaining 2-aminomethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.8). TPL 235-237°C.

Analysis for C12H17N2O4PS+0,205HBr:

Calculated:From:43,30;N:to 5.21;N:to 8.41;
found:From:43,66;N:a 4.83;N:8,02.

Following the above procedures or in some cases with minimal changes to them, receive the following connections.

(9.9) 2-Carbarnoyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C11H11N2About5PS+0,15HBr:

calculated:From:40,48;N:3,44;N:8,58;
found:From:40,28;N:3,83;N:to 8.34.

(9.10) 2-Carbarnoyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole.

Analysis for C10H11N2O5PS+0,N2O:

calculated:From:38,04;N:3,99;N:8,87;
found:From:37,65;N:3,93;N:8,76.

Example 10

Getting 4-[2-(5-phosphono)furanyl]oksazolov and 4-[2-(5-phosphono)furanyl]imidazole

Stage A. a Solution of 5-diethylphosphino-2-[(2-bromo-4-methyl-1-oxo)pentyl]furanyl (1 mmol) in t-BuOH treated urine is different (10 mmol) by boiling under reflux for 72 hours Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]oxazole and 2-hydroxy-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazole.

Stage C. 2-Amino-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]oxazole processed in accordance with the stage of example 3, obtaining 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole (10.1). TPL 250°C (decomp).

Analysis for C11H15N2O5P:

calculated:From:46,16;N:5,28;N:9,79;
found:From:45,80;N:5,15;N:of 9.55.

Stage C. 2-Hydroxy-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazol processed in accordance with the stage of example 3, obtaining 2-hydroxy-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole (10.14). TPL 205°C (decomp).

Analysis for C11H15N2O5P:

calculated:From:46,16;N:5,28;N:9,79;
found:From:45,80;N:4,90;N:9,73.

Alternate is but 4-[2-(5-phosphono)furanyl]oksazolov and 4-[2-(5-phosphono)furanyl]imidazoles can be obtained as follows.

Stage D. a Solution of 5-diethylphosphino-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmol) in acetic acid is treated with sodium acetate (2 mmol) and ammonium acetate (2 mmol) at 100°C for 4 h Evaporation and chromatography gave 2-methyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]oxazole, 2-methyl-4-isobutyl-5-[2-(5-diethylphosphino)furanyl]oxazole and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazole.

Stage E. 2-Methyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]oxazole, 2-methyl-4-isobutyl-5-[2-(5-diethylphosphino)furanyl]oxazole and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazol processed in accordance with the stage of example 3, obtaining the following connections.

(10.18) the hydrobromide 2-methyl-4-isobutyl-5-[2-(5-phosphono)furanyl]oxazole. TPL > 230°C.

Analysis for C12H17BrNO5P+0,4H2O:

calculated:From:38,60;N:4,81;N:3,75;
found:From:38,29;N:br4.61;N:3,67.

(10.19) the hydrobromide 2-methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C12H17BrNO5P:

calculated:From: 39,36;N:4,68;N:3,83;
found:From:39,33;N:4,56;N:3,85.

(10.21) the hydrobromide 2-methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C12H18BrN2O4P+0,2NH4Br:

calculated:From:37,46;N:4,93;N:8,01;
found:From:37,12;N:5,11;N:8,28.

Alternative 4-[2-(5-phosphono)furanyl]imidazoles can be obtained as follows.

Stage F. a Solution of 5-diethylphosphino-2-(bromoacetyl)furan (1 mmol) in ethanol is treated with cryptorchidism (2 mmol) at 80°C for 4 h Evaporation and chromatography gave 2-trifluoromethyl-4-[2-(5-diethylphosphino)furanyl]imidazole in the form of oil.

Stage g 2-Trifluoromethyl-4-[2-(5-diethylphosphino)furanyl]imidazol processed in accordance with the stage of example 3, obtaining 2-trifluoromethyl-4-[2-(5-phosphono)furanyl]imidazole (10.22). MP 188°C (decomp.).

Analysis for C8H6F3N2O4R+0,5HBr:

calculated: From:RUR 29.79;N:2,03;N:8,68;
found:From:29,93;N:2,27;N:8,30.

Alternative 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]imidazole can be obtained as follows.

Stage N. A solution of 5-diethylphosphino-2-furaldehyde (1 mmol), ammonium acetate (1.4 mmol), 3,4-butandione (3 mmol) and isobutylamine (3 mmol) in glacial acetic acid is heated at 100°within 24 hours Evaporation and chromatography give 4,5-dimethyl-1-isobutyl-2-[2-(5-diethylphosphino)furanyl]imidazole as a yellow solid.

Stage I. 4,5-Dimethyl-1-isobutyl-2-[2-(5-diethylphosphino)furanyl]imidazol processed in accordance with the stage of example 3, obtaining 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]imidazole (10.23).

Analysis for C13H19N2O4P+1,35HBr:

calculated:From:38,32;N:5,03;N:6,87;
Found:From:38,09;N:5,04;N:7,20.

Following the above procedures or in some cases, with some small changes, the mi them receive the following connections.

(10.2) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 250°C (decomp).

Analysis for C10H13N2O5P:

calculated:From:44,13;N:4,81;N:10,29;
found:From:43,74;N:4,69;N:9,92.

(10.3) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C9H11N2O5R+0,4H2O:

calculated:From:by 40.73;N:4,48;N:10,56;
found:From:40,85;N:4,10;N:of 10.21.

(10.4) 2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C8H9N2O5P+0,1N2O:

calculated:From:39,07;N:of 3.77;N:is 11.39;
found:From:38,96;N:3,59;N:11,18.

Analysis for C7H7N2O5P+0,6N2O:

calculated:From:34,90;N:3,43;N:11,63;
found:From:34,72;N:is 3.08;N:11,35.

(10.6) the hydrobromide of 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C11H16N2O5BrP+0,4H2O:

calculated:From:35,29;N:to 4.52;N:of 7.48;
found:From:35,09;N:4,21;N:7,34.

(10.7) 2-Amino-5-phenyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H11N2O5P:

calculated:From:50,99;N:3,62;N:9,15;
found:From:50,70;N:3,43;N:8,96.

(10.8) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C14H13N2 5P+1,1H2O:

calculated:From:49,45;N:4,51;N:8,24;
found:From:49,35;N:4,32;N:8,04.

(10.9) 2-Amino-5-cyclohexylmethyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C14H19N2O5P+0,3H2About:

calculated:From:50,70;N:5,96;N:8,45;
found:From:50,60;N:5,93;N:scored 8.38.

(10.10) 2-Amino-5-allyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C10H11N2O5R+0,4HBr+0,3H2About:

calculated:From:39,00;N;3,93;N:9,10;
found:From:39,31;N:3,83;N:8,76.

(10.11) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C11H14NO5P:

calculated:From:48,72;N:5,20;N:5,16;
found:C:48,67;N:5,02;N:5,10.

(10.12) 2-Amino-5-butyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C11H15N2O5P+0,2H2O:

calculated:From:45,59;N:are 5.36;N:9,67;
found:From:45,32;N:of 5.29;N:9,50.

(10.13) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole-2-it. Analysis for C11H14NO6P+0,39HBr:

calculated:From:is 41.45;N:4,55;N:4,39;
found:From:41,79;N:4,22;N:Android 4.04.

(10.15) 5-Cyclohexylmethyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C14H19N2O5P+0,05HBr:

calculated:From:5090; N:5,81;N:8,48;
found:From:51,06;N:of 5.83;N:8,25.

(10.16) 5-Butyl-2-hydroxy-4-[2-(5-phosphono)furanyl].

Analysis for C11H15N2O5P+0,2N2About:

calculated:From:45,59;N:are 5.36;N:9,67;
found:From:45,77;N:5,34;N:9,39.

(10.17) 5-Benzyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C14H13N2O5P:

calculated:From:52,51;N:4.09 to;N;8,75;
found:From:52,29;N:4,15;N;at 8.36.

(10.20) the hydrobromide 2-methyl-5-propyl-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C11H16BrN2O4P+0,5H2O:

N:
calculated:From:36,69;N:4,76;7,78;
found:From:36,81;N:4,99;N:7,42.

(10.24) 2-Amino-5-(2-thienylmethyl)-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C12H11N2O5PS+0,9HBr:

calculated:From:36,12;N:3,01;N:7,02;
found:From:36,37;N:2,72;N:7,01.

(10.25) the hydrobromide of 2-dimethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H20BrN2O5P+0,05HBr:

calculated:From:39,11;N:5,06;N:7,02;
found:From:39,17;N:a 4.83;N:6,66.

(10.26) 2-Isopropyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Analysis for C14H20NO5P+0,8HBr:

calculated:From:44,48;N:5,55;N:3,71;
found:From:44,45;H:5,57;N:to 3.73.

(10.27) 2-Amino-5-etoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 245°C (decomp.).

Analysis for C10H11N2O7R:

calculated:From:39,75;N:3,67;N:9,27;
found:From:39,45;N:3,71;N:8,87.

(10.28) hydrobromide 2-methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C12H18BrN2O5P+0,7N2O:

calculated:From:36,60;N:equal to 4.97;N:7,11;
found:From:36,50;N:5,09;N:? 7.04 baby mortality.

(10.29) the hydrobromide of 2-ethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H19BrNO5P:

calculated:From:41,07;N:5,04;N:3,68;
Nai the network: From:41,12;N:4,84;N:3,62.

(10.30) the hydrobromide of 2-ethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H20BrN2O5R:

calculated:From:39,51;N:5,10;N:7,09;
found:From:39,03;N:5,48;N:8,90.

(10.31) 2-Vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H16NO5P+0,25HBr:

calculated:From:49,18;N:5,16;N:to 4.41;
found:From:48,94;N:5,15;N:4,40.

(10.32) 2-Amino-5-pentyl-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C12H17N2O5P+0,5H2O:

calculated:From:46,61;N:by 5.87;N:9,06;
found:From:46,38; N:5,79;N:9,07.

(10.33) 2 Pentyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C12H17N2O5P:

calculated:From:48,00;N:5,71;N:was 9.33;
found:From:48,04;N:5,58;N:9,26.

(10.45) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]oxazole. TPL 196°C (decomp.).

Analysis for C8H9N2O5PS:

calculated:From:34,79;N:3,28;N:10,14;
found:From:34,60;N:2,97;N:10,00.

(10.35) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 230°C (decomp.).

Analysis for C15H13N2O7P+0,7N2O:

calculated:From:47,81;N:3,85;N:7,43;
found:From:47,85;N: 3,88;N:7,21.

(10.36) 2-Amino-5-isopropoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 221°C (decomp.).

Analysis for C11H13N2O7P+0,9H2O:

calculated:From:39,75;N:4,49;N:8,43;
found:From:39,72;N:4,25;N:8,20.

(10.37) 2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 240°C (decomp.).

Analysis for C9H9N2O7R+0,3H2About+0.1 acetone:

calculated:From:37,31;N:3,43;N:9,36;
found:From:37,37;N:3,19;N:9,01.

(10.38) 2-Amino-5-[(N-methyl)carbarnoyl]-4-[2-(5-phosphono)furanyl]oxazole. TPL 235°C (decomp.).

Analysis for C9H10N3About6R:

calculated:From:37,64;N:3,51;N:14,63;
on the Deno: From:37,37;N:3,22;N:14,44.

(10.39) 2-Amino-5-ethylthiomethyl-4-[2-(5-phosphono)furanyl]oxazole. TPL 225°C (decomp.).

Analysis for C10H11N2About6PS:

calculated:From:37,74;N:3,48;N:8,80;
found:From:37, 67;N:3,27;N:8,46.

(10.40) 2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C10H13N2O5PS+0,2HBr:

calculated:From:37,48;N:4,15;N:a total of 8.74;
found:From:37,39;N:4,11;N:8,56.

(10.41) 2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C13H11N2O5PS+0,25HBr:

calculated:From:43,55;N:3,16;N:7,81;
found:From: 43,82;N:3,28;N:to 7.59.

(10.42) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C9H11N2O5PS+0,85HBr:

calculated:From:30,11;N:3,33;N:7,80;
found:From:30,18;N:3,44;N:7,60.

(10.43) 2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C10H13N2O5+H2O:

calculated:From:37,27;N:4,69;N:8,69;H2O:5,59;
found:From:37,27;N:4,67;N:at 8.60;H2O:5,66.

(10.44) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]oxazole.

Analysis for C11H15N2O5PS+0,25HBr:

calculated:From:39,03;N:4,54;N:8,28;
Nai the network: From:39,04;H:4,62;N:8,06.

(10.34) 4,5-Dimethyl-2-[2-(5-phosphono)furanyl]imidazole.

Analysis for C9H11N2O4P+1,25N2O:

calculated:From:40,84;N:5,14;N:of 10.58;
found:From:41,02;N:5,09;N:10,27.

Example 11

Obtaining N-alkyl 4-[2-(5-phosphono)furanyl]imidazoles and 4-[2-(5-phosphono)furanyl]oksazolov

Stage A. a Suspension of cesium carbonate (1.5 mmol) and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazole (1 mmol) in DMF is treated with iodomethane (1.5 mmol) at 25°C for 16 h Extraction and chromatography to give 1,2-dimethyl-4-isobutyl-5-[2-(5-diethylphosphino)furanyl]imidazole and 1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]the imidazole.

Stage C. 1,2-Dimethyl-4-isobutyl-5-[2-(5-diethylphosphino) furanyl]imidazole and 1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphino)furanyl]imidazol processed in accordance with the stage of example 3, obtaining the following connection.

(11.1) hydrobromide 1,2-dimethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole.

Analysis for C13H20N2O4PB+0,8H 2O:

calculated:From:39,67;N:of 5.53;N:7,12;
found:From:39,63;N:5,48;N:7,16.

Example 12

Getting 2-[(2-(6-phosphono)pyridyl]pyridine

Stage A. a Solution of 2,2'-bipyridyl (1 mmol) in dichloromethane is treated with m-chloroperoxybenzoic acid (2 mmol) at 0°and the reaction mixture is stirred at 25°C for 2 h Extraction and chromatography to give 2,2'-bipyridyl-N-oxide.

Stage C. (Redmore, D., J. Org. Chem., 1970, 35, 4114).

A solution of methyl ester 2,2'-bipyridyl-N-oxide (1 mmol, obtained from dimethylsulfate and 2,2'-bipyridyl-N-oxide in diethylphosphate) is added slowly at -30°to a solution of n-utility (1 mmol) in diethylphosphate at -30°C. the resulting reaction mixture was stirred at 25°C for 12 hours Extraction and chromatography to give 2-[2-(6-diethylphosphino)pyridyl]pyridine.

Stage C. 2-[2-(6-Diethylphosphino)pyridyl]pyridine treated in accordance with the stage of example 3, obtaining 2-[2-(6-phosphono)pyridyl]pyridine (12.1). TPL 158-162°C.

Analysis for C10H9N2O3R+0,5H2O+0,1HBr:

vechicle what about: From:47,42;N:as 4.02;N:11,06;
found:From:47,03;H:3,67;N:10,95.

Example 13

Getting 4,6-dimethyl-2-(phosphonomethoxy)pyridine

Stage A. a Solution of 2,4,6-collidine (1 mmol) in carbon tetrachloride treated with NBS (5 mmol) and Dibenzoyl peroxide (0.25 mmol) at 80°C for 12 h, the Reaction mixture was cooled to 0°and the precipitate is filtered off. The filtrate was concentrated in vacuo. Chromatography gives 2-methyl bromide-4,6-dimethylpyridin.

Stage C. the Solution diethylhydroxylamine (1 mmol)in toluene is treated with sodium hydride (1.1 mmol) at 0°and after 15 min add 2-methyl bromide-4,6-dimethylpyridin (1 mmol). After 3 h the reaction mixture was subjected to extraction and chromatography, obtaining 2-diethylphosphonate-4,6-dimethylpyridin.

Stage C. 2-Diethylphosphonate-4,6-dimethylpyridin processed in accordance with the stage of example 3, receiving 4,6-dimethyl-2-(phosphonomethoxy)pyridine (13.1).TPL 109-112°C.

Analysis for C9H14NOP+1,0N2O+0,5HBr:

calculated:From:37,32;N:5,74;N: 4,84;
found:From:37,18;N:5,38;N:4,67.

Similarly receive the following connection.

(13.2) 2-Amino-4-methyl-5-propyl-6-phosphonomethylglycine. TPL 153-156°C.

Analysis for C10H18N3O4P+1,25N2O+1,6HBr:

calculated:From:28,11;N:to 5.21;N:9,84;
found:From:28,25;N:4,75;N:9,74.

Example 14

Getting diethyl-5-tributylstannyl-2-parentstate

A solution of diethyl-2-parentstate (1 mmol, obtained as in stage From example 1) in THF cooled at -78°and transferred via cannula into a solution of N-isopropyl-N-cyclohexylamine lithium in THF at -78°C for 15 minutes. The resulting mixture was stirred at -78°C for 2 h and transferred via cannula into a solution of chloride of anti (1 mmol) in THF at -78°C for 20 minutes the mixture is Then stirred at -78°C for 1 h and at 25°C for 12 hours Extraction and chromatography to give compound (14) as a pale yellow oil.

Example 15

Obtain 6-[2-(5-phosphono)furanyl]pyridine the

Stage A. a Solution of 2,6-dichloropyridine (120 mmol) in ethanol is treated with an aqueous solution of America (28%, excess) at 160-165°C for 60 h in a sealed tube. Extraction and chromatography gave 2-amino-6-chloropyridin in the form of a white solid.

Stage C. a Solution of 2-amino-6-chloropyridine (1 mmol) and compound 14 (1 mmol) in p-xylene is treated with tetrakis(triphenylphosphine)palladium (0.05 mmol) at boiling point under reflux for 12 hours Extraction and chromatography gave 2-amino-6-[2-(5-diethylphosphino)furanyl] pyridine as a pale yellow solid.

Stage C.

2-Amino-6-[2-(5-diethylphosphino)furanyl]pyridine treated in accordance with the stage of example 3, obtaining 2-amino-6-[2-(5-phosphono)furanyl]pyridine (15.1). TPL 186-187°C.

Analysis for C9H9N2O4P+0,4HBr:

calculated:From:39,67;N;3,48;N:10,28;
found:From:39,95;N;3,36;N:10,04.

Stage D. a Solution of 2-amino-6-[2-(5-diethylphosphino)furanyl]pyridine (1 mmol) in acetic acid is treated with a solution of bromine in acetic acid (1N, 1 mmol) at 25°C for 0.5 hours, Oparian the e and chromatography gave 2-amino-5-bromo-6-[2-(5-diethylphosphino)furanyl]pyridine and 2-amino-3,5-dibromo-6-[2-(5-diethylphosphino)furanyl]pyridine.

Stage E. 2-Amino-5-bromo-6-[2-(5-diethylphosphino)furanyl]pyridine and 2-amino-3,5-dibromo-6-[2-(5-diethylphosphino)furanyl]pyridine treated in accordance with the stage of example 3, obtaining the following connections:

(15.2) 6-Amino-3-bromo-2-[2-(5-phosphono)furanyl]pyridine.

Analysis for C9H8BrN2O4R+0,7H2O+0,9HBr+0,12h3:

calculated:From:28,44;N:2,73;N:6,74;
found:From:28,64;N:2,79;N:of 6.31.

(15.3) 6-Amino-3,5-dibromo-2-[2-(5-phosphono)furanyl]pyridine. MP.. 233-235°C.

Analysis for C9H7Br2N2O4P+1,2HBr:

calculated:From:21,84;N:1,67;N:5,66;
found:From:21,90;N:1,52;N:5,30.

Stage F. a Solution of 2-amino-3,5-dibromo-6-[2-(5-diethylphosphino)furanyl]pyridine (1 mmol) in DMF handle tributyl(vinyl)tin (1.2 mmol) and tetrakis(triphenylphosphine)palladium (0.2 mmol) at 85°C for 4 h Evaporation and chromatography the raffia give 2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphino)furanyl]pyridine.

Stage G. a Solution of 2-amino-N,5-bis(vinyl)-6-[2-(5-diethylphosphino)furanyl]pyridine (1 mmol) in ethyl acetate is treated with palladium on carbon (10%) at 25°C in an atmosphere of hydrogen (1 ATM) for 12 h Filtration, evaporation and chromatography gave 2-amino-3,5-diethyl-6-[2-(5-diethylphosphino)furanyl]pyridine.

Stage N. 2-Amino-3,5-diethyl-6-[2-(5-diethylphosphino)furanyl]pyridine treated in accordance with the stage of example 3, obtaining 2-amino-3,5-diethyl-6-[2-(5-phosphono)furanyl]pyridine (15.4). TPL 217-218°C.

Analysis for C13H17N2O4P+0,7N2O+1,0HBr:

calculated:From:40,06;N:5,02;N:7,19;
found:From:40,14;N:4,70;N:6.87 in.

Stage I. a Solution of 2-amino-6-picoline (1 mmol) in 48% Hydrobromic acid (4.4 mmol) is treated with bromine (3 mmol) at 0°C for 1 h and Then added an aqueous solution of sodium nitrite and rectional the mixture was stirred at 0°C for 0.5 hours Then add an aqueous solution of sodium hydroxide (9.4 mmol) and the reaction mixture is stirred at 25°C for 1 h Extraction and chromatography to give 2,3-dibromo-6-picoline and 2,3,5-tribrom-6-picoline.

The Study Is J. 2,3-Dibromo-6-picoline processed in accordance with stage b of example 15, and then in accordance with the stage of example 3, receiving 5-bromo-2-methyl-6-[2-(5-phosphono)furanyl]pyridine (15.5). TPL 207-208°C.

Analysis for C10H9BrNO4P+0,6HBr:

calculated:From:32.76ˆ;N:2,64;N:3,88;
found:From:32,62;H:2,95;N:3,55.

Following the above procedures or in some cases making some small changes, using ordinary chemical reaction, given the following connections.

(15.6) 2-[2-(5-Phosphono)furanyl]pyridine. TPL 220-221°C. Analysis for C9H8NO4P+0,1N2O+0,45HBr:

calculated:From:41,05;N:3,31;N:5,32;
found:From:41,06;N:3,10;N:5,10.

(15.7) 2-Amino-3-nitro-6-[2-(5-phosphono)furanyl]pyridine. TPL 221-222°C.

Analysis for C9H8N3About6R+0,55HBr+0,02h3:

calculated:From:33,12;N:2,65;N:12,68;
found:From:33,22;N:2,43;N:of 12.26.

(15.8) 2,3-Diamino-6-[2-(5-phosphono)furanyl]pyridine. TPL 150-153°C.

Analysis for C9H10N3O4P+1,5HBr+0,05h3:

calculated:From:29,46;N:3,15;N:11,02;
found:From:29,50;N:3,29;N:or 10.60.

(15.9) 2-Chloro-6-[2-(5-phosphono)furanyl]pyridine. TPL 94-96°C.

Analysis for C9H7ClNO4P+0,25HBr:

calculated:From:38,63;N:2,61;N:5,01;
found:From:38,91;N:3,00;N:5,07.

(15.10) 3,5-Dichloro-2-[2-(5-phosphono)furanyl]pyridine. TPL 180-181°C.

Analysis for C9H6ClNO4R+0,7HBr:

calculated: From:31,61;N:2,01;N:3,94;
found:From:31,69;N:2,09;N:3,89.

(15.11) 3-Chloro-5-trifluoromethyl-2-[2-(5-phosphono)furanyl]pyridine. TPL 253-254°C.

Analysis for C10H6ClF3NO4P:

calculated:From:36,67;N:1,85;N:4,28;
found:From:36,69;N:1,89;N:4,30.

(15.12) 2-Amino-3-ethyl-6-[2-(5-phosphono)furanyl]pyridine. TPL 220-221°C.

Analysis for C11H13N2O4P+0,6HBr+0,2N2O:

calculated:From:41,24;N:4,40;N:a total of 8.74;
found:From:41,02;N:4,57;N:8,68.

(15.13) 6-Amino-3-ethyl-2-[2-(5-phosphono)furanyl]pyridine.

Analysis for C11H13N2O4P+1,0HBr+0,3H2O:

calculated:From: 37,27;N:4,15;N:of 7.90;
found:From:37,27;N:4,19;N:7,51.

(15.14) 6-Amino-3-propyl-2-[2-(5-phosphono)furanyl]pyridine. TPL 252-253°C.

Analysis for C12H15N2O4P+1,0HBr+1,0N2O+0,32h3:

calculated:From:41,65;N:of 5.05;N:6,82;
found:From:41,97;N:5,19;N:6,83.

(15.15) 2,4-Dimethyl-3-bromo-6-[2-(5-phosphono)furanyl]pyridine. TPL 232-233°C.

Analysis for C11H11BrNO4R+0,45HBr:

calculated:From:35,85;N:3,13;N:3,80;
found:From:35,98;N:3,10;N:3,71.

(15.16) of 2-Chloro-4-amino-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C9H8N2O4PCl+HBr+0,5SH2O+Meon:

calculated:C: 30,99;N:3,38;N:of 7.23;
found:C:31,09;N:3,21;N:of 6.96.

(15.17) 3-Hydroxy-2-[2-(5-phosphono)furanyl]pyridine.

Analysis for C9H8NO5P+1,1HBr+0,SN3Ph:

calculated:From:37,26;N:3,24;N:3,91;
found:From:37,66;N:3,55;N:3,84.

(15.19) 2-Amino-3-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C12H13N2O4PCl+HBr+0,4H2O:

calculated:From:39,13;N:4,05;N:to 7.61;
found:From:39,06;N:3,85;N:7,37.

(15.20) 2-Amino-5-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C12H13N2O4P+HBr+0,SN3Ph:

calculated:From:47,69;N:N:to 6.58;
found:From:47,99;N:4,62;N:6,91.

(15.21) 5-Amino-2-methoxy-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C10H11N2O5P+0,2H2O:

calculated:From:43,87;N:4,20;N:10,23;
found:From:43,71;N:of 3.77;N:9,77.

(15.22) 2-Methyl-5-cyano-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C11H9N2O4P+0,75HBr+0,5H2O+0,5MePh:

calculated:From:45,84;N:3,91;N:7,37;
found:From:45,93;N:3,56;N:of 7.36.

(15.23) 2-Amino-3,5-bis(cyano)-4-methyl-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C12H9N4O4P+0,7N2O:

17,68;
calculated:From:45,49;N:3:31;N:
found:From:45,48;N:3,06;N:17,51.

(15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine.

Analysis for C10H6N2O4PCl:

calculated:From:42,20;N:2,13;N:9,84;
found:From:41,95;N:2,10;N:for 9.47.

Example 16

Obtain 2-[2-(5-phosphono)furanyl]pyrimidine and 4-[2-(5-phosphono)furanyl]pyrimidines

Stage A. a Solution of 5-diethylphosphino-2-[(1-oxo)pentyl]furan in dimethylacetal N,N-dimethylformamide is refluxed for 12 hours Evaporation and chromatography to give diethyl-5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanostanol.

Stage C. a Solution of diethyl-5-(2-propyl-3-N,N-dimethylamino) acryloyl-2-parentstate (1 mmol) in ethanol is treated with guanidine hydrochloride (1.2 mmol) and ethoxide sodium (1 mmol) at 80°C for 12 h, the Reaction mixture was evaporated and the residue is dissolved in water. The aqueous solution is neutralized with HCl (2N) and concentrate under reduced pressure. The residue is evaporated together with toluene, obtaining 2-amino-5-propyl-4-[2-(5-ethylphosphonic)furanyl]eremein in the form of a yellow solid.

Stage C. 2-Amino-5-propyl-4-[2-(5-ethylphosphonic)furanyl]pyrimidine (1 mmol) and thionyl chloride are heated at the boil under reflux for 2 hours, the Reaction mixture was evaporated to dryness, the residue is dissolved in methylene chloride and treated with excess pyridine and ethanol at 25°C for 12 h of Evaporation and chromatography gave 2-amino-5-propyl-4-[2-(5-diethylphosphino)furanyl]pyrimidine.

Stage D. 2-Amino-5-propyl-4-[2-(5-diethylphosphino)furanyl]pyrimidine processed in accordance with the stage of example 3, obtaining 2-amino-5-propyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.1). TPL 258-259°C.

Analysis for C11H14N3O4P+1,N2O:

calculated:From:43,01;N:5,47;N:13,68;
found:From:43,18;N:5,31;N:13,30.

Following this procedure receive connection (16.2) - 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]pyrimidine. TPL 218-220°C.

Analysis for C12H16N3O4P+0,75HBr+0,3h3:

calculated:From:43,92;N:5,01;N:10,90
found:From:44,02;N:4,62;N:10,69.

Alternatively, according to the following methods, you can get other 4-[2-(5-phosphono)furanyl]pyrimidines.

Stage E. the Connection 2.2 processed in accordance with stage a of example 16, receiving diethyl-5-(3-N,N-dimethylamino)acryloyl-2-furanostanol as an orange solid.

Stage F. a Solution of diethyl-5-(3-N,N-dimethylamino)acryloyl-2-parentstate (1 mmol), ethanol solution ethoxide sodium (2 mmol) and guanidine hydrochloride (1.1 mmol) is heated at 55°C for 2 h, the Reaction mixture is cooled in a bath with ice and neutralized 1N HCl. Evaporation and chromatography gave 2-amino-4-[2-(5-diethylphosphino)furanyl]pyrimidine as a yellow solid.

Stage G. of 2-Amino-4-[2-(5-diethylphosphino)furanyl]pyrimidine processed in accordance with the stage of example 3, obtaining 2-amino-4-[2-(5-phosphono)furanyl]pyrimidine (16.3). TPL > 230°C.

Analysis for C8H8N3O4P+0,N2O+0,2HBr:

calculated:From:35,48;N:3,61;N:15,51;
found:From:35,42;N: 3,80;N:15,30.

Stage N. A solution of 2-amino-4-[2-(5-diethylphosphino)furanyl]pyrimidine (1 mmol) in methanol and chloroform is treated with NBS (1.5 mmol) at 25°C for 1 h Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5-diethylphosphino)furanyl]pyrimidine as a yellow solid.

Stage I. 2-Amino-5-bromo-4-[2-(5-diethylphosphino)furanyl]pyrimidine processed in accordance with the stages F and G of example 15 with the following processing in accordance with the stage of example 3, obtaining 2-amino-5-ethyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.4). TPL > 225°C.

Analysis for C10H12N3O4P+1,4N2O+0,2HBr+0,25h3:

calculated:From:42,30;N:5,14;N:12,59;
found:From:42,74;N:4,94;N:12,13.

Following the above procedures or in some cases making some small changes, using ordinary chemical reaction, given the following connections.

(16.5) 2-[2-(5-Phosphono)furanyl]pyrimidine. TPL 194-196°C.

Analysis for C8H7N2O4P+0,1N2O+0,55HBr:

calculated:
From:of 35.27;N:2,87;N:10,28;
found:From:35,26;N:2,83;N:9,89.

(16.6) 2-Amino-6-methyl-4-[2-(5-phosphono)furanyl]pyrimidine. TPL 238-239°C.

Analysis for C9H10N3About4P+0,9HBr:

calculated:From:32,96;N:3,35;N:12,81;
found:From:33,25;N:3,34;N:12,46.

(16.7) 2-Methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. TPL 228-229°C.

Analysis for C9H9N2O4PS+0,5H2O:

calculated:From:38,44;N:to 3.58;N:9,96;
found:From:38,19;N:3,25;N:9,66.

(16.8) 2-Methyl-4-[2-(5-phosphono)furanyl]pyrimidine. TPL 206-212°C.

Analysis for C9H9N2O4P+0,N2O+0,25HBr:

the calc is keno: From:34,05;N:3,30;N:8,82;
found:From:34,02;N:3,06;N:8,75.

(16.9) 4,6-Dimethyl-5-bromo-2-[2-(5-phosphono)furanyl]pyrimidine. TPL 251-252°C.

Analysis for C10H10BrN2O4R:

calculated:From:36,06;N:3,03;N:to 8.41;
found:From:35,89;N:2,82;N:8,11.

(16.10) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]pyrimidine.

Analysis for C8H7ClN3O4R+0,5H2About:

calculated:From:33,76;N:2,83;N:of 14.76;
found:From:33,91;N:2,86;N:14,20.

(16.11) 2-Amino-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine.

Analysis for C9H10N3O4PS+HBr:

calculated:From:29, 36 the; N;3,01;N:11,41;
found:From:29,63;N:3,02;N:11,27.

(16.12) 2-Amino-5-bromo-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine.

Analysis for C9H9N3O4PSBr+0,8HBr+0,2h:

calculated:From:27,80;N:2,56;N:9,35;
found:From:27,74;N:2,40;N:8,94.

(16.13) 2-Amino-(4-morpholino)-4-[2-(5-phosphono)furanyl]pyrimidine. TPL > 230°C.

Analysis for C12H15N4O5P+HBr+0,05MePh:

calculated:From:36,02;N:4,01;N:13,61;
found:From:35,98;N:Android 4.04;N:13,33.

(16.14) 6-Amino-4-chloro-2-[2-(5-phosphono)furanyl]pyrimidine. TPL > 230°C.

Analysis for C8H7N3O4PCl+0,5H2O:

calculated:From:N:2,83;N:of 14.76;
found:From:33,83;N:2,54;N:14, 48mm.

Example 17

Obtain 2-[2-(5-phosphono)furanyl]pyrazino and 2-[2-(5-phosphono)furanyl]triazines

Stage A. set forth in example 16, the method can also be applied to the synthesis of analogs of 2-[2-(5-phosphono)furanyl]pyrazine and 2-[2-(5-phosphono)furanyl]triazine, and in some cases to use them with some small modifications, using conventional chemical methods.

In accordance with this receive the following connections.

(17.1) 2,5-Dimethyl-3-[2-(5-phosphono)furanyl]pyrazin. TPL 212-213°C.

Analysis for C10H11N2O4P+0,75HBr:

calculated:From:38,15;N:3,76;N:8,90;
found:From:38,41;N:3,93;N:8,76.

(17.2) 2-Chloro-6-[2-(5-phosphono)furanyl]pyrazin. TPL 204-205°C.

Analysis for C8H6ClN2O4P+0,3HBr+0,02h3:

calculated:From:34,10;N:2,27; N:9,77;
found:From:to 34.36;N:2,07;N:9,39.

(17.3) 2-Amino-3-propyl-6-[2-(5-phosphono)furanyl]pyrazin. TPL 227-228°C.

Analysis for C11H14N3O4P+0,7HBr:

calculated:From:38,87;N:4,36;N:12,36;
found:From:39,19;N:4,36;N:11,92.

(17.4) 2-Amino-6-[2-(5-phosphono)furanyl]pyrazin. TPL 235-236°C.

Analysis for C8H8N3O4P+1,15 NM2O+0,3h3:

calculated:From:37,26;N:4,01;N:15,88;
found:From:37,09;N:3,67;N:15,51.

(17.5) 2-Amino-3-bromo-6-[2-(5-phosphono)furanyl]pyrazin.

Analysis for C8H7N3O4PBr+1HBr:

calculated:From:23,97;N:2,01;N: 10,48;
found:From:24,00;N:2,00;N:10,13.

(17.6) 3-Methylthio-2-[2-(5-phosphono)furanyl]pyrazin.

Analysis for C9H9N2O4PS+0,3H2O:

calculated:From:up 38.94;N:3,49;N:to 10.09;
found:From:38,99;N:3,11;N:9,67.

(17.7) 6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazin.

Analysis for C9H10N3O4PS+1,5H2O+1,7HBr+0,25h:

calculated:From:27,19;N:3,54;N:cent to 8.85;
found:From:27,10;N:3,85;N:8,49.

(17.8) 6-Amino-5-methylthio-2-[2-(5-phosphono)furanyl]pyrazin.

Analysis for C9H10N3O4PS+1,1HBr+0,05MePh:

calculated:From:29,49;N:3.04 from;N:11,03;
found: From:29,23;N:2,79;N:10,87.

(17.9) 6-Amino-5-methoxycarbonyl-3-chloro-2-[2-(5-phosphono)furanyl]pyrazin.

Analysis for C10H9N3About6PCl+0,3HBr+0,04MePh:

calculated:From:34,15;N:2,68;N:are 11.62;
found:From:34,20;N:2,90;N:11,21.

(17.10) Ammonium salt of 6-amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine.

Analysis for C9H13N4O4PS+0,8HBr:

calculated:From:29,30;N:of 3.77;N:15,18;
found:From:29,03;N:3,88;N:15,08.

(17.11) 2-Amino-4-phenyl-6-[2-(5-phosphono)furanyl]triazine.

Analysis for C13H11N4O4R+HBr+0,1EtOAc:

39,77;
calculated:From:39,45;N:3,16;N:13,73;
found:From:N:3,26;N:13,48.

Example 18

Obtaining analogues with X representing methoxycarbonyl, methylthiouracil, methylaminomethyl, methylcobalamin

Getting 4-phosphoramidocyanidates and 4-phosphonomethyliminodiacetic

Stage A. a Solution of 2-amino-4-ethoxycarbonylmethyl (1 mmol) in 1,4-dioxane (5 ml) is treated with di-tert-BUTYLCARBAMATE (1.2 mmol), TMEDA (0.1 mmol) and DMAP (0.1 mmol) at room temperature. After stirring the reaction mixture for 20 h her evaporated to dryness. The residue is subjected to extraction, receiving 2-[N-Boc(amino)]-4-ethoxycarbonylmethyl in the form of a yellow solid.

Stage C. a Solution of 2-[N-Boc(amino)]-4-ethoxycarbonylmethyl (1 mmol) in a mixture of 2:1 EtOH:H2O (10 ml) is treated with NaOH (3N, 3 mmol) and the reaction mixture stirred at 60°C for 4 h, the Reaction mixture was cooled to 0°C, neutralized to pH 5 using 3N HCl and the resulting solid is collected by filtration, obtaining 2-[N-Boc(amino)]-4-carboxylases in the form of a white solid.

Stage C. a Suspension of 2-[N-Boc(amino)]-4-carboxylate (1 mmol) in CH2CL2(5 ml) is treated with thionyl chloride (4 mmol) at room temperature. After stirring for 4 h the reaction mixture was evaporated to dryness. The residue is dissolved in CH2Cl2( ml) and added to a solution of diethyl(hydroxymethyl)phosphonate (1.5 mmol) and pyridine (2 mmol) in CH 2Cl2(5 ml) at 0°C. the Reaction mixture is heated to room temperature and stirred for 4 h the Reaction is quenched with water and the mixture is subjected to extraction, receiving 2-[N-Boc(amino)]-4-diethylphosphonoacetate in the form of a thick yellow oil.

Alternative ester bond can be obtained using the method of mixed anhydrides, as shown in the following methods.

A solution of 2-[N-Boc(amino)]-4-carboxylate (1 mmol) in pyridine (5 ml) is treated with para-toluensulfonate (2 mmol), and then diethyl(hydroxymethyl)phosphonate (2 mmol) at room temperature for 4 hours Evaporation, extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonoacetate in the form of a thick yellow oil.

Stage D. a Solution of 2-[N-Boc(amino)]-4-diethylphosphonoacetate (1 mmol) and anisole (0.1 mmol) in methylene chloride (5 ml) and triperoxonane acid (5 ml) stirred at 0°C for 1 h and at room temperature for 1 h Evaporation, extraction and chromatography gave 2-amino-4-diethylphosphonoacetate in the form of solids.

Stage E. 2-Amino-4-diethylphosphonoacetate processed in accordance with the stage of example 3, obtaining 2-amino-4-phosphoramidocyanidates (18.1) in the form of solids. TPL > 240°C (decomp.).

Analysis for C5Hsub> 7N2O5PS:

calculated:From:25,22;N:2,96;N:11,76;
found:From:25,30;N:2,86;N:11,77.

Stage F. a Solution of 2-[N-Boc(amino)]-4-diethylphosphonoacetate (1 mmol) in CH2Cl2(5 ml) is treated with bromine (2 mmol) at room temperature for 4 h Evaporation and extraction give 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonoacetate in the form of an orange oil, which is processed in accordance with the stage D of example 18, and then in accordance with the stage of example 3, obtaining 2-amino-5-bromo-4-phosphoramidocyanidates (18.2) in the form of solids. TPL > 230°C (decomp.).

Analysis for C5H6N2O5PSBr:

calculated:From:18,94;N:1,91;N:8,84;
found:From:19,08;N:1,76;N:8,67.

Stage G. a Solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonoacetate (1 mmol) and dichlorobis(triphenylphosphine (II) (0.1 mmol) in DMF (5 ml) is treated with tributyl(vinyl)tin (2.5 mmol) and the reaction mixture stirred at 60° C for 2 hours the Solvent is removed and the residue absorb EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonoacetate in the form of a yellow solid.

Stage N. A suspension of 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonoacetate (1 mmol) and 10% Pd/C (0.5 mmol) in Meon (5 ml) stirred in an atmosphere of H2(balloon) at room temperature for 15 hours Filtration and evaporation gave 2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonoacetate in the form of a yellow solid, which was processed in accordance with the stage D of example 18, and then in accordance with the stage of example 3, obtaining 2-amino-5-ethyl-4-phosphoramidocyanidates (18.3) in the form of solids. TPL > 230°C (decomp.).

Analysis for C7H11N2O5PS:

calculated:From:31,58;N:4,16;N:10,52;
found:From:31,80;N:Android 4.04;N:10,18.

Stage I. a Solution of methyl ester of N-[bis(methylthio)methylene]glycine (1 mmol) in anhydrous THF (2 ml) was added to a solution of t-BuOK (1.4 mmol) in anhydrous THF (10 ml) at -78°and with whom the return is stirred for 30 minutes Then add a solution ethylisothiocyanate (1 mmol) in anhydrous THF (2 ml) and the reaction mixture stirred at -78°C for 30 min and at room temperature for 2 hours the Reaction is quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylmethyl in the form of a yellow solid, which was processed in accordance with the stages b and C of example 18, and then in accordance with the stage of example 3, obtaining 2-methylthio-5-(N-ethylamino)-4-phosphoramidocyanidates (18.4) in the form of solids. TPL > 200°C (decomp.).

Analysis for C8H13N2O5PS2+0,1HBr:

calculated:From:29.99 is;N:4,12;N:a total of 8.74;
found:From:29,71;N:4,10;N:at 8.60.

Stage J. a Solution of 1 mmole of acid chloride of 2-[N-Boc(amino)]-4-thiazolecarboxamide (1 mmol) and pyridine (2 mmol) in CH2Cl2(5 ml) cooled to -78°and bubbled through a solution of H2S (gas) for 10 minutes, the Reaction mixture was stirred at -78°C for 30 min and then warmed to room temperature. The mixture was washed with 3N HCl. The organic phase is separated, dried and concentrated, obtaining 2-[-Boc(amino)]-4-thiazolecarboxamide acid as a yellow solid.

Stage K. the Solution of the obtained 2-[N-Boc(amino)]-4-thiazolecarboxamide acid (1 mmol) in THF (5 ml) cooled to -78°and treated With small portions NaH (2 mmol). After 10 min, the reaction mixture is treated with a solution of diethylphosphonoacetate in THF (5 ml). The reaction mixture was stirred at -78°C for 1 h and then quenched with H2O. Extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonoacetate in the form of a thick oil, which is processed in accordance with the stage D of example 18, and then in accordance with the stage of example 3, obtaining 2-amino-4-phosphonomethyliminodiacetic (18.5) in the form of solids. TPL > 230°C (decomp.).

Analysis for C5H7N2O4PS2:

calculated:From:23,62;N:2,78;N:11,02;
found:From:23,77;N:2,61;N:of 10.73.

Getting 4-[(N-phosphonomethyl)carbarnoyl]thiazole, 3-[(N-phosphonomethyl)carbarnoyl]isothiazole and 2-[(N-phosphonomethyl)carbarnoyl]pyridine

Stage L. the Solution of 2-[N-Boc(amino)]-4-thiazolecarboxamide acid (1 mmol) in DMF (5 ml) is treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 1.5 mm is l) and 1-hydroxybenzotriazole (HOBt, 1.5 mmol) followed by the addition diethylaminoethylamine (1.5 mmol) at room temperature for 24 h, the Reaction mixture is subjected to evaporation, extraction and chromatography, obtaining 2-[N-Boc(amino)]-4-[(N-diethylphosphonate)carbarnoyl]thiazole as a white solid, which is subjected to processing in accordance with the stage D of example 18, and then in accordance with the stage of example 3, obtaining 2-amino-4-[(N-phosphonomethyl)carbarnoyl]thiazole (18.6) in the form of light brown solid. TPL > 245°C (decomp.).

Analysis for C5H8N3O4PS+1,05HBr:

calculated:From:18,64;N:2,83:N:13,04;
found:From:18,78;N:2,43;N:12,97.

Getting 2-[(N-phosphonacetyl)amino]thiazole and 2-[(N-phosphonacetyl)amino]pyridine

Stage M Solution of the hydrochloride of 2-amino-4,5-dimethylthiazole (2 mmol) and diethylphosphonate acid (1 mmol) in DMF (5 ml) was treated with EDCI (1.5 mmol), HOBt (1.5 mmol) and triethylamine (2 mmol) at room temperature for 24 h, the Reaction mixture is subjected to evaporation, extraction and chromatography, obtaining 2-[(N-diethylphosphonoacetate)amino]-4,5-dimethylthiazol in the IDA yellow solid, which is subjected to processing in accordance with the stage D of example 18, and then in accordance with the stage of example 3, obtaining 4,5-dimethyl-2-[(N-phosphonacetyl)amino]thiazole (18.7) as a light brown solid. TPL > 250°C.

Analysis for C7H11N2O4PS:

calculated:From:33,60;N:4,43;N:11,20;
found:From:33,62;H:4,29;N:10,99.

Using some of the procedures described above or some of these techniques may be amended slight modifications, using conventional chemistry, will receive the following connections.

(18.8) 2-[(N-Phosphonomethyl)carbarnoyl]pyridine.

Analysis for C7H9N2O4R+HBr+0,67H2O:

calculated:From:27,20;N:3,70;N:9,06;
found:From:27,02;N:3,71;N:8,92.

(18.9) 2-[(N-phosphonacetyl)amino]pyridine.

Analysis for C7H9N2O4P+HBr+0,N2O:

calculated:From:27,20;N:3,70;N:9,06;
found:From:27.05 per;N:3,59;N:8,86.

(18.10) 4-Etoxycarbonyl-2-[(N-phosphonacetyl)amino]thiazole.

Analysis for C8H11N2O6PS:

calculated:From:32,66;N:of 3.77;N:9,52;
found:From:32,83;N:to 3.58;N:9,20.

(18.11) 2-Amino-5-bromo-4-[(N-phosphonomethyl)carbarnoyl]thiazole. TPL 232°C (decomp.).

Analysis for C5H7N3O4PSBr+0,15HBr+0,1 hexane:

calculated:From:19,97;N:2,56;N:12,48;
found:C:19,90;N:to 2.29;N:of 12.33.

(18.12) 2-Amino-5-(2-thienyl)-4-[(N-phosphonomethyl)carbarnoyl]thiazole. TPL 245°C (decomp.).

Analysis for C9H10N3About4PS2+HBr+0,1EtOAc:

calculated:From:27,60;N:2,91;N:10,27;
found:From:27,20;N:to 2.67;N:9,98.

(18.13) 4,5-Dichloro-3-[(N-phosphonomethyl)carbarnoyl]isothiazol. TPL 189-191°C.

Analysis for C5H5N2O4PSCl2:

calculated:From:20,63;N:1,73;N:9,62;
found:From:20,43;N:1,54;N:9,51.

(18.14) 2-Amino-5-bromo-4-{[N-(1-phosphono-1-phenyl)methyl] carbarnoyl}thiazole. TPL > 250°C.

Analysis for C11H11N3About4PSBr:

calculated:From:33,69;N:2,83;N:10,71;
found:From:33,85;N:2,63;N:10,85.

(18.15) 2-Amino-5-(2-thienyl)-4-phosphoramidocyanidates. TPL > 230°C (decomp.).

Analysis for C9H9N2O5PS2:

calculated:From:33,75;N:2,83;N:8,75;
found:From:33,40;N:2,74;N:8,51.

(18.16) 2-Amino-5-benzyl-4-phosphoramidocyanidates. TPL > 230°C (decomp.).

Analysis for C12H13N2O5PS:

calculated:From:43,91;N:3,99;N:8,53;
found:From:43,77;N:4,03;N:8,25.

(18.17) 2-Methylthio-5-methylamine-4-phosphoramidocyanidates.

Analysis for C7H11N2O5PS2+0,2HBr:

calculated:From:26,74;N:3,59;N:8,91;
found:From:26,79;N:to 3.89;N:8,89.

(18.18) 2-Amino-5-ethyl-4-[(N-phosphonomethyl)carbarnoyl]thiazole. TPL 180°C (decomp).

Analysis for C7H12N3O4PS2+HBr+0,4CH2Cl2:

calculated:From:23,49;N:3,67;N:11,18;
found:From:23,73;N:3,29;N:11,42.

(18.19) 2-Amino-5-isopropyl-4-[(N-phosphonomethyl)carbarnoyl] thiazole. TPL 247-250°C.

Analysis for C8H14N3O4PS:

calculated:From:34,41;N:of 5.05;N:15,05;
found:From:34,46;N:4,80;N:14,68.

(18.20) 2-Amino-5-isopropyl-4-phosphoramidocyanidates. TPL > 230°C.

Analysis for C8H13N2O5PS:

calculated:From:34,29;N:4,68;N:10,00;
found:From:33,97;N:4,49;N:9,70.

(18.21) 2-Amino-5-phenyl-4-phosphoramidocyanidates. TPL > 230°C.

Analysis for C11H11N2O5PS:

calculated:
From:42,04;N:3,53;N:8,91;
found:From:42,04;N:3,40;N:8,72.

(18.22) 2-Amino-4-phosphonomethyliminodiacetic.

Analysis for C5H7N2About6R+0,09HBr:

calculated:From:26,18;N:3,12;N:12,21;
found:From:26,29;N:3.04 from;N:11,90.

(18.23) 2-Amino-6-[(N-phosphonacetyl)amino]pyridine.

Analysis for C7H10N3O4P+1,1HBr+0,mon:

calculated:From:26,54;N:3,72;N:12,80;
found:From:26,79;N:3,63;N:to 12.44.

(18.24) 2-Amino-5-methyl-4-[(N-phosphonomethyl)carbarnoyl]thiazole. TPL > 250°C.

Analysis for C6H10N3O4PS+0,06EtOAc:

calculated:From: 29,22;N:4,12;N:16,38;
found:From:29,03;N:3,84;N:16,01.

(18.25) 2-Amino-3-bromo-6-[(N-phosphonacetyl)amino]pyridine.

Analysis for C7H9N3O4PBr+1,25HBr+0,8EtOAc:

calculated:From:25,43;N:3,48;N:8,72;
found:From:25,58;N:3,71;N:8,56.

(18.26) 2-Amino-3,5-dibromo-6-[(N-phosphonacetyl)amino]pyridine.

Analysis for C7H8N3O4PBr2+HBr+0,5EtOAc:

calculated:From:21,03;N:2,55;N:8,18;
found:From:21,28;N:2,55;N:to $ 7.91.

(18.27) 2-Amino-5-methyl-4-phosphoramidocyanidates. TPL 230°C (decomp.).

Analysis for C6H9N2O5PS:

calculated:From:28,58;N: 3,60;N:to 11.11;
found:From:28,38;N:3,49;N:11,10.

(18.28) 2-Amino-3,5-diethyl-6-[(N-phosphonacetyl)amino]pyridine. MS for C11H18N3O4R+N: calculated 288, found 288.

(18.29) 2-Amino-3,5-dibromo-6-{[N-(2,2-dibromo-2-phosphono)acetyl]amino}pyridine.

Analysis for C7H6N3O4PBr4+0,5HBr+EtOAc:

calculated:From:19,56;N:2,16;N:6,22;
found:From:(Jn 19 : 26;N:to 2.29;N:5,91.

(18.30) 2-Amino-5-isopropyl-4-phosphonomethyliminodiacetic.

Analysis for C8H13N2O6P+0,2HBr:

calculated:From:34,27;N:4,75;N:9,99;
found:From:34,47;N:4,84;N:9,83.

(18.31) 2-Amino-5-[1-(2-cyclohexylethyl)ethinyl]-4-phosphoramidocyanidates. TPL 230°C (decomp.).

Analysis for C14H19N 2O5PS+0,1HBr:

calculated:From:45,89;N:5,25;N:of 7.64;
found:From:45,85;N:4,96;N:7,44.

(18.32) 2-Amino-5-[1-(4-cyano)butenyl]-4-phosphoramidocyanidates. TPL 230°C (decomp.).

Analysis for C10H10N3About5PS+0,25HBr:

calculated:From:35,80N:is 3.08;N:12,53;
found:From:35,92N:2,99;N:12,20.

(18.33) 2-Amino-5-methyl-4-phosphonomethyliminodiacetic.

Analysis for C6H9N2O6R+0,15HBr:

calculated:From:29,03;N:3,71;N:11,28;
found:From:28,98;N:3,66;N:11,21.

(18.34) 2-Amino-5-[1-(4-cyano)butyl]-4-phosphoramidocyanidates. TPL 230°C (decomp.).

Analysis for C10the 14N3O5PS:

calculated:From:37,62;N:4,42;N:13,16;
found:From:37,23;N:4,18;N:12,79.

(18.35) 2-Amino-5-pentyl-4-phosphonomethyliminodiacetic.

Analysis for C10H17N2O6P:

calculated:From:41,10;N;5,86;N:9,59;
found:From:41,16;N:5,75;N:9,50.

(18.36) 2-[N-Boc(amino)]-4-[(2-phosphono)etoxycarbonyl]thiazole.

Analysis for C11H17N2O7PS:

calculated:From:37,50;N:4,86;N:7,95;
found:From:37,10;N:4,59;N:7,84.

(18.37) the hydrobromide of 2-amino-4-[(2-phosphono)etoxycarbonyl]thiazole.

Analysis for C6H9N2O5PS+HBr:

calculated:From:21,63;N:3,03;N:to 8.41;
found:From:22,01;N:2,99;N:8,15.

(At 18.38) 2-Amino-5-butyl-4-phosphonomethyliminodiacetic.

Analysis for C9H15N2About6R:

calculated:From:38,86;N:5,43;N:10,07;
found:From:38,59;N:5,43;N:9,96.

(18.39) 2-Amino-5-[1-(1-oxo-2,2-dimethyl)propyl]-4-phosphoramidocyanidates.

Analysis for C10H15N2O6PS:

calculated:From:37,27;N:4,69;N:8,69;
found:From:37,03;N:4,69;N:8,39.

(18.40) 2-Amino-5-propyl-4-phosphonomethyliminodiacetic.

Analysis for C8H13N2O6P+0,35EtOAc+0,05HBr:

calculated: From:37,75;N:5,34;N:9,37;
found:From:37,69;N:to 5.21;N:9,03.

(18.41) 2-Amino-5-propyl-4-phosphoramidocyanidates. TPL 134°C (decomp.).

Analysis for C8H13N2O5PS:

calculated:From:34,29;N:4,68;N:10,00;
found:From:33,90;N:4,30;N:being 9.61.

(18.42) 2-Amino-5-pentyl-4-phosphoramidocyanidates. TPL 130°C (decomp.).

Analysis for C10H17N2About5PS:

calculated:From:38,96;N:5,56;N:a 9.09;
found:C:38,69;N:5,25;N:cent to 8.85.

(18.43) 2-Amino-5-bromo-4-phosphonomethyliminodiacetic. TPL 230°C (decomp.). Analysis for C5H6N2O5PS2Br:

calculated: 18,03;N:1,82;N:to 8.41;
found:From:is 18.40;N:1,93;N:8,18.

(18.44) 2-Amino-5-(2-furanyl)-4-phosphoramidocyanidates. TPL 230°C (decomp.).

Analysis for C9H9N2O6PS:

calculated:From:35,53;N:2,98;N:of 9.21;
found:From:35,78;N:3,05;N:8,11.

(18.45) 2-Amino-5-ethyl-4-phosphonomethyliminodiacetic. TPL 141°C (decomp.).

Analysis for C7H11N2O6R:

calculated:From:33,61;N:4,43;N:11,20;
found:From:33,79;N:4,47;N:11,09.

(18.46) 5-Methyl-4-[(N-phosphonomethyl)carbarnoyl]imidazole.

Analysis for C6H10N3O4R:

calculated:From:32,89; N:4,60;N:MT 19 : 18;
found:From:33,04;N:4,65;N:18,84.

Example 19

Obtain 3-[2-(5-phosphono)furanyl]pyrazoles

Stage A. a Solution of diethyl-5-(2-isobutyl-3-N,N-dimethylamino)acryloyl-2-parentstate (1 mmol, obtained in accordance with stage a of example 17) in ethanol is treated with hydrazine (1.2 mmol) at 80°C for 12 h of Evaporation and chromatography to give 4-isobutyl-3-[2-(5-diethylphosphino)furanyl]pyrazole.

Stage C. 4-Isobutyl-3-[2-(5-diethylphosphino)furanyl]pyrazole processed in accordance with the stage of example 3, receiving 4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole

(19.1). TPL 210-215°C.

Analysis for C11H15N2O4P:

calculated:From:48,89;N:the ceiling of 5.60;N:10,37;
found:From:48,67;N:5,55;N:10,20.

Stage C. 4-Isobutyl-3-[2-(5-diethylphosphino)furanyl]pyrazole processed in accordance with stage a of example 11, receiving 1-methyl-4-isobutyl-3-[2-(5-diethylphosphino)furanyl]pyrazole.

Stage d 1-Methyl-4-isobutyl-3-[2-(5-di is tilefono)furanyl]pyrazole processed in accordance with the stage of example 3, getting 1-methyl-4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole (19.2).

Analysis for C12H17N2O4P+0,85HBr+0,N2O:

calculated:From:39,32;N:5,32;N:of 7.64;
found:From:39,59;N:5,30;N:7,47.

Example 20

Obtain 3-[2-(5-phosphono)furanyl]isoxazole

Stage A. a Solution of 5-diethylphosphino-2-furaldehyde (1 mmol) in ethanol is treated with hydroxylamine (1.1 mmol) and sodium acetate (2.2 mmol) at 25°C for 12 hours Extraction and chromatography to give 5-diethylphosphino-2-furaldehyde.

Stage C. a Solution of 5-diethylphosphino-2-furaldehyde (1 mmol) in DMF is treated with N-chlorosuccinimide (1.1 mmol) at 25°C for 12 h of Extraction gives 5-diethylphosphino-2-chlorodibenzofuran.

Stage C. a Solution of 5-diethylphosphino-2-chlorodibenzofuran (1 mmol) and ethylpropyl (5 mmol) in diethyl ether is treated with triethylamine (2 mmol) at 25°C for 12 hours Extraction and chromatography to give 5-etoxycarbonyl-3-[2-(5-diethylphosphino)furanyl]isoxazol.

Stage D. 5-Etoxycarbonyl-3-[2-(5-diethylphosphino)furanyl]isoxazol processed in accordance with stage a of example 9, but for the eat in accordance with the stage of example 3, receiving 5-carbarnoyl-3-[2-(5-phosphono)furanyl]isoxazol (20.1).

TPL 221-225°C.

Analysis for C8H7N2About6R+0,25EtOH:

calculated:From:37,86;N:3,18;N:accounted for 10.39;
found:From:37,90;N:3,02;N:of 10.05.

In accordance with the specified method will receive the following connections.

(20.2) 5-Etoxycarbonyl-4-methyl-3-[2-(5-phosphono)furanyl]isoxazol. TPL 150-152°C.

Analysis for C11H12NO7P+0,25N2O+0,15HBr:

calculated:From:41,57;N:4,01;N:to 4.41;
found:From:41,57;N:4,20;N:4,54.

(20.3) 4,5-Bis(etoxycarbonyl)-3-[2-(5-phosphono)furanyl]isoxazol.

Analysis for C13H14NO9P:

calculated:From:43,47;N:3,93;N:3,90;
found:From:43,26; to 3.92;N:3,97.

(20.4) 5-Amino-4-etoxycarbonyl-3-[2-(5-phosphono)furanyl]isoxazol. TPL 190°C (decomp.).

Analysis for C10H11N2O7R+0,25HBr:

calculated:From:37,25;N:3,52;N:8,69;
found:From:37,56;N:3,50;N:cent to 8.85.

(20.5) 4,5-Bis(carbarnoyl)-3-[2-(5-phosphono)furanyl]isoxazol. TPL > 220°C.

Analysis for C9H8N3About7R:

calculated:From:35,90;N:2,68;N:13,95;
found:From:35,67;N:2,55;N:13,62.

(20.6) 4-Etoxycarbonyl-5-trifluoromethyl-3-[2-(5-phosphono)furanyl]isoxazol.

Analysis for C11H9F3NO7R+0,25HBr:

calculated:From:35,20;N:2,48;N:to 3.73;
found:From:35,25; N:2,34;N:3,98.

(20.7) 5-Amino-4-(2-furyl)-3-[2-(5-phosphono)furanyl]isoxazol. TPL > 220°C.

Analysis for C12H9N2O7P+0,1AcOEt:

calculated:From:44,73;N:2,97;N:to 8.41;
found:From:45,10;N:2,58;N:8,73.

(20.8) 4-Amino-5-cyano-3-[2-(5-phosphono)furanyl]isoxazol.

Analysis for C8H6N3O5P+0,1 h2O+0,2HBr:

calculated:From:35,18;N:2,36;N:15,39;
found:From:35,34;N:2,50;N:15,08.

(20.9) 4-Cyano-5-phenyl-3-[2-(5-phosphono)furanyl]isoxazol.

Analysis for C14H9N2O5P+0,15HBr:

calculated:From:51,21;N:2,81;N:8,53;
found:From:51,24;N:3,09;N: 8,33.

Example 21

Obtain 2-[2-(5-phosphono)furanyl]thiazolo

Stage A. Diethyl-5-tributylstannyl-2-furanostanol (14) and 2-bromo-4-ethoxycarbonylmethyl processed in accordance with stage a of example 6, receiving 4-etoxycarbonyl-2-[2-(5-diethylphosphino)furanyl]thiazole.

Stage C. 4-Etoxycarbonyl-2-[2-(5-diethylphosphino)furanyl]thiazole processed in accordance with stage a of example 9, and then in accordance with the stage of example 3, receiving 4-carbarnoyl-2-[2-(5-phosphono)furanyl]thiazole (21.1). TPL 239-240°C.

Analysis for C8H7N2O5PS+0,2N2O:

calculated:From:34,59;N:2,68;N:10,08;
found:From:34,65;N:2,69;N:9,84.

Example 22

Getting 4-(3,3-debtor-3-phosphono-1-propyl)thiazolo

Stage A. a Solution of 3-(tert-butyldiphenylsilyl)-1-propanol (1 mmol) in methylene chloride (7 ml) is treated with powdered molecular sieves (4Å, 0.5 EQ. wt./wt.) and chlorbromuron pyridinium (1.5 mmol) at 0°C. the resulting mixture was stirred at room temperature for 2 h, diluted with diethyl ether (7 ml) and stirred at whom atoi temperature for another 30 minutes Filtration, evaporation and chromatography to give 3-(tert-butyldiphenylsilyl)-1-propanol in the form of a clear oil.

Stage C. a Solution of LDA (1.06 mmol) in THF is treated with a solution diethyldithiophosphate (1 mmol) at -78°C for 45 minutes Then the reaction mixture is treated with a solution of 3-(tert-butyldiphenylsilyl)-1-propanal (1.07 mmol) in THF and the resulting solution was stirred at -78°C for another 4 h the Reaction is quenched by penishealthinformation (2.14 mmol) and the reaction mixture is subjected to extraction and chromatography, getting diethyl-4-(tert-butyldiphenylsilyl)-3-phenoxythiocarbonyl-2,2-deformational in the form of a clear oil.

Stage C. a Solution of diethyl-4-(tert-butyldiphenylsilyl)-3-phenoxythiocarbonyl-2,2-deformational (1 mmol) in toluene (1 ml) is treated with a hydride tri-n-butyanova (1.5 mmol) and AIBN (0.1 mmol) and the reaction mixture is refluxed for 2 hours Evaporation and chromatography to give diethyl-4-(tert-butyldiphenylsilyl)-2,2-deformational in the form of a clear oil.

Stage D. a Solution of diethyl-4-(tert-butyldiphenylsilyl)-2,2-deformational (1 mmol) in methanol (1 ml) is treated with hydrochloric acid (4N, 4 mmol) at 0°and the resulting reaction mixture was stirred at room temperature for 2 hours Evaporation and chrome is tography give diethyl-4-hydroxy-2,2-deformational in the form of a clear oil.

Stage means that the Solution obtained diethyl-4-hydroxy-2,2-deformational (1 mmol) in acetone (10 ml) is treated with Jones reagent (10 mmol) at 0°C for 30 minutes the Reaction is quenched with 2-propanol (10 ml) and the resulting mixture was filtered through a layer of celite. Evaporation of the filtrate, followed by extraction gives diethyl-3-carboxy-2,3-deformability in the form of oil.

Stage F. a Solution of diethyl-3-carboxy-2,3-debtorprotection (1 mmol) in thionyl chloride (3 ml) is refluxed for 2 hours, the Reaction mixture was evaporated to dryness, the residue dissolved in diethyl ether (1 ml) and treated with an ethereal solution of diazomethane (10 mmol) at 0°C for 30 min. the reaction mixture was added a solution of HBr in acetic acid (30%, 1 ml) and the resulting solution was stirred at room temperature for 1 h, the Reaction mixture was evaporated to dryness and the residue dissolved in a mixture of THF-EtOH (1:1.5 ml) and treated with thiourea (1 mmol). The resulting reaction mixture is heated to 75°C for 1 h Evaporation followed by extraction and chromatography gives 2-amino-4-[1-(3-diethylphosphino-3,3-debtor)propyl]thiazole in the form of solid, which is subjected to processing in accordance with the stage of example 3, obtaining 2-amino-4-[1-(3-phosphono-3,3-debtor)propyl]thiazole (22.1) as a solid.

Analysis for C6H9N2O3 PSF2+HBr:

calculated:From:each holding 21.25;N:2,97;N:compared to 8.26;
found:From:21,24;H:3,25;N:8,21.

In a similar way we obtain 2-amino-5-methylthio-4-[1-(3-phosphono-3,3-debtor)propyl]thiazole (22,2). MS: m/e 305 (M+H).

Example 23

Getting 2-methylthio-5-phosphonomethyl-1,3,4-thiadiazole and 2-phosphonomethylglycine

Stage A. a Solution of 2-methylthio-1,3,4-thiadiazole-5-thiol (1 mmol) in THF (5 ml) is treated with sodium hydride (60%, 1.1 mmol) at 0°and the resulting mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was cooled to 0°and treat diethylphosphonoacetate (1.1 mmol). After stirring at room temperature for 12 h the reaction is quenched with saturated ammonium chloride. Extraction and chromatography gave 2-methylthio-5-diethylphosphoramidite-1,3,4-thiadiazole in the form of oil.

Stage C. 2-Methylthio-5-diethylphosphoramidite-1,3,4-thiadiazole processed in accordance with the stage of example 3, obtaining 2-methylthio-5-phosphonomethyl-1,3,4-thiadiazole (23.1) as a yellow solid.

Analysis for C4H7N2About3PS3+0,2HBr

calculated:From:17,50;N:2,64;N:of 10.21;
found:From:17,64;N:2,56;N:10,00.

Alternative phosphonomethylglycine heteroaromatic compounds receive, using the following method, illustrated by the synthesis of 2-phosphonomethylglycine.

Stage C. a Solution of 2,2'-veridicality (1 mmol) in THF is treated with tri-n-butylphosphine (1 mmol) and diethylhydroxylamine at 0°C. the resulting reaction solution was stirred at room temperature for 18 hours Extraction and chromatography to give 2-diethylphosphonoacetate in the form of a yellow oil.

Stage D. 2-Diethylphosphonoacetate processed in accordance with the stage of example 3, obtaining 2-phosphonomethylglycine (23.2) as a yellow solid. Analysis for C6H8NO3PS+0,62HBr:

calculated:From:28,22;N:3,40;N:5,49;
found:From:28,48;N:3,75;N: 5,14.

Example 24

Getting 2-[(2-phosphono)ethinyl]pyridine

Stage A. a Solution of 2-ethynylpyridine (1 mmol) in THF (5 ml) is treated with LDA (1.2 mmol) at 0°C for 40 minutes To the reaction mixture add diethylphosphate (1.2 mmol) and the resulting reaction solution was stirred at room temperature for 16 hours the Reaction is quenched with saturated ammonium chloride and then subjected to extraction and chromatography, obtaining 2-[(2-diethylphosphino)ethinyl]pyridine as a yellow oil.

Stage C. 2-[(2-Diethylphosphino)ethinyl]pyridine treated in accordance with the stage of example 3, obtaining 2-[1-(2-phosphono)ethinyl]pyridine (24.1) as a brown solid. TPL 160°C (decomp.), MS: m/e 184 (M+H).

Example 25

Getting 5-[2-(5-phosphono)furanyl]tetrazole

Stage A. To a mixture of tetrazole (1 mmol) and powdered To2CO3(1.5 mmol) in 1 ml DMF, cooled to 0°add benzylcarbamoyl simple ester (1.2 mmol) and the resulting mixture stirred for 30 min at 0°and then for 16 h at room temperature. The mixture is diluted with water and ether. Extraction and chromatography gave 2-benzyloxyethanol in the form of a colorless oil.

Stage C. To a solution of 2-benzyloxyethanol (1 mmol) and TMEDA (2 mmol) in 3 ml of diethyl ether at -78°add n-BuLi in hexano (1 mmol). The mixture autosmooth mixed for 5 min at -78° And then it is added to pre-cooled (-78° (C) a solution of (n-Bu)3SnCl (1 mmol) in 2 ml of diethyl ether. After stirring at -78°C for 30 min, the reaction mixture was diluted with water and diethyl ether. Extraction and chromatography gave 2-benzoyloxymethyl-5-(tributylstannyl)tetrazol in the form of a colorless oil.

Stage C. a Mixture of 5-iodine-2-diethylphosphonate (1 mmol), 2-benzoyloxymethyl-5-(tributylstannyl)tetrazole (1.05 mmol), tetrakis(triphenylphosphine)palladium (0) (0.03 mmol) and copper iodide (I) (0.07 mmol) in 3 ml of toluene is refluxed at 110°C for 20 hours Evaporation and chromatography to provide 2-benzoyloxymethyl-5-[2-(5-diethylphosphino)furanyl]tetrazole in the form of oil.

Stage D. a Mixture of 2-benzoyloxymethyl-5-[2-(5-diethylphosphino)furanyl]tetrazole (1 mmol) and 6M HCl (1 ml) in 10 ml of ethanol is heated at 70°C for 20 h and then the solvent is concentrated by evaporation, alkalinized 1N NaOH and extracted with EtOAc. The aqueous layer is acidified and extracted with EtOAc. EtOAc extract evaporated, receiving 5-[2-(5-diethylphosphino)furanyl]tetrazole in the form of solid, which is subjected to processing in accordance with the stage of example 3, receiving 5-[2-(5-phosphono)furanyl]tetrazole (25.1) in the form of solids: TPL 186-188°C.

Analysis for C5H5N4O4P+1,5H2O:

calculated:From:24,70;N:3,32;N:23,05;
found:From:a 24.57;N:to 2.57;N:23,05.

Stage E.

Stage 1. A mixture of 5-[2-(5-diethylphosphino)furanyl]tetrazole (1 mmol), 1-iodine-2-methylpropane (2 mmol) and powdered To2CO3(2 mmol) in 5 ml DMF was stirred at 80°C for 48 h and then diluted with CH2Cl2and water and the layers separated. CH2Cl2layer evaporated and combined with the product of the following reaction for carrying out chromatography.

Stage 2. The aqueous layer was stage 1 is acidified and extracted with EtOAc. The obtained extract was evaporated and the residue is heated at 80°With 2 ml SOCl2for 3 h and then the solvent is evaporated. The residue is dissolved in 5 ml of CH2Cl2and add 0.3 ml NEt3and 0.5 ml of EtOH. After stirring for 1 h at room temperature the mixture was diluted with CH2Cl2and water. The organic extract combine with CH2Cl2the layer obtained in stage 1, and subjected to chromatography, obtaining 1-isobutyl-5-[2-(5-diethylphosphino)furanyl]tetrazole and 2-isobutyl-5-[2-(5-diethylphosphino)furanyl]tetrazole, each in the form of oil.

Stage 3. 1-Isobutyl-5-[2-(5-diethylphosphino)furanyl]tetrazole all Laut processing in accordance with the stage of example 3, getting 1-isobutyl-5-[2-(5-diethylphosphino)furanyl]tetrazole (25.2) in the form of solids. TPL 200-202°C.

Analysis for C9H13N4O4P:

calculated:From:39,71;N:4,81;N:20,58;
found:From:39,64;H:4,63;N:20,21.

Stage F. the Mixture of 2-isobutyl-5-[2-(5-diethylphosphino)furanyl]tetrazole (1 mmol) and TMSBr (10 mmol) in 10 ml of CH2Cl2stirred at room temperature for 16 hours the Solvent is evaporated and the residue dissolved in a mixture of 10:1 CH3CN:water, solvent is evaporated and the residue precipitated from acetone by the addition of dicyclohexylamine (2 mmol)to give N,N-dicyclohexylamine salt of 2-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole (25.3) in the form of solids. TPL 226-228°C.

Analysis for C9H13N4O4R+C12H23N:

calculated:From:55,62;N:8,00;N:15,44;
found:From:55,55;N:8,03;N:15,07.

When is EP 26

High-efficiency synthesis of various 2-(5-phosphono)furnishedin heteroaromatic compounds

Phase A. Similarly, the method steps In example 15 receive various 2-(5-diethylphosphino)furnishedin heteroaromatic compounds and some of these compounds are used for high-performance synthesis of compounds listed in Table 26.1 and 26.2.

Stage C. a Mixture of 2-chloro-6-[2-(5-diethylphosphino)furanyl]pyridine (0.01 mmol) and TMSBr (0.1 ml) in CH2Cl2(0.5 ml) was stirred at room temperature for 16 h and then evaporated and diluted with 0.5 ml of a mixture of 9:1 CH3CN:water. Evaporation gives 2-chloro-6-[2-(5-phosphono)furanyl]pyridine.

Stage C. a Mixture of 2-chloro-6-[2-(5-diethylphosphino)furanyl]pyridine (0.01 mmol) and solution of their propoxide sodium propanol (0,25M, 0.4 ml) maintained at 85°C for 14 h, the Reaction mixture was evaporated and the residue is subjected to processing in accordance with stage b of example 26, receiving 2-propyloxy-6-[2-(5-phosphono)furanyl]pyridine.

Stage D. a Mixture of 2-chloro-6-[2-(5-diethylphosphino)furanyl]pyridine (0.01 mmol) and 1-methylpiperazine (0.2 ml) in ethylene glycol (0.2 ml) is heated at 145°within 24 hours the mixture is Then diluted with 0.5 ml of CH3CN and 0.1 ml of water and then add 150 mg formiates resin Dowex 12-100. After 30 minutes of mixing the resin is filtered and washed On the f (2× 10 ml), CH3CN (2×10 ml) and then with a mixture of 9:1 CH3CN:water (1×10 ml). Finally, the resin is stirred with a mixture of 9:1 TFU:water for 30 min, filtered and the filtrate evaporated. The resulting residue is subjected to processing in accordance with stage b of example 26, receiving 2-[1-(4-methyl)piperazinil]-6-[2-(5-phosphono)furanyl]pyridine.

Phase that is a Mixture of 3-chloro-5-[2-(5-diethylphosphino)furanyl] pyrazine (0.01 mmol), 5-tributylstannyl (0.04 mmol), Pd(PPh3)4(0.001 mmol) and CuI (0.002 mmol) in dioxane (0.5 ml) is heated at 85°C for 16 h, then the solvent is evaporated. The obtained residue and TMSBr (0.1 ml) in 0.5 ml of CH2Cl2stirred at room temperature for 16 h, then evaporated and diluted with 0.5 ml of a mixture of 9:1 CH3CN:water. To the solution was added 150 mg formiates resin Dowex 12-100 and after 30 minutes of mixing the resin is filtered and washed with DMF (2×10 ml), CH3CN (2×10 ml) and then with a mixture of 9:1 CH3CN:water (1×10 ml). Finally, the resin is stirred with a mixture of 9:1 TFU:water for 30 min, filtered and the filtrate is evaporated, obtaining 3-(2-thienyl)-5-[2-(5-phosphono)furanyl]pyrazin.

Stage F. a Mixture of 3-chloro-5-[2-(5-diethylphosphino)furanyl]pyrazine (0.01 mmol), 1-hexyne (0.04 mmol), diisopropylethylamine (0.1 mmol), Pd(PPh3)4(0.001 mmol) and CuI (0.002 mmol) in dioxane (0.5 ml) is heated at 85°C for 16 h, then the solvent volume is more. The resulting residue is subjected to processing in accordance with stage b of example 26, receiving 3-(1-hexyne-1-yl)-5-[2-(5-phosphono)furanyl]pyrazin.

Getting carboxymethylstarch resin

Stage G. the Solution trimethylphosphate (30,9 mmol), 2-(trimethylsilyl)ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene (25 ml) is refluxed for 48 h in an atmosphere of N2. After cooling, the solution was diluted with EtOAc and washed with 1N HCl and then with water. The organic solution is dried over sodium sulfate and concentrated in vacuo, obtaining oil. The residue is treated LiI (10.4 mmol) in 2-butanone (30 ml) and refluxed over night in an atmosphere of N2. The solution was diluted with EtOAc, washed with 1N HCl, dried over Na2SO4and concentrated in vacuo, obtaining the SEM protected carboxymethylation in the form of a colorless oil.

Stage N. Hydroxymatairesinol (2,35 mmol) receive for the binding, combined with anhydrous THF (40 ml), carefully shaking for 20 min and then removing the excess solvent by means of a cannula. This procedure was repeated 3 times. Then the swollen resin was suspended in THF (40 ml) and DIPEA (to 21.2 mmol). To this mixture, via cannula, a solution of SEM-protected carboxymethylphosphinates (obtained in stage G) (7.1 mmol), DIAD (7.1 mmol) and Tris(4-chlorophenyl)phosphine (7.1 mmol) in THF (15 ml), kotoryjrazrabatyvaet for 15 min before adding. After shaking the mixture overnight under a layer of N2the resin is filtered off, washed with THF (3×40 ml), DMF (3×40 ml) and again THF (3×40 ml), then dried in vacuum, obtaining 3.8 g associated phosphonate resin.

Stage I. To related phosphonate resin (2,41 mmol) in THF (100 ml) is added 1M TBAF in THF solution (12 ml). The mixture is shaken overnight, then filtered and the resin washed with THF (3×40 ml)to give the desired carboxymethylthio resin in the form of tetrabutylammonium salt.

The combination carboxymethylstarch resin with the heteroaromatic amine

Stage I. In 2-ml vessel unite heteroaromatic amine (0.14 mmol), resin (0.014 mmol), Rubor (0.14 mmol) and TEA (0.36 mmol) in DMF (1,45 ml) and shaken for 48 h at room temperature. Then the treated resin is filtered off, washed with DMF (3x) and CH2Cl2(3). The selected resin is again suspended in CH2Cl2(900 ml), combined with TMSBr (100 μl) and stirred for 6 hours the Mixture is filtered, the resin washed with anhydrous CH2Cl2(500 ml) and the filtrate concentrated in vacuo. To the selected residue is added a solution of CH3CN/N2O (9:1, 300 ml). After shaking for 30 min the solvents are removed, obtaining required [{N-(phosphono)acetyl]amino}substituted heteroaromatic analogues. In accordance with the data met what digami synthesized compounds 26.97-26.119 and 26.146-26.164, which are presented in Table Table 26.1 and 26.2.

Getting aminomethylphosphonate resin

Stage K. the solution dimethylphenylphosphine (37 mmol) in 2-butanone (150 ml) was added LiI (for 38.9 mmol). After boiling under reflux overnight in an atmosphere of N2the solution was diluted with EtOAc, washed with 1N HCl, dried over MgSO4and concentrated in vacuo, getting monomethyldibenzothiophene in the form of a white solid.

Stage L. As described above at the stage N, monomethyldibenzothiophene are combined with hydroxymethylglutaryl, getting associated with resin phthalimidomethyl onomatology ester.

Stage M To the linked resin phthalimidomethyl monomethionine complex ether (6.8 mmol) in DMF (7 ml) is added anhydrous hydrazine (3 ml). After shaking at room temperature for 24 h the resin was filtered, washed with DMF (3×10 ml), CH2Cl2(3×10 ml) and then dried in vacuum, obtaining 832 mg of the desired associated with resin aminomethylphosphonate nanometrology of ester.

The combination of various heteroaromatic carboxylic acids linked resin aminomethylphosphonate monometallism complex air

Stage N. In 2-ml tube combine heteroaromatic carboxylic acid (0.2 mmol), see the Lu (0.02 mmol), EDC (0.2 mmol) and NOUT (0.2 mmol) in DMF (0.5 ml) and shaken for 24 h at room temperature. Then the treated resin was filtered, washed with DMF (3x) and CH2Cl2(3). The selected resin is again suspended in CH2Cl2(500 µl), together with TMSBr (50 ál) and mixed for 6 hours the Mixture is filtered, the resin washed with anhydrous CH2Cl2(500 ml) and the filtrate concentrated in vacuo. To the selected residue is added a solution of CH3CN/N2O (9:1, 300 ml). After shaking for 30 min the solvents are removed, obtaining the required (N-phosphonomethyl)carbamoylation heteroaromatic analogues. In accordance with the methods of the synthesized compounds 26.120-26.145, which are presented in Table 26.2.

The following connections get in line with some of the above methods or by using all the above methods. These compounds were characterized using HPLC (as described below) and mass spectrometry (chemical ionization at atmospheric pressure (APCI), negative ion), and these characteristic data are presented in Table Table 26.1 and 26.2.

HPLC is carried out, using a column YMC ODS-Aq, Aq-303-5, 250×4.6 mm ID, particle size S-5 μm, pore size 120 Å, with the UV detector set at 280 nm.

The program elution HPLC: flow rate of 1.5 ml/min

Time (min)% acetonitrile (A)% buffera(In)
01090
7,59010
12,49010
12,51090
151090
andBuffer = 95:5:0.1 to water:methanol:acetic acid

TABLE 26.1
Room syntheti. exampleAndInXY'HPLC

time by keeping. (min)
M-1

found
26.146NBrNHC(O)CH2Sto 6.58299/301
26.147NPhNHC(O)CH2Sto 6.57297
26.148PhNNHC(O)CH2Sthe 6.06297
26.149PhEtNHC(O)CH2 O309
26.150NNNHC(O)CH2S4,22221
26.151of substitutedMeNHC(O)CH2S6,59369
26.152Bu-tBrNHC(O)CH2S6,62355/357
26.153NPh(-4-Br)NHC(O)CH2S6,62375/377
Room syntheti. exampleA*In*XY'HPLC

time by keeping. (min)
M-1

found
26.154NNNHC(O)CH2Oof 6.68205
26.155noNH2NHC(O)CH2O6,6221
26.156NHMenoNHC(O)CH2S3,82251
26.157MeNNHC(O)CH2
26.158NNNHC(O)CH2NH
26.159HENNHC(O)CH2NH
26.160Bu-tNNHC(O)CH2O6,62261
26.161no3-pyridylNHC(O)CH2Oto 6.58283
26.162CH2-Ph-(2,6-dichloro)noNHC(O)CH2O
26.163Brnofuran-2,5-diylNH4,46292/294
26.164Brnofuran-2,5-diylS5,96309/311
* when a or b is missing, then the corresponding G is N.

td align="center"> CF3 26.42 312
TABLE 26.2
Room syntheti. exampleA*In*XD*E*HPLC

time by keeping. (min)
M-1

found
26.1NH2Clfuran-2,5-diylMenull11,06288
26.2HOC(O)(Ph-2,6-dichloro)furan-2,5-diylNN3,99413
26.3OMeNfuran-2,5-diylCH2OHNto 8.34284
26.4OMeNfuran-2,5-diylC(O)NH2N8,23297
26.5OMeNfuran-2,5-diylCO2NN9,54298
26.6HENfuran-2,5-diylCF3C(O)NH23,91351
26.7OMeNfuran-2,5-diylC(O)NH29,14365
26.8OTSG.Nfuran-2,5-diylNOMe9,72255
26.9no.Nfuran-2,5-diylNHEto 4.52241
26.10HENfuran-2,5-diylMeno.3,79255
26.11OMeNfuran-2,5-diylMeno.6,44269
26.12NH2nofuran-2,5-diylHEN3,96256
26.13NH2nofuran-2,5-diylOMeN8,02270
26.14NOMefuran-2,5-diylno.N7,22255
26.15NHEfuran-2,5-diylno.N4,82241
OMeNfuran-2,5-diylno.Nof 7.48255
At 26.17OEtNfuran-2,5-diylNN9,72268
26.18OEtNfuran-2,5-diylCH2OHN5,26298
26.19no.Nfuran-2,5-diylMeOEt7,80283
26.20no.Nfuran-2,5-diylMeHE3,80255
26.21HENfuran-2,5-diylMeno.of 3.77255
26.22OEtNfuran-2,5-diylMeno.7,33283
26.23NH2nofuran-2,5-diylHEN3,94256
26.24NH2nofuran-2,5-diylOEt N5,66284
26.25NH2Nfuran-2,5-diylOEtno.5,90284
26.26NH2Nfuran-2,5-diylHEno.3,78256
At 26.27NOEtfuran-2,5-diylno.N9,74269
26.28NHEfuran-2,5-diylno.N4,81241
At 26.29OEtNfuran-2,5-diylno.N9,78269
26.30BrNfuran-2,5-diylNNO27,78347/349
26.31ClNfuran-2,5-diylNC(O)OEtRS 9.69330
At 26.32BrNfuran-2,5-diylNC(O)OEtRS 9.69374/376
26.33ClN furan-2,5-diylMeC(O)NH23,72315
26.34ClCF3furan-2,5-diylNCF39,04394
26.35ClNfuran-2,5-diylNH2H4,89273
At 26.36ClNfuran-2,5-diylCNHto 7.93283
26.37ClNfuran-2,5-diylCH2OHH5,38288
26.38ClNfuran-2,5-diylC(O)NH2Hto 5.57301
26.39ClNfuran-2,5-diylC(O)OEtH8,54330
26.40Cl1-triazinyl-(3-amino-5-methyl-thio)furan-2,5-diylNH8,91398
26.41ClNfuran-2,5-diylMeCNby 8.22297
ClNfuran-2,5-diylCF3NH28,60341
26.43ClNfuran-2,5-diylCF3CN8,66351
26.44no.CH3furan-2,5-diylMeBra 9.25331/333
26.45no.CH3furan-2,5-diylMeCla 9.25287
26.46BrCH3furan-2,5-diylNno.5,62317/319
26.47BrBrfuran-2,5-diylNno.3,54381/383/ 385
26.48BrNfuran-2,5-diylMeno.5,55317/319
26.49NNH2furan-2,5-diylBrno.4,78318/320
26.50BrClfuran-2,5-d is Il Brno.scored 8.38417/419
26.51SMePhfuran-2,5-diylBrno.9,26425/427
26.52NH2Nfuran-2,5-diylBrno.4,87318/320
26.53NH2Nfuran-2,5-diylHEno.3,70256
26.54BrNfuran-2,5-diylBrno.for 9.64381/383/385
26.55BrNfuran-2,5-diylClno.for 9.64337/339
26.56NBrfuran-2,5-diylno.N5,08303/305
26.57NH2Clfuran-2,5-diylno.C(O)OMe3,34332
At 26.58OPr-nNfuran-2,5-diylMeno.8,14 297
26.59NOPr-nfuran-2,5-diylno.N8,45283
26.60NO(CH2)2-OEtfuran-2,5-diylno.N7,82313
26.61NH2no.furan-2,5-diylHEN3,97256
26.62NH2no.furan-2,5-diylOPr-nNto 7.84298
26.63OPr-nHfuran-2,5-diylCH2HEN4,36312
At 26.64OBu-nHfuran-2,5-diylCH2HEN8,58326
26.65O-(CH2)2-OEtHfuran-2,5-diylCH2HEN4,13342
26.66NN2Hfuran-2,5-diylOPr-nno.of 7.96298
26.67 NH2Hfuran-2,5-diylOBu-nno.3,86312
26.68HOBu-hardfuran-2,5-diylnoN8,80297
At 26.69NO(CH2)2-OEtfuran-2,5-diylnoN7,14299
26.70HO(CH2)2-NMe2,furan-2,5-diylnoN4,57312
26.71NH2no.furan-2,5-diylOBu-hardNof 8.06312
26.72NH2no.furan-2,5-diylO(CH2)2OmeN4,84314
26.73NH2Hfuran-2,5-diylOBu-hardno.8,70312
26.74BrHfuran-2,5-diylC(O)NH2N7,68346/348
26.7 NH2no.furan-2,5-diylClN4,77274
26.76NH-(CH2)2-OHHfuran-2,5-diylMeno.4,56298
26.77HNH(CH2)2OHfuran-2,5-diylNoN4,55284
26.78NH2no.furan-2,5-diylNH-(CH2HEN4,58299
26.79NH-(CH2)2-OHHfuran-2,5-diylNH2OTSG.4,58299
26.80NH-(CH2)2-OHHfuran-2,5-diylCH2OHNof 4.44313
At 26.81NH2Hfuran-2,5-diylNH-(CH2HEno.4,33299
26.82NH-CH-CH-(OH)-IUNfuran-2,5-diylSNno.4,65
At 26.83NH2nofuran-2,5-diylNHCH2-CH(OH)-IUN4,63313
26.84NH-CH2-CH-(OH)- MeNfuran-2,5-diylNH2no.4,63313
26.85NH-CH2-CH-(OH)-IUNfuran-2,5-diylCH2HENto 4.52327
26.86NH2Nfuran-2,5-diylNHCH2-CH(OH)-IUno.4,65313
At 26.87NH-(CH2)3-HENfuran-2,5-diylMeno.to 4.62312
26.88NH2nofuran-2,5-diylNH-(CH2)3HEN4,48313
26.89NH-(CH2)3-HENfuran-2,5-diylNH2no.4,48313
26.90NH2NH-(CH2) 3-HEfuran-2,5-diylno.C(O)NH-(CH2)3HE4,76414
26.91N4-morpho-linylfuran-2,5-diylno.N6,46310
26.924-morpholinylNfuran-2,5-diylMeno.6,53324
26.93NH2no.furan-2,5-diyl4-morpholinylN6,15325
26.944-morpholinylNfuran-2,5-diylNH2no.4,84325
26.95NH24-morpholinylfuran-2,5-diylno.C(O)-(4-morpholinyl7,47438
26.96NH2Nfuran-2,5-diyl4-morpholinylno.and 5.30325
26.97MeNNHC(O)CH2HHto 6.58229
26.9 HMeNHC(O)CH2HH6,60229
26.99NH2NNHC(O)CH2HCl6,63264
26.100NH2ClNHC(O)CH2HH6,63264
26.101NHENHC(O)CH2HH6,54231
26.102MeNNHC(O)CH2MeH6,59243
26.103NNNHC(O)CH2HCl7,02249
26.104NNNHC(O)CH2HBr8,01293/295
26.105MeNNHC(O)CH2HBr6,64307/309
26.106NNNHC(O)CH2HH6,72215
26,107 NNHC(O)CH2HMe6,54229
26.108NNNHC(O)CH2MeH6,53229
26.109MeClNHC(O)CH2Meno.3,93279
26.110ClNNHC(O)CH2no.H4,20251
26.111NBrNHC(O)CH2HMe6,44307/309
26.112NH2NNHC(O)CH2NH-(Ph-4-Br)no.4,42401/403
26.113NH2BnNHC(O)CH2HBnof 6.49410
26.114NNNHC(O)CH2EtHto 6.57243
26.115MeEtNHC(O)CH2HH6,54257
MeNNHC(O)CH2HVG6,55307/309
26.117NBrNHC(O)CH2HMe6,51307/309
26.118NMeNHC(O)CH2HVG6,52307/309
26.119MeBrNHC(O)CH2HVGto 6.19385/387/389
26.120NNC(O)NHCH2HH3,74215
26.121MeNC(O)NHCH2HH229
26.122HENC(O)NHCH2HH3,72231
26.123BrNC(O)NHCH2HH5,02293/295
26.124ClNC(O)NHCH2HH4,60249/251
26.125 NNC(O)NHCH2ClH5,18249/251
26.126NBrC(O)NHCH2OHH3,60310/312
26.127NNC(O)NHCH2no.H3,70216
26.128NNC(O)NHCH2NO2H5,00260
26.129NNC(O)NHCH2HBu-n8,35271
26.130NOPr-nC(O)NHCH2HH7,46273
26.131ClClC(O)NHCH2HH4,23283/285/ 287
26.132ClCF3C(O)NHCH2HH8,05317/319
26.133NClC(O)NHCH2HCF3of 6.49317/319
NClC(O)NHCH2ClCl7,20318/320/ 322
26.135NC(O)PhC(O)NHCH2HH7,00319
26.136NOEtC(O)NHCH2HCF36,65327
26.137SMeClC(O)NHCH2Hno.of 5.82296/298
26.138SMeBrC(O)NHCH2Hno.of 5.40340/342
26.139NO(Ph-3-CF3)C(O)NHCH2no.H376
26.140NNC(O)NHCH2no.Me3,75230
26.141NMeC(O)NHCH2HH4,96229
26.142ClClC(O)NHCH2ClCl351/353/ 355/357
26.143NFC(O)NHCH2OHno.250
26.144MeFC(O)NHCH2OHno.264
26.145HEFC(O)NHCH2OHno.3,93266
* when a, b, D or E are absent, then the corresponding G' is n

Section 2

The synthesis of compounds of formula X

Example 27

Obtaining 2-amino-4-phosphonomethoxy-6-bromobenzimidazole

Stage A. a Solution of AlCl3(5 mmol) in EtSH (10 ml) cooled to 0°and treated With 2-amino-4-methoxybenzothiazole (1 mmol). The mixture is stirred at 0-5°C for 2 hours Evaporation and extraction give 2-amino-4-hydroxybenzothiazole in the form of a white solid.

Stage C. a Mixture of 2-amino-4-hydroxybenzothiazole (1 mmol) and NaH (1.3 mmol) in DMF (5 ml) stirred at 0°C for 10 min and then treated diethylphosphoramidite what formatlangandan (1.2 mmol). After stirring at room temperature for 8 h, the reaction mixture was subjected to extraction and chromatography, obtaining 2-amino-4-diethylphosphonoacetate in the form of oil.

Stage C. a Solution of 2-amino-4-diethylphosphonoacetate (1 mmol) in Asón (6 ml) is cooled to 10°and treated With bromine (1.5 mmol) in Asón (2 ml). After 5 min the mixture is stirred at room temperature for 2.5 hours, a Yellow precipitate is collected by filtration and washed with CH2Cl2getting 2-amino-4-diethylphosphonoacetate-6-bromobenzimidazole.

Stage D. a Solution of 2-amino-4-diethylphosphonoacetate-6-bromobenzimidazole (1 mmol) in CH2Cl2(4 ml) is treated with TMSBr (10 mmol) at 0°C. After stirring for 8 h at room temperature the reaction mixture is evaporated to dryness and the residue absorb water (5 ml). The precipitate is collected by filtration and washed with water, obtaining 2-amino-4-phosphonomethoxy-6-bromobenzimidazole (27.1) in the form of solids. TPL > 220°C (decomp.).

Analysis for C8H8N2O4PSBr:

calculated:From:of 28.34;N:2,38;N:compared to 8.26;
found:From:weighing 28.32;N:2,24;N: 8,06.

Similarly, in accordance with the above-described methods have the connection (27.2) - 2-amino-4-phosphonomethyliminodiacetic. TPL > 250°C (decomp.).

Analysis for C8H9N2O4PS+0,4H2About:

calculated:From:35,93;N:3,69;N:10,48;
found:From:35,90;N:3,37;N:10,37.

Example 28

Obtaining 2-amino-4-phosphonomethoxy-6-bromo-7-chlorobenzothiazole

Stage A. a Solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmol) in chloroform (10 ml) is cooled to 10°and treated With bromine (2.2 mmol) in chloroform (10 ml). The reaction mixture is stirred at 10°C for 20 min and at room temperature for 0.5 h, the resulting suspension is heated at boiling temperature under reflux for 0.5 hours the Precipitate is collected by filtration (washed with CH2Cl2)to give 2-amino-4-methoxy-7-chlorobenzothiazole, which is treated in accordance with the stages a, b, C and D of example 27, receiving 2-amino-4-phosphonomethoxy-6-bromo-7-chlorobenzothiazole (28.1). TPL > 220°C (decomp.).

Analysis for C8H7N2O4PSClBr:

calculated:C:25,72;H:1,89;N:7,50;
found:C:25,66;H:1,67;N:7.23 percent.

Similarly, in accordance with the above-described methods have the following connections.

(28.2) 2-Amino-4-phosphonomethoxy-6-bromo-7-methylbenzothiazol. TPL > 220°C (decomp.).

Analysis for C9H10N2O4PSBr:

calculated:From:30,61;N:2,85;N:7,93;
found:From:30,25;H:2,50;N:to 7.77.

(28.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazol. TPL > 220°C (decomp.).

Analysis for C9H11N2O4PS+1,0N2O:

calculated:From:36,99;N:4,48;N:9,59;
found:From:36,73;N:4,23;N:9,38.

(28.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole. TPL > 220°C (decomp.).

Analysis for C8H8N2O4PSCl+0,1 h2O:

calculated:From:32,41;N:2,79;N:9,45;
found:From:32,21;N:2,74;N:which 9.22.

Example 29

Obtaining 2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazol

Stage A. 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalen processed in accordance with stage b of example 27, receiving 3-amino-2-diethylphosphonoacetate-5,6,7,8-tetrahydronaphthalen.

Stage C. a Solution of KSCN (16 mmol) and CuSO4(7.7 mmol) in Meon (10 ml) is treated with a solution of 3-amino-2-diethylphosphonoacetate-5,6,7,8-tetrahydronaphthalene (1 mmol) in Meon (5 ml) at room temperature. The mixture is heated at the boiling point under reflux for 2 hours Filtration, extraction and chromatography gave 2-amino-4-diethylphosphonoacetate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole in the form of a light brown solid.

Stage C. 2-Amino-4-diethylphosphonoacetate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole processed in accordance with the stage D of example 27, receiving 2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole (29.1). TLL > 220°C (decomp.).

Analysis for 12H15N2O4PS+0,5SH2O:

calculated:From:45,86;N:4,81;N:8,91;
found:From:44,68;N:4,77;N:8,73.

In accordance with the above-described methods have the following connections.

(29.2) 2-Amino-4-phosphonomethoxy[1,2-d]negotiator. TPL > 240°C (decomp.).

Analysis for C12H11N2About4PS+0,2HBr:

calculated:From:44,15;N:of 3.46;N:8,58;
found:From:44,13;N:of 3.46;N:8,59.

(29.3) 2-Amino-5,7-dimethyl-6-thiocyanato-4-phosphoramidocyanidates. TPL > 240°C (decomp.).

Analysis for C11H12N3O4PS2+0,2CH2Cl2:

calculated:From:37,13;N:3,45;N:11,60;
found:From:37,03;N:3,25; N:11,65.

(29.4) Based on 2-hydroxy-5-phenylaniline and using the same sequence of reactions as described above, was obtained 2-amino-7-phenyl-6-thiocyanato-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C15H12N3O4PS2+0,2N2O:

calculated:From:45,38;N:3,15;N:of 10.58;
found:From:45,25;N:3,21;N:10,53.

(29.5) Based on 2-hydroxy-3,5-dichloro-4-methylaniline and using the same sequence of reactions as described above (except that the phase cyclization is carried out, using the B2, AcOH way, i.e. phase a of example 33), get 2-amino-5,7-dichloro-6-methyl-4-phosphoramidocyanidates. TPL > 230°C (decomp.).

Analysis for C9H9N2O4PSCl2:

calculated:From:31,50;N:2,64;N:8,16;
found:From:31,61;H:2,66;N:8,08.

(29.6) Based on the C 2-hydroxy-4-methoxycarbonylamino and using the same sequence of reactions, as stated above, get the 2-amino-4-phosphonomethoxy-6-carboxybenzoyl. TPL > 230°C (decomp.).

Analysis for C9H9N2About6PS:

calculated:From:35,53N:2,98;N:of 9.21;
found:From:35,56;N:3,26N:9,03.

Example 30

Obtaining 2-amino-7-methoxy-6-thiocyanato-4-phosphonomethyliminodiacetic

Stage A. 2-Hydroxy-5-methoxyethanol processed in accordance with stage b of example 27, receiving 2-diethylphosphonoacetate-5-methoxyethanol.

Stage C. a Solution of SnCl2(4 mmol) in their methanolic HCl (10 ml) is added to a cold (0° (C) to a solution of 2-diethylphosphonoacetate-5-methoxyethanol (1 mmol) in Meon (5 ml). The mixture is heated to room temperature and stirred for 3 hours Evaporation, extraction and chromatography to give 2-diethylphosphonoacetate-5-methoxyaniline.

Stage C. 2-Diethylphosphonoacetate-5-methoxyaniline processed in accordance with stage b of example 29, receiving 2-amino-4-diethylphosphonoacetate-6-thiocyano-7-methoxybenzothiazole, which is treated in accordance with the stage D of example 27, received the 2-amino-7-methoxy-6-thiocyanato-4-phosphoramidocyanidates (30.1). TPL > 170°C (decomp.).

Analysis for C10H10N3O5PS2:

calculated:From:34,58N:2,90;N:12,10;
found:From:34,23N:2,68N:11,77.

Similarly, in accordance with the above methods have the following connections.

(30.2) 2-Amino-5,6-debtor-4-phosphoramidocyanidates. TPL > 240°C (decomp.).

Analysis for C8H7N2O4PSF2:

calculated:From:32,44;N:2,38;N:9,46;
found:From:32,30;N:of 2.26;N:9,17.

(30.3) 2-Amino-5-fluoro-7-bromo-4-phosphoramidocyanidates. TPL > 190°C (decomp.).

Analysis for C8H7N2O4PSBrF:

calculated:From:26,91N:1,98;N:7,84;
found:From:27,25N: 1,92;N:7,54.

(30.4) 2-Amino-7-etoxycarbonyl-4-phosphoramidocyanidates. TPL > 240°C (decomp.).

Analysis for C11H13N2O6PS+0,2HBr+0,DMF:

calculated:From:38,15N:3,94;N:8,27;
found:From:38,51N:3,57;N:8,66.

Example 31

Obtaining 2-amino-7-bromo-6-thiocyanato-4-phosphonomethyliminodiacetic

Stage A. a Solution of 2-fluoro-5-bromonitromethane (1 mmol) in DMF (5 ml) cooled to 0°and treated With a solution of their sodium salt diethylhydroxylamine (1.2 mmol) in DMF (5 ml). The mixture is stirred at room temperature for 16 hours Evaporation, extraction and chromatography to give 2-diethylphosphonoacetate-5-bromonitromethane.

Stage Century. 2 Diethylphosphonoacetate-5-pantropical processed in accordance with stage b of example 30, step In example 29 and the stage D of example 27, receiving 2-amino-7-bromo-6-thiocyanato-4-phosphoramidocyanidates (31.1). TPL > 250°C (decomp.).

Analysis for C9H7N3O4PS2Br:

C:
calculated:27,29H:1,78;N:10,61;
found:C:26,90;H:1,58;N:10,54.

Similarly, in accordance with the above methods have the following connections:

(31.2) 2-Amino-7-fluoro-6-thiocyanato-4-phosphoramidocyanidates. TPL > 136°C (decomp.).

Analysis for C9H7N3O4PFS2+0,3HBr:

calculated:From:30,07;N:2,05;N:of 11.69;
found:From:30,27;N:2,01;N:11,38.

(31.3) from 2-fluoro-4-chloronitrobenzene and using the same sequence of reactions as described above will receive 2-amino-6-chloro-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C8H8N2O4PSCl:

calculated:From:32,61;N:2,74;N:9,51;
found:From:32,27;N:to 2.67;N:9,18.

(31.4) from 2-fluoro-4,5-dichloronitrobenzene and using the same sequence of reactions as described above will receive 2-amino-6,7-dichloro-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C8H7N2O4PSCl2:

calculated:From:29,20;N:2,14:N:8,51;
found:From:29,11;N:2,11;N:at 8.36.

Example 32

Obtaining 2-amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethyliminodiacetic

Stage A. 2-Chloro-5-familytreedna processed in accordance with stage a of example 31, receiving 2-diethylphosphonoacetate-5-familytreedna.

Stage C. a Solution of 2-diethylphosphonoacetate-5-familytreedna (1 mmol) in methanol (5 ml) is treated with 10% palladium on carbon (0.05 mmol) in hydrogen atmosphere (1 ATM) at room temperature for 12 hours Filtration followed by evaporation gives 2-diethylphosphonoacetate-5-hydroxymethylbilane, which is treated in accordance with stage b of example 29, and then in accordance with the stage D of example 27, receiving 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphoramidocyanidates (32,1). TPL 181-184° C.

Analysis for C10H10N3O5PS2+0,N2About:

calculated:From:33,97N:3,05;N:11,88;
found:From:33,76;N:2,66;N:of 11.61.

A similar technique is used to obtain the following compounds.

(32.2) from 2-fluoro-4-methylnitrobenzene and using the same sequence of reactions as described above will receive 2-amino-6-methyl-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C9H11N2O4PS+0,2CH2Cl2:

calculated:From:37,94N:3,95;N:9,62;
found:From:38,16;N:4,18;N:9,39.

(32.3) Based on 2-chloro-5-canonicalise and using the same sequence of reactions as described above will receive 2-amino-7-cyano-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C9H8N3O4PS+0,N2O:

calculated:From:35,86;N:3,28;N:13,94;
found:From:35,07;N:2,88;N:of 13.58.

Example 33

Obtaining 2-amino-6-bromo-7-fluoro-4-phosphonomethyliminodiacetic

Stage A. a Solution of 2-diethylphosphonoacetate-4-bromo-5-foronline (1 mmol, obtained as in example 4, step b) and KSCN (2 mmol) in Asón (8 ml) is cooled to 10°and treated With a solution of bromine (2 mmol) in Asón (5 ml). After stirring at room temperature for 0.5 h, the reaction mixture was evaporated to dryness and the residue purified by chromatography, obtaining 2-amino-7-fluoro-6-bromo-4-diethylphosphonoacetate, which is treated in accordance with the stage D of example 27, receiving 2-amino-6-bromo-7-fluoro-4-phosphoramidocyanidates (33.1).

Analysis for C8H7N2O4PSBrF+0,1HBr:

calculated:From:26,31N:1,96;N:to 7.67;
found:From:25,96;N:1,94;N:7,37.

Example 34

Obtaining 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxy is ASALA

Stage A. a Solution of 2-diethylphosphonoacetate-5-bromonitromethane (1 mmol, obtained as in example 31, step A, from 2-fluoro-5-bromonitromethane) in DMF (5 ml) is treated with tributyl(vinyl)tin (1.2 mmol) and bis(triphenylphosphine)palladium dichloride (0.1 mmol) and the mixture is heated at 60°C in nitrogen atmosphere for 6 hours Evaporation and chromatography gave 2-diethylphosphonoacetate-5-vinylsilanes in the form of oil, which is processed in accordance with the stage In the example 31, step In example 29 and the Stage D of example 27, receiving 2-amino-7-ethyl-6-thiocyano-4-phosphoramidocyanidates (34.1). TPL > 167°C (decomp.).

Analysis for C11H12N3O4PS2:

calculated:From:38,26N:3,50;N:12,17;
found:From:37,87;N:3,47;N:11,93.

A similar technique is used to obtain the following compounds.

(34.2) 2-Amino-7-propyl-6-thiocyanato-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C12Hl4N3O4PS2:

calculated:From:40,11N: 3,93;N:of 11.69;
found:From:39,72N:3,82;N:11,50.

Use allyltrimethylsilane.

(34.3) 2-Amino-7-(2-furyl)-6-thiocyanato-4-phosphoramidocyanidates.

Analysis for C14P11N3O5BrPS2+0,6MeOH:

calculated:From:33,79;N;2,79;N:8,69;
found:From:34,10;N;2,83;N:8,35.

Use 2-furniturewalla.

(34.4) 2-Amino-6-thiocyanato-7-(2-thienyl)-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C13H10N3About4PS3:

calculated:From:39,09;N:2,52;N:10,52;
found:From:38,91;N:2,41;N:10,34.

Use 2-tinytipoptions.

(34.5) 2.5-Debtor-4-pantropical treated in the same way, receiving the 2-amino-6-ethyl-7-fluoro-4-phosphoramidocyanidates. PL > 250°C (decomp.).

Analysis for C10H12N2O4PSF:

calculated:From:to 39.22;N:3,95;N:9,15;
found:From:38,83;H:3,55;N:9,02.

(34.6) 2.5-Debtor-4-pantropical handle 2-tiertribunals in the second stage, receiving 2-amino-7-fluoro-6-[2-(5-thiocyanato)thienyl]-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C13H9N3O4PS3F+0,6N2About:

calculated:From:36,46;N:2,40;N:9,81;
found:From:36,16;N:2,10;N:9,68.

Example 35

Obtaining 2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethyliminodiacetic

Stage A. a Suspension of 2-diethylphosphonoacetate-5-vinilkarbazola (1 mmol, obtained as in stage a of example 33) and Pd(OAc)2(0.1 mmol) in ether (8 ml) is treated with a solution of diazomethane (obtained from 3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether at 0°C. After paramesh the cation at room temperature for 20 h, the reaction mixture was evaporated to dryness and the residue is subjected to chromatography getting 2 diethylphosphonoacetate-5-cyclopropylmethanol, which is treated in accordance with stage b of example 30, step In example 29 and the stage D of example 27, receiving the hydrobromide of 2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethyliminodiacetic (35.1).

Analysis for C12H13N3O4PS2Br+0,1HBr:

calculated:From:27,76N:2,72;N:8,09;
found:From:27,54;N:3,05;N:7,83.

Example 36

Obtaining 2-amino-4-phosphonomethoxy-6-chloro-7-methylbenzothiazole

Stage A. 2-Methoxy-4-chloro-5-methylaniline processed in accordance with the stages a and b of example 27, step In example 29 and the stage D of example 27, receiving 2-amino-4-phosphonomethoxy-6-chloro-7-methylbenzothiazol (36.1). TPL > 250°C (decomp.).

Analysis for C9H10N2O4PS2Cl+0,3H2O+0,4HBr:

calculated:From:31,20;N:3,20;N:8,09;
found:From:31,37;N:2,87;N:7,89

Similarly, in accordance with the above methods have the connection (36.2) - 2-amino-7-phenyl-6-thiocyanato-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C15H12N3O4PS2+0,2N2O:

calculated:From:45,38;N:3,15;N:of 10.58;
found:From:45,25;N:3,21;N:10,53.

Example 37

Obtain 2-bromo-4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazol

Stage A. a Solution of 2-amino-4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole (1 mmol) in CH3CN (4 ml) cooled to 0°and process CuBr2(1.2 mmol), followed by processing solidities (1.5 mmol) drip method. The obtained dark mixture is stirred for 3.5 hours Evaporation and chromatography gave 2-bromo-4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole in the form of oil.

Stage C. 2-Bromo-4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole processed in accordance with the stage D of example 27, receiving 2-bromo-4-phosphonomethoxy-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole (37.1) in the form of solids. TPL 220-230°C.

Analysis for C12H 13NO4PSBr:

calculated:From:38,11;N:of 3.46;N:3,70;
found:From:37,75;N:3,26;N:3,69.

(37.2) the same technique is used for the interaction of 2-amino-4-diethylphosphonate-6-chloro-7-methylbenzothiazole with CuCl2getting 2-chloro-4-phosphonomethoxy-6-chloro-7-methylbenzothiazol. TPL > 250°C (decomp.).

Analysis for C9H8NO4PSCl2+0,7HBr:

calculated:From:28,10;N:2,28;N:3,64;
found:From:28,23;N:2,20;N:3,79.

Example 38

Getting 4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazol

Stage A. the Solution isoamylamine (1.5 mmol) in DMF (1 ml) at 65°treated With 2-amino-4-diethylphosphonate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole (1 mmol) in DMF (3 ml). After 30 min, the cooled reaction solution is subjected to evaporation and chromatography, receiving 4 diethylphosphonoacetate-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole in the form of oil, unto the / establishment, which was processed in accordance with the stage D of example 27, getting 4 phosphonomethoxy-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole (38.1) in the form of solids. TPL 215-220°C.

Analysis for C12H14NO4PS+1,3HBr:

calculated:From:35,63;N:3,81;N:of 3.46;
found:From:35,53;H:of 3.46;N:3,40.

(38.2) the same sequence of reactions used to convert 2-amino-4-diethylphosphonate-6-chloro-7-methylbenzothiazole 4-phosphonomethoxy-6-chloro-7-methylbenzothiazol. TPL 195-198°C.

Analysis for C9H9NO4PSCl+0,5H2O:

calculated:From:35,71;N:3,33;N:4,63;
found:From:35,49;N:3,19;N:4,65.

Example 39

Obtaining 2-amino-4-phosphonomethyliminodiacetic

Stage A. 2-Diethylphosphonoacetate obtained in stage b of example 27, was processed in accordance with stage b of example 29, receiving 2-amino-4-diethylphosphonoacetate.

Stage C. 2-Amino-4-diethylphosphonate OpenSocial processed in accordance with the stage D of example 34, getting 2-amino-4-phosphonomethyliminodiacetic (39.1) in the form of foam.

Analysis for C8H10N2About3PS2+0,4H2O:

calculated:From:35,63;N:3,81;N:of 3.46;
found:From:35,53;N:of 3.46;N:3,40.

Example 40

Obtaining 2-amino-7-hexyl-6-thiocyano-4-phosphonomethyliminodiacetic

Stage A. a Solution of 1 mmole of 2-diethylphosphonoacetate-5-bromonitromethane (obtained as in example 30, step A) in diethylamine (5 ml) obrabatyvat 1-hexyne (1.2 mmol), CuI (0.1 mmol) and bis(triphenylphosphine)palladium dichloride (0.1 mmol) and the mixture is heated at 60°C in nitrogen atmosphere for 14 hours Evaporation and chromatography gave 2-diethylphosphonoacetate-5-(1-hexyne)benzene in the form of oil, which is processed in accordance with stage b of example 32 phase In example 29 and the stage D of example 27, receiving 2-amino-7-hexyl-6-thiocyano-4-phosphoramidocyanidates.

(40.1) 2-Amino-6-thiocyanato-7-(n-hexyl)-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for Cl5H20N3O4PS2:

calculated:From: 44,88;N:5,02;N:10,47;
found:From:44,54;N:4,75;N:10,37.

Similarly receive the following connection.

(40.2) Solution of 1 mmole of 2-diethylphosphonoacetate-5-bromonitromethane (obtained as in example 30, step A) is subjected to processing in accordance with the stage of example 27, follow the same sequence as for the connection 40.1, receiving 2-amino-6-methyl-7-(n-hexyl)-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C15H23N2O4PS+0,25HBr:

calculated:From:47,58;N:to 6.19;N:7,40;
found:From:47,40;N:6,07;N:7,54.

Example 41

Obtaining 2-amino-6-methoxy-7-methyl-4-phosphonomethyliminodiacetic

Stage A. a Solution of 2-chloro-4-fluoro-5-methylnitrobenzene (1 mmol) in DMF (5 ml) is treated with fresh sodium methoxide (1.1 mmol) and the mixture is stirred for 6 hours Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.

Stage C. 2-Chloro-4-methoxy-5-methylnitrobenzene processed in the accordance with stage a of example 31, stage In example 32, stage a of example 33 and the stage D of example 27, receiving 2-amino-6-methoxy-7-methyl-4-phosphoramidocyanidates (41.1). TPL > 250°C (decomp.).

Analysis for C10H13N2O4PS:

calculated:From:39,48;N:or 4.31;N:of 9.21;
found:From:39,39;N:4,17;N:8,98.

Similarly receive the following connections.

(41.2) 2-Amino-7-methyl-6-methylthio-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C10H13N2O4PS2+0,45HBr:

calculated:From:33,67;N:3,80;N:the 7.85;
found:From:33,62;N:3,86;N:7,76.

(41.3) 2-Amino-6-ethoxy-7-methyl-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C11H15N2O5PS:

calculated:From:41,51;N:4,75;N:
found:From:41,80;N:4,59;N:8,95.

(41.4) 2-Amino-6-isobutoxy-7-methyl-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C13H19N2O5PS+0,15HBr:

calculated:From:43,56;N:5,38;N:7,81;
found:From:43,59;N:5,38;N:7,86.

Example 42

Obtaining 2-amino-6-ethyl-4-phosphonomethyliminodiacetic

Stage A. To a solution of 1 mmole of 3-bromchlorenone in 2 ml conc. H2SO4add 1.5 mmole 79% HNO3at -10°C. After stirring for 30 min the mixture was poured into a mixture of ice/water. The yellow precipitate is filtered and dried, obtaining a mixture of 2-chloro-4-bromonitromethane (required) and 4-chloro-2-bromonitromethane.

Stage C. 2-Chloro-4-pantropical processed in accordance with stage a of example 34, step In example 32, step In example 29 and the stage D of example 27, receiving 2-amino-6-ethyl-4-phosphoramidocyanidates (42.1). TPL > 220°C (decomp.).

Analysis for C10H13N2O4PS+0,3HBr:

calculated:
From:38,43;N:4,29;N:8,96;
found:From:38,35;N:of 4.44;N:8,75.

Similarly receive connection (42.2) - 2-amino-6-propyl-4-phosphoramidocyanidates. TPL > 220°C (decomp.).

Analysis for C11H15N2O4PS+0,2HBr:

calculated:From:41,49;N:4,81;N:8,80;
found:From:41,85;N:4,12;N:8,31.

Example 43

Obtaining 2-amino-6-thio-7-ethyl-4-phosphonomethyliminodiacetic

Stage A. a Solution of 1 mmole of 2-amino-6-thio-7-ethyl-4-diethylphosphonoacetate (for more, see example 34) in 3 ml of 48% HBr in Asón heated at 90°C for 16 hours the Solvent is removed and the residue is washed with water, obtaining 2-amino-6-thio-7-ethyl-4-phosphoramidocyanidates (43.1). TPL > 220°C (decomp.).

Analysis for C10H13N2O4PS2+0,2HBr:

calculated:From:35,69;N:3,95;N: 8,33;
found:From:35,49;N:3,74;N:8,33.

Example 44

Obtaining 2-amino-7-propyloxy-6-thiocyano-4-phosphonomethyliminodiacetic

Stage A. To a solution of 1 mmole of 2-chloro-5-hydroxyitraconazole in 5 ml of DMF added 1.2 mmol of NaH at 0°C. After 3 minutes add allylbromide and the mixture is stirred at room temperature for 16 hours the Solvent is removed and the residue is washed with water and extracted with EtOAc, receiving 2-chloro-5-propiloxibenzoat.

Stage C. 2-Chloro-5-propiloxibenzoat processed in accordance with stage a of example 31, step In example 32, stage a of example 33 and the stage D of example 27, receiving 2-amino-7-propyloxy-6-thiocyano-4-phosphoramidocyanidates (44.1). TPL > 220°C (decomp.).

Analysis for C12H14N3O5PS2+0,15HBr+0,N2About:

calculated:From:37,06;N:3,71;N:10,8;
found:From:37,46;N:3,48;N:10,38.

Example 45

Obtaining 2-amino-6-methoxy-4-phosphonomethyliminodiacetic

Stage A. 2-Hydroxy-4-methoxyethanol was subjected to the Ute processing in accordance with stage b of example 32, stage In example 21, step In example 29, stage D of example 21, receiving 2-amino-6-methoxy-4-phosphoramidocyanidates (45.1). TPL > 230°C (decomp.).

Analysis for C9H11N2O5PS+0,5H2About:

calculated:From:36,12;N:Android 4.04;N:9,36;
found:From:36,18;N:3,81;N:for 9.47.

Example 46

2-Amino-7-ethyl-6-methyl-4-phosphoramidocyanidates

Stage A. 2-Fluoro-4-methylnitrobenzene processed in accordance with stage a of example 31, the stage From example 27, stage a of example 34, step In example 32, step In example 29, stage D of example 27, receiving (46.1) 2-amino-7-ethyl-6-methyl-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C11H15N2O4PS+0,1HBr:

calculated:From:42,57;N:4,90;N:9,03;
found:From:42,32;N:4,71;N:8,87.

Example 47

2-Amino-7-bromo-6-methyl-4-phosphoramidocyanidates

Stage A. 2-Fluoro-methylnitrobenzene processed in accordance with stage a of example 31, stage From example 27, step In example 30, stage a of example 33, stage D of example 27, receiving 2-amino-7-bromo-6-methyl-4-phosphoramidocyanidates (47.1). TPL > 250°C (decomp.).

Analysis for C9H10N2O4PSBr+0,3HBr:

calculated:From:28,64;N:2,75;N:7,42;
found:From:28,62;N:2,60;N:7,42.

Example 48

2-Amino-7-fluoro-6-methyl-4-phosphoramidocyanidates

Stage A. 2-Hydroxy-4-methyl-5-ftorirovannom processed in accordance with stage b of example 27, step In example 32, stage a of example 33, stage D of example 27, receiving (48.1) - 2-amino-7-fluoro-6-methyl-4-phosphoramidocyanidates. TPL > 250°C (decomp.).

Analysis for C9H10N2O4PSF+0,1HBr:

calculated:From:35,99;N:3,39;N:was 9.33;
found:From:35,84;N:3,32;N:9,31.

(48.2) Based on 2-hydroxy-5-chloro-4-methylaniline and using the sequence of reactions, as the decree is but the above (except what stage of recovery NO2carried out using the method SnCl2i.e. stage In example 30)will receive 2-amino-7-chloro-6-methyl-4-phosphoramidocyanidates (48.2). TPL > 250°C (decomp.).

Analysis for C9H10N2O4PSCl+0,6N2About:

calculated:From:34,62;N:3,36;N:8,97;
found:From:34,48;N:3,40;N:8,72.

Example 49

2-Amino-6-bromo-7-methoxy-4-phosphoramidocyanidates

Stage A. 2-Amino-4,7-dimethoxybenzoate [obtained from 1-(2,5-acid)-2-thiourea using the technique of stage a of example 28] treated in accordance with stage C receives 2-amino-4,7-dimethoxy-6-bromobenzimidazole.

Stage C. To a solution of 1 mmole of 2-amino-4,7-dimethoxy-6-bromobenzimidazole in CH2Cl2add 2.2 mmole BBr3in CH2Cl2when 0°C for 16 hours, treated with water and chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxybenzothiazole.

Stage C. 2-Amino-4-hydroxy-6-bromo-7-methoxybenzothiazole processed in accordance with stage b of example 27, stage D of example 27, receiving (49.1) - 2-amino-6-bromo-7-methoxy-4-phosphoramidocyanidates. So on the. > 250°C (decomp.).

Analysis for C9H10N2O5PSBr:

calculated:From:29,28;N:2,73;N:to 7.59;
found:From:28,90;N:3,05;N:7,20.

Example 50

A General method of obtaining bis-phosphoramidic prodrugs

Education dechlorinate

To a suspension of 1 mmole of phosphonic acid in 5 ml of dichloroethane add 0.1 mmol of pyridine (or 0.1 mmol DMF) followed by addition of 6 mmol of thionyl chloride and the mixture is refluxed for 2.5 hours, the Solvent and excess thionyl chloride are removed under reduced pressure and dried, obtaining dichloride.

The reaction mix

Method a: the Crude dichloride absorb 5 ml of dry CH2Cl2and added 8 mmol of ester of the amino acid at 0°C. the mixture allow to reach room temperature where it stirred for 16 hours, the Reaction mixture was treated with water and chromatography.

Method: Untreated dichloride absorb 5 ml of dry CH2Cl2and add a mixture of 4 mmol of ester amino acid and 4 mmol of N-methylimidazole at 0°C. Received the th mixture allow to reach room temperature, when it is stirred for 16 hours, the Reaction mixture was treated with water and chromatography.

In this way we obtain the following connections.

(50.1) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(diethyl ether L-glutamic acid)phosphoramide)furanyl]thiazole.

Analysis for C29H45N4O10PS:

calculated:From:51,78;N:6,74;N:8,33;
found:From:51,70;N:H,64;N:8,15.

(50.2) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(dimensiony ester of L-alanine)phosphoramide)furanyl]thiazole.

Analysis for C31H37N4O6PS:

calculated:From:59,60;N:5,97;N:8,97;
found:From:59,27;N:5,63;N:a total of 8.74.

(50.3) 2-Amino-5-isobutyl-4-{2-[5-N,N-bis(benzyloxycarbonylamino)phosphorodiamidic]furanyl}thiazole.

Analysis for C19H25N4O6PS+0,3CH2Cl2:

calculated: From:46,93;N:5,22;N:11,34;
found:From:46,92;N:5,00;N:11,22.

(50.4) 2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylamino)phosphorodiamidic]furanyl}thiazole.

Analysis for C29H33N4O6PS:

calculated:From:58,38;N:5,57;N:9,39;
found:From:58,20;N:5,26;N:9,25.

(50.5) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R)-1-methoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C19H29N4O6PS+0,6CH2Cl2:

calculated:From:44,97;N:of 5.82;N:10,70;
found:From:44,79;N:5,46;N:10,48.

(50.6) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole. TPL 164-165°C.

Analysis for C21H33N4O6 PS+0,61CH2Cl2:

calculated:From:46,99;N:6,24;N:10,14;
found:From:47,35;N:5,85;N:9,85.

(50.7) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((tert-butoxycarbonyl)methyl)phosphoramide]furanyl}thiazole.

Analysis for C23H37H4O6PS+0,SN2Cl2:

calculated:From:51,36;N:6,94;N:10,35;
found:From:51,34;N:of 6.96;N:10,06.

(50.8) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(etoxycarbonyl)methyl)phosphoramide]furanyl}thiazole.

Analysis for C19H29N4O6PS+0,1EtOAc+0,47CH2Cl2:

calculated:From:45,79;N:5,94;N:10,75;
found:From:46,00;N:5,96;N:10,46.

(50.9) 2-Amino-5-isobutyl-4-{2-[(O-(2-bis(N-(1-methyl-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole. TPL 142-145°C.

Analysis for C23H37N4O6PS:

calculated:From:52,26;N:7,06;N:or 10.60;
found:From:52,21;N:6,93;N:to 10.62.

(50.10) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(ethoxycarbonylmethyl)-N,N'-dimethylformamide)]furanyl}thiazole.

Analysis for C21H33N4O6PS:

calculated:From:50,39;N:6,65;N:11,19;
found:From:50,57;N:6,56;N:11,06.

(50.11) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)propyl)phosphoramide]furanyl}thiazole.

Analysis for C35H45N4O6PS+0,5H2About:

calculated:From:60,94;N:6,72;N:8,12;
found:From:61,01;N:6,48;N:of 7.82.
/p>

(50.12) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-methoxycarbonyl-3-methyl)butyl)phosphoramide]furanyl}thiazole.

Analysis for C25H41N4O6PS:

calculated:From:53,94;N:7,42;N:10,06;
found:From:54,12;N:7.62mm;N:9,82.

(50.13) 2-Amino-5-isobutyl-4-{2-[5-(N,N-bis((R)-1-etoxycarbonyl-2-(S-benzyl)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C35H45N4O6PS3+0,toluol:

calculated:From:58,07;N:6,21;N:7,17;
found:From:57,87;N:6,14;N:for 6.81.

(50.14) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl-3-(S-methyl))butyl)phosphoramide]furanyl}thiazole.

Analysis for C23H37N4O6PS3:

calculated:From:46,61;N:6,92;N:9,45;
found:From: 46,26;H:6,55;N:9,06.

(50.15) 2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-((S)etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C20H31N4O6PS2:

calculated:From:46,32;N:6,03;N:10,80;
found:From:46,52;N:6,18;N:10,44.

(50.16) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)isobutyl)phosphoramide]furanyl}thiazole.

Analysis for C37H49N4O6PS:

calculated:From:62,69;N:6,97;N:of 7.90;
found:From:62,85;N:7,06;N:7,81.

(50.17) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl-3-methyl)butyl)phosphoramide]furanyl}thiazole.

Analysis for C27H45N4O6PS:

calculated:From:55,46;N:7,76;N: 9,58;
found:From:55,35;N:7,94;N:9,41.

(50.18) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl-2-methyl)propyl)phosphoramide]furanyl}thiazole.

Analysis for C25H41N4O6PS:

calculated:From:53,94;N:7,42;N:10,06;
found:From:54,01;N:7,58;N:9,94.

(50.19) 2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl-2-phenyl)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C33H41N4O6PS+0,SN2Cl2:

calculated:From:59,83;N:6,26;N:8,42;
found:From:59,88;N:6,28;N:8,32.

(50.20) 2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-methylethanolamine)ethyl)phosphoramide]furanyl}thiazole. TPL 110-115°C.

Analysis for C22H35N4O6PS2+0,4HCl+0,5Et2O:

calculated:
From:48,18;N:for 6.81;N:9,36;
found:From:48.38 per;N:6,60;N:8,98.

(At 50.21) 2-Amino-5-methylthio-4-{2-[5-(N,N'-bis(1-methyl-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C20H31H4O6PS2+0,5H2O:

calculated:From:45,53;N:6,11;N:to 10.62;
found:From:45,28;N:5,85;N:10,56.

Example 51

General methods for mixed bis-phosphoramidate prodrugs

To a solution of crude dichloride (1 mmol, obtained as described in example 50) in 5 ml dry CH2Cl2add amine (1 mmol) followed by addition of 4-dimethylaminopyridine (3 mmol) at 0°C. the mixture allow to warm to room temperature and stirred for 1 h, the Reaction mixture was cooled again to 0°With, then add ester amino acid (2 mmol) and left at room temperature for 16 hours, the Reaction mixture is treated with water and mixed the OE bis-phosphoramidate the prodrug purified column chromatography.

Similarly receive the following connections.

(51.1) 2-Amino-5-isobutyl-4-{2-[5-(N-morpholino-N'-(1-methyl-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole. TPL 182-183°C.

Analysis for C21H33N4O5PS:

calculated:From:52,05;N:6,86;N:to 11.56.
found:From:51,66;N:6,68;N:11,31.

(51.2) 2-Amino-5-isobutyl-4-{2-[5-(N-pyrrolidino-N'-(1-methyl-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole. TPL 189-190°C.

Analysis for C21H33N4O4PS:

calculated:From:53,83;N:7,10;N:11,96;
found:From:EUR 54.15;N:of 7.48;N:12,04.

Example 52

Synthesis of bis-phosphoramide prodrugs using Mukaiyama method with some modifications (J. Am. Chem. Soc. 1972, 94, 8528).

To a suspension of 1.0 mmole of phosphonic acid and 2.0 mmol of the salt of ester of the amino acids (such as HCl salt of the ethyl ester of alanine) in 9 ml of pyridine, Et3N and 1,3-d is methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine (DMPU) (1:1:1) add a pre-mixed solution of 4 mmol altricial and 4 mmol PPh 3in 3 ml of pyridine. After 16 h at 90°With solvents, pyridine and Et3N removed under reduced pressure. The solution remaining oily crude product was diluted with hexane (100 ml) and purified using chromatography.

Using this method, you receive the following connections.

(52.1) 2-Amino-4-[(N,N'-(1-(S)-etoxycarbonyl)ethyl)phosphorodiamidate]-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole. TPL 153-156°C.

Analysis for C22H33N4O6PS:

calculated:From:51,55;N:of 6.49;N:of 10.93;
found:From:51,39;N:6,24;N:10,96.

(52.2) 2-Amino-5-isopropyl-4-[(N,N'-(1-(S)-etoxycarbonyl)ethyl)phosphorodiamidate]thiazole.

Analysis for C18H31N4O7PS:

calculated:From:45,18;N:6,53;N:11,71;
found:From:45,33;N:6,56;N:11,46.

(52.3) 2-Amino-7-ethyl-5-fluoro-1-isobutyl-2-[5-({N,N'-(1-(S)-etoxycarbonyl)ethyl}FD is fonogenico)furanyl]benzimidazole.

Analysis for C27H39N5O6PF:

calculated:From:55,95;N:to 6.78;N:12,08;
found:From:55,73;N:6,65;N:11,72.

(52.4) 2-Amino-5-etoxycarbonyl-4-[2-(5-({N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphono)furanyl]thiazole.

Analysis for C20H29N4O8PS+0,3CH2Cl2:

calculated:From:44,99;N:5,50;N:10,34;
found:From:44,68;N:5,30;N:10,37.

(52.5) 2-Amino-4-[(N,N'-(1-(S)-etoxycarbonyl)methyl)phosphorodiamidate]-5,6,7,8-tetrahydronaphthyl[1,2-d]thiazole. TPL 177-178°C.

Analysis for C20H29H4O6PS:

calculated:From:49,58;H:6,03;N:to 11.56;
nasdeo:From:49,20;H:5,95;N:11,51.

(5.6) 2-Amino-5-isopropyl-4-[(N,N'-(1-(S)-etoxycarbonyl)methyl)phosphorodiamidate]thiazole. TPL 122-125°C.

Analysis for C16H27N4O7PS:

calculated:From:42,66;N:6,04;N:to 12.44;
found:From:42,60;N:between 6.08;N:12,43.

(52.7) 2-Amino-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-bromo-7-chlorobenzothiazole. TPL 210-212°C.

Analysis for C18H25N4O6PSBrCl:

calculated:From:37,81;N:to 4.41;N:9,80;
found:From:37,88;N:4,35;N:9,84.

(52.8) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-methoxycarbonyl-2-(tert-butoxy)ethyl)phosphoramide]furanyl}thiazole.

Analysis for C26H43N4O8PS2:

(52.9) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-etoxycarbonyl-2-methylbutyl)phosphoramide]furanyl}thiazole.

Analysis for C26H43N4O6PS2:

calculated:From:49,20;N:6,83;N:8,83;
found:From:49,38;N:6,68;N:8,65.
calculated:From:51,81;N:7,19;N:of 9.30;
found:From:52,03;N:to 6.78;N:9,04.

(52.10) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-etoxycarbonyl-2-methylpropyl)phosphoramide]furanyl}thiazole.

Analysis for C24H39N4O6PS2:

calculated:From:50,16;N:6,84;N:9,75;
found:C:repossessed a 50.01;N:6,76;N:9,66.

(52.11) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-methoxycarbonyl-2-(tert-butoxy)propyl)phosphoramide]furanyl}thiazole.

Analysis for C28H47H4O6PS2:

calculated:From:50,74;N:7,15;N:8,45;
found: 51,08;N:7,33;N:8,25.

(52.12) 2 Aminopropyl-4-{2-[5-(N,N'-bis(1-etoxycarbonyl)cyclopentyl)phosphoramide]furanyl}thiazole.

Analysis for C26H39N4O6PS2:

calculated:From:52,16;N:6,57;N:9,36;
found:From:52,55;N:6,53;N:9,31.

(52.13) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-etoxycarbonyl)propylphosphonate]furanyl}thiazole.

Analysis for C22H35N4O6PS2:

calculated:From:48,34;N:6,45;N:of 10.25;
found:From:48,65;N:6,29;N:10,23.

(52.14) 2-Amino-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7-methylbenzothiazol. TPL 178-180°C.

Analysis for C19H28N4O6PSCl:

calculated:From:45,02;N:5,57; N:11,05;
found:From:45,12;N:5,49;N:10,92.

(52.15) 2-Amino-5-methylthio-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}thiazole. TPL 94-95°C.

Analysis for C18H27N4O6PS2:

calculated:From:44,07;N:5,55;N:11,42;
found:From:44,42;N:5,44;N:11,29.

(At 52.16) 2 Aminopropyl-4-[2-{5-(N,N'-bis((S)-1-etoxycarbonyl)butyl)phosphoramide)}furanyl]thiazole.

Analysis for C24H39N4O6PS2:

calculated:From:50,16;N:6,84;N:9,75;
found:From:49,96;N:6,91;N:9,68.

(52.17) 2 Aminopropyl-4-[2-{5-(N,N'-bis((S)-1-etoxycarbonyl)cyclohexenylmethyl)phosphoramide)}furanyl]thiazole.

Analysis for C30H47N4O6PS2:

From:55,03;N:of 7.23;N:8,56;
found:From:54,89;N:7,14;N:8,42.

(52.18) 2-Amino-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-methoxybenzothiazole. TPL 144-146°C.

Analysis for C19H29N4O7PS:

calculated:From:46,72;N:5,98;N:11,47;
found:From:46,76;N:5,72;N:11,33.

(52.19) 2-Amino-4-{N,N'-(etoxycarbonyl)methyl}phosphonomethoxy-6-methoxybenzothiazole. TPL 150-152°C.

Analysis for C17H25N4O7PS:

calculated:From:44,35;N:5,47;N:12,17;
found:From:44,74;N:the 5.45;N:11,99.

(52.20) 2-Amino-7-ethyl-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-methylbenzothiazol. Analysis for C21H33N4O6PS:

calculatedC:50,39;N:6,65;N:11,19;
found:From:50,22N:6,34;N:11,30.

(52.21) 2-Amino-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-methylbenzothiazol.

Analysis for C19H29N4O6PS:

calculated:From:48,30;N:to 6.19;N:up 11,86;
found:From:48,67;N:5,90;N:up 11,86.

(52.22) 2-Amino-4-{N,N'-(1-methyl-1-etoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7-methylbenzothiazol. TPL 170-172°C.

Analysis for C21H32N4O6PSCl:

calculated:From:47,15;N:6,03;N:10,47;
found:From:47,22;N:by 5.87;N:10,08.

(52.23) 2-Amino-7-ethyl-4-{N,N'-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-methylbenzothiazol.

Analysis for C19H29N4O6PS:

p>
calculated:From:48,30;N:to 6.19;N:up 11,86;
found:From:47,98;N:6,36;N:11,88.

(52.24) 2-Amino-4-{N,N'-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-methylbenzothiazol.

Analysis for C17H25N4O6PS+0,5H2O:

calculated:From:45,03;N:5,78;N:12,36;
found:From:44,80;N:6,10;N:12,40.

(52.25) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis((S)-1-tert-butoxycarbonyl)ethyl)phosphoramide)]furanyl}thiazole.

Analysis for C24H39N4O6PS2:

calculated:From:50,16;N:6,84;N:9,75;
found:From:50,26;N:of 6.71;N:9,51.

(52.26) 2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-n-butoxycarbonyl)ethyl)phosphoramide)}furanyl]t is an azole.

Analysis for C24H39N4O6PS2:

calculated:From:50,16;N:6,84;N:9,75;
found:From:50,38;N:6,64;N:for 9.64.

(52.27) 2-Amino-5-etoxycarbonyl-4-[2-(5-({N,N'-(1-(S)-etoxycarbonyl)propyl}phosphono)furanyl]thiazole.

Analysis for C22H33N4O8PS:

calculated:From:48,52;N:6,11;N:10,29;
found:From:48,62;N:6,02;N:10,26.

(52.28) 2-Amino-5-etoxycarbonyl-4-[2-(5-({N,N'-(1-(S)-etoxycarbonyl)butyl}phosphono)furanyl]thiazole.

Analysis for C24H37N4O8PS:

calculated:From:50,34;N:6,51;N:9,78;
found:From:50,34;N:6,57;N:9,65.

(52.29) 2-Amino-5-etoxycarbonyl-4-[2-(5-({N,N'-(1-et is xianbei)cyclopentyl}phosphono)furanyl]thiazole.

Analysis for C26H37N4O8PS:

calculated:From:52,34;N:6,25;N:9,39;
found:From:52,02;N:6,20;N:9,34.

(52.30) 2-Amino-5-etoxycarbonyl-4-[2-{5-(N,N'-bis(S)-1-etoxycarbonyl-2-methylpropyl)phosphoramide}furanyl]thiazole.

Analysis for C24H37N4O8PS:

calculated:From:50,34;N:6,51;N:9,78;
found:From:50,56;N:6,40;N:9,65.

(At 52.31) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis-coumarin)phosphoramide]furanyl}thiazole.

Analysis for C28H23N4O6PS2:

calculated:From:55,44;N:3,82;N:9,24;
found:From:55,52;N:3,66;N:9,01.

(52.32) 2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-isop oxicarbide)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C22H35N4O6PS2:

calculated:From:48,34;N:6,45;N:of 10.25;
found:C:48,03;N:6,45;N:accounted for 10.39.

(52.33) 2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-n-propoxycarbonyl)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C22H35N4O6PS2:

calculated:From:48,34;N:6,45;N:of 10.25;
found:From:48,39;N:6,27;N:10,20.

(52.34) 2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-cyclohexyloxycarbonyl)ethyl)phosphoramide)}furanyl]thiazole. Analysis for C26H39H4O6PS2;

calculated:From:52,16;N:6,57;N:9,36;
found:From:52,07;N:6,51;N:9,10.

(52.35) 2-Amino-6-e of the Il-7-fluoro-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphoramidocyanidates.

Analysis for C20H30N4O6PSF:

calculated:From:47,61;N:5,99;N:11,10;
found:From:47,59;N:5,79;N:10,90.

(52.36) 2-Amino-6-ethyl-7-fluoro-4-{N,N'-(1-etoxycarbonyl)methyl}phosphoramidocyanidates.

Analysis for C18H26N4O6PSF:

calculated:From:45,38;N:5,50;N:11,76;
found:From:45,07;N:5,25;N:11,49.

(52.37) 2-Amino-7-bromo-4-{N,N'-(1-(S)-etoxycarbonyl)ethyl}phosphonomethoxy-6-methylbenzothiazol.

Analysis for C19H28N4O6PSBr:

calculated:From:41,39;N:5,12;N:10,16;
found:From:41,40;N:of 5.05;N:9,94.

(52.38) 2-Amino-4-{N,N'-(1-etoxycarbonyl)methylethyl}hostname the XI-6-methylbenzothiazol.

Analysis for C21H33N4O6PS+0,5H2O:

calculated:From:49,50;N:of 6.73;N:11,00;
found:From:49,18;N:6,61;N:is 11.39.

(52.39) 2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-etoxycarbonyl)propyl)phosphoramide)}furanyl]thiazole.

Analysis for C23H37N4O6PS:

calculated:From:52,26N:7,06N:or 10.60;
found:From:52,47N:7,29N:10,77.

(52.40) 2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-cyclohexyloxycarbonyl)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C30H47N4O6PS2:

calculated:From:55,03;N:of 7.23;N:8,56;
found:From:55,08;N:7,35;N:8,39.

(52.41) 2-Amin is-5-isobutyl-4-[2-{5-(1-etoxycarbonyl)cyclopentyl)phosphoramide)}furanyl]thiazole.

Analysis for C27H41N4O6PS:

calculated:From:55,85;N:7,12;N:9,65;
found:From:55,62;N:for 6.81;N:9,66.

(52.42) 2-Amino-4-{N,N'-(1-etoxycarbonyl)cyclopentyl}phosphonomethoxy-7-fluoro-6-methylbenzothiazol. Analysis for C26H38N4O6PSF+0,15Et2O:

calculated:From:53,63;N:6,68;N:9,40;
found:From:53,93;N:6,39;N:9,50.

(52.43) 2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-neopentecostal)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C27H45N4O6PS+0,1 h2O:

calculated:From:55,29;N:to 7.77;N:of 9.55;
found:From:54,90;N:7,68;N:9,44.

(52.44) 2-Amino-5-isobut the-4-{2-[5-(N,N'-bis(R,S)-1-(1-etoxycarbonyl)ethyl)phosphoramide)]furanyl}thiazole. TPL 143-146°C.

Analysis for C21H33N4O6PS:

calculated:From:50,39;N:6,65;N:11,19;
found:From:50,33;N:to 6.58;N:11,00.

(52.45) 2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-isopropoxycarbonyl)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C23H37N4O6PS:

calculated:From:52,26;N:7,06;N:or 10.60;
found:From:52,34;N:7,02;N:10,50.

(52.46) 2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-propoxycarbonyl)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C23H37N4O6PS+0,1 CH2Cl2:

calculated:From:51,66;N:6,98;N:10,43;
found:From:51,50;N:7,01;N:10,63.

(52.47) 2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-isobutoxide)ethyl)phosphoramide)}furanyl]thiazole.

Analysis for C25H4lN4O6PS:

calculated:From:53,94;N:7,42;N:10,06;
found:From:53,59;N:of 7.64;N:9,98.

(52.48) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis((S)-1-etoxycarbonyl)ethyl)phosphoramide]furanyl}oxazol.

Analysis for C20H31N4O7PS:

calculated:From:47,80;N:6,22;N:of 11.15;
found:From:47,90;N:6,17;N:10,92.

(52.49) 2-Amino-5-propylthio-4-{2-[5-(N,N'-bis-1-etoxycarbonyl)methyl)phosphoramide]furanyl}oxazol.

Analysis for C18H27N4O7PS:

calculated:From:45,57;N:5,74;N:11,81;
found:From:45,87;N:568; N:11,68.

(52.50) 2-Amino-5-(isobutyl-d9)-4-[2-{5-(N,N'-bis(S)-1-(1-etoxycarbonyl)ethylphosphonate}furanyl]thiazole.

Analysis for C2lH24D9N4O6SP:

calculated:From:49,50;N:4,75;N:10,99;
found:From:49,89;N:6,55;N:10,97.

Examples of the method of the invention include the following. It should be understood that these examples are illustrative and that the method of the invention is not limited to only these examples.

To make clarity and conciseness in the following biological examples of chemical compounds are indicated by the number of example of synthesis.

The compound a is 4-amino-5-fluoro-7-ethyl-1-isobutyl-2-(2-phosphono-5-furanyl)benzimidazole.

The connection is 4-amino-5-fluoro-1-cyclopropylmethyl-2-(2-phosphono-5-furanyl)benzimidazole.

The connection is 2-amino-5-isobutyl-4-{2-[N-(1-methyl-1-carboxy)ethylenebisstearamide]furanyl}thiazole.

In addition, the following examples of tests that may be useful to identify compounds that inhibit gluconeogenesis, including the t following animal models of diabetes.

i. Animals with pancreatic β-cells destroyed specific chemical cytotoxins, such as alloxan or streptozotocin (e.g., mouse, rat, dog and monkey treated streptozotocin). Kodama, H., Fujita, M., Yamaguchi, I., Japanese Journal of Pharmacology, 66, 331-336 (1994) (mouse); Youn, J.H., Kirn, J.K., Buchanan, T.A., Diabetes 43, 564-571 (1994) (rat); Le Marchand, Y., Loten, E.G., Assimacopoulos-Jannet, F. et al. Diabetes 27, 1182-88 (1978) (dog); and Pitkin. R., Reynolds, W.A., Diabetes 19, 70-85 (1970) (monkey).

ii. Mutant mice, such as C57BL/Ks db/db, C57BL/Ks db/db and C57BL/6J ob/ob from the Jackson Laboratory, Bar Harbor, and others, such as yellow fat, T-QC, and new Zealand fat. Coleman, D.L., Hummel, K.R., Diabetologia 3, 238-248 (1967) (C57BL/Ks db/db); Coleman, D.L., Diabetologia 14, 141-148 (1978) (C57BL/6J ob/ob); Wolff, G.L., Pitot, H.C., Genetics 73, 109-123 (1973) (yellow fat); Dulin, W.E., Wyse, B.M., Diabetologia 6, 317-323 (1970) (T-CC); and Bielschowsky, M., Bielschowsky, F. Proceedings of the University of Otago Medical School 31, 29-31 (1953) (new Zealand obese).

iii. Mutant rats, as, for example, the rat line Zucker fa/fa purchased with diabetes as a result of processing streptozotocin or dexamethasone, diabetic fatty rat line and fatty Zucker rat Wistar (Kyoto). Stolz, K.J., Martin, R.J. Journal of Nutrition 112, 997-1002 (1982) (streptozotocin); Ogawa, A., Johnson, J.H., Ohnbeda, M., McAllister, C.T., Inman, L., Alam, T., Unger, R.H., The Journal of Clinical Investigation 90, 497-504 (1992) (dexamethasone); Clark, J.B., Palmer, C.J., Shaw, N. W., Proceedings of the Society for Experimental Biology and Medicine 173, 68-75 (1983) (diabetic fatty rat line Zucker); and Idida, H., Shino, A., Matsu, So et al., Diabetes 36, 1045-1050 (1981) (fatty rat Wistar (Kyoto)).

iv. Animals with spontaneous diabetes, as, for example, Chinese hamster, Guinea pig, new Zealand white rabbit and non-human-like primates, such as rhesus monkeys and squirrel monkey. Gerritsen, G.C., Cornel, M.A., Blanks, M.C., Proceedings of the Nutrition Society 40, 237-245 (1981) (Chinese hamster); Lang, C.M., Munger, B.L., Diabetes 25, 434-443 (1976) (Guinea pig); Conaway, H.H., Brown, C.J., Sanders, L.L. et al. Journal of Heredity 71, 179-186 (1980) (new Zealand white rabbit); Hansen, B.C., Bodkin, M.L., Diabetologia 29, 713-719 (1986) (rhesus monkeys); and Davidson, I.W., Lang, C.M., Blackwell, W.L, Diabetes 16, 395-401 (1967) (squirrel monkey).

v. Animals with diabetes caused by restartovanim, such as sand rat, spiny rice hamster, clawed Mongolian gerbil and rat with diabetes (Cohen), caused by sucrose. Schmidt-Nielsen, K., Hainess, NV, Hackel, D.B., Science 143, 689-690 (1964) (sand rat); Gonet, A.E., Stauffacher, W., Pictet, R. et al. Diabetologia 1, 162-171 (1965) (spiny rice hamster); Boquist, L., Diabetologia 8, 274-282 (1972) (clawed Mongolian gerbil); and Cohen, A.M., Teitebaum, A., Saliteknik, R., Metabolism 21, 235-240 (1972) (rats with diabetes induced by sucrose (Cohen)).

vi. Any other animal with one of the following characteristics, or a combination of the following characteristics, which are the result of genetic predisposition, genetic engineering, selective breeding, or chemical induction, or induction by restartovanie: improved the glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated gluconeogenesis, increased glucose release by the liver.

Example A. Inhibition Fbpase human liver.

The BL21 strain of E. coli, in which the cells transformed by a plasmid that encodes Fbpase human liver was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. The enzyme was usually isolated from 10 liters of culture of recombinant E. coli as described (M. Gidh-Jain et al, 1994, The Journal of Biological Chemistry 269, pp 27732-27738). Enzymatic activity was determined spectrophotometrically in the reactions, which match the formation of the product (fructose-6-phosphate) with the restoration of the bromide dimethylterephthalate (MTT) through NADP+and finishingtouches (PMS), using phosphoglucomutase and glucose-6-phosphate dehydrogenase as a binder enzymes. The reaction mixture (200 μl) were prepared in 96-well titration microplate, and they consisted of 50 mm Tris-HCl, pH 7.4, 100 mm KCl, 5 mm EGTA, 2 mm MgCl2, 0.2 mm NADP, 1 mg/ml BSA (BSA), 1 mm MTT, 0, 6 mm PMS, 1 unit/ml phosphoglucomutase, 2 units/ml glucose-6-phosphate dehydrogenase, and 0.150 mm substrate (fructose-1,6-bisphosphate). The concentration of inhibitor was varied from 0.01 μm to 10 μm. Reactions were initiated by addition of 0.002 units net pcfvbazy (hlFBPase) and monitored for 7 minutes at 590 nm using a spectrophotometer to read the plan is billing purposes (Molecular Devices Plate Reader) (37° C).

The table below presents the values IR50for several of the compounds obtained. IR50for AMP (AMP) is 1 μm.

Inhibition Fbpase rat liver

The BL21 strain of E. coli, in which the cells transformed by a plasmid that encodes Fbpase rat liver was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. Recombinant Fbpase was purified as described (El-Maghrabi, M.R., and Pilkis, S.J. (1991) BioChem. Biophys. Res. Commun. 176, 137-144). Analysis of the enzyme was identical to the analysis (definition fermentative activity)described above for Fbpase human liver.

The table below presents the values IR50for several of the compounds obtained. IR50for AMF is 20 μm.

Connection # IR50(pcffa), microns
3.10,18
3.22,5
3.250,5
3.260,25
3.58*0,05 (*not HBr salt)
3.700,15
6.30,5
10.12
10.22,5
10.272,9
10.430,8
15.2 1,3
15.44,1
15.67
15.200,6
15.140,68
16.11,8
18.200,28
18.30,49
34.10,16
And0,55
In2,1

Example C. the Binding site of the AMF.

To estimate, contact connections with the allosteric AMP binding site pcfvbazy, the enzyme is incubated with radiolabelled AMP in the presence of several concentrations of the test compounds. The reaction mixture composed of 25 mm3H-AMP (54 MCI/mmol) and 0-1000 mm test compound in 25 mm Tris-HCl, pH 7.4, 100 mm KCl and 1 mm MgCl2. 1,45 mg homogeneous Fbpase (± nmol) is added last. After incubation for 1 minute AMF associated with Fbpath, separated from unbound AMP with a device for centrifugal ultrafiltration ("Ultrafree-MC, Millipore), used in accordance with manufacturer's instructions. Using a liquid scintillation counter Beckman, quantitatively determine the radioactivity of the aliquot (100 µl) of the upper branch of the device (retentate, which contains the enzyme and label) and the lower branch (the filtrate, which content is t unbound label). The number of AMF associated with the enzyme, determined by comparing the accounts in the filtrate (unbound label) with a total score in retentate.

Example C. Inhibition of gluconeogenesis in liver cells of rats.

Liver cells receive from starving during the night rats Sprague-Dawley (250-300 g) in accordance with the method of Berry and Friend (Berry, M.N, Friend, D.S., 1969, J. Cell. Blol. 43, 506-520), modified Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J,M., 1982, Eur. J. BioChem. 122, 87-93). Liver cells (75 mg wet weight/ml) incubated in 1 ml Krebs-bicarbonate buffer containing 10 mm lactate, 1 mm pyruvate, 1 mg/ml BSA and the concentration of the test compounds from 1 to 500 microns.

Incubation is carried out in an atmosphere of 95% oxygen, 5% carbon dioxide in closed Falcon tubes 50 ml, immersed in a strongly vibrating bath of water (37°). After 1 hour take an aliquot (0.25 ml), transferred into an Eppendorf tube and centrifuged. Then 50 μl of the supernatant analyzed for glucose content using a set of glucose oxidase from Sigma, in accordance with the manufacturer's instructions.

The following table lists the values of IR50for compounds selected for this test.

ConnectionThe production of glucose, IR50, mcm
3.12,5
3.226
3.2610
3.58*2,0 (*not HBr salt)
10.115
10.216
16.110
50.62,0
50.92,2
50.22,1

Example D. Inhibition of the production of glucose and accumulation of fructo-1.6-bisphosphate in the hepatic cells of rats.

Isolated liver cells of rats receive, as described in example C, and incubated under conditions identical to the above. The reaction being removed by removing aliquots (250 μl) of cell suspension and passing it through a layer of oil (0.8 ml of a mixture 4/1 silicone/mineral oil) in a layer of 10% perchloric acid (100 μl). After removing a layer of butter acid extract of cells is neutralized by adding 1/3 (by volume) mixture of 3M KOH/3M KHCO3. After thorough mixing and centrifugation, the supernatant analyzed for glucose, as described in the example, and, in addition, the content of fructose-1,6-bisphosphate. Fructose-1,6-bisphosphate analyzed spectrophotometrically, matching its enzymatic conversion into glycerol-3-phosphate by the oxidation of NADH, which is controlled at 340 nm. The reaction mixture (1 ml) consist of 200 mm Tris-HCl, pH 7.4, 0.3 mm NADH, 2 units the s/ml glycerol-3-phosphate dehydrogenase, 2 units/ml triosephosphate and 50-100 μl of the extract of the cells. After a 30-minute pre-incubation at 37°add 1 unit/ml of aldolase and control the change of absorption until then, until you get a stable value. In this reaction oxidizes 2 mol of NADH per mole of fructose-1,6-bisphosphate present in the cellular extract.

The establishment of dose-dependent inhibition of the production of glucose, followed by a dose-dependent accumulation of fructose-1,6-bisphosphate (substrate Fbpase), suggests that the enzyme is a target involved in gluconeogenesis road metabolism, Fbpase, subject to inhibition.

Example E. Chemical stability.

Purpose: to evaluate the stability of prodrugs 50.6, 50.9, 50.15 and 50.20 in phosphate buffered aqueous solution at neutral pH.

Methods: solution of the prodrug with a concentration of 50 or 100 µg/ml in the buffer based on potassium phosphate at pH 7 (room temperature) analyze daily for up to 10 days. Samples analyzed HPLC with reversed-phase column using Beckman Ultrasphere CI8 (4,6×250 mm). Column balancing and elute with a gradient from 50 mm phosphate, pH 5.5, up to 70% acetonitrile at a flow rate of 1.5 ml/min Detection is carried out at 300 or 315 nm, column temperature 40°C. In these conditions, prodrugs well the Department who are from the standards of the original connection; retention time for prodrugs is in the range from 16 to 18 minutes, while the parent compound, 3.1 and 3.58 (not HBr salt), suiryudan 9 and 10 minutes, respectively.

Results: prodrugs, evaluated, demonstrating good stability at neutral pH. It was noted the decomposition of prodrugs less than 10% during a 4-day incubation period. Thus, t90 (time for 90% stability) to 50.6, 50.9, 50.15 and 50.20 at pH 7 was > 96 hours.

Example F. Assessment of oral bioavailability in rat.

Objective: to assess the oral bioavailability of prodrugs (evaluation) excretion of the parent compound in the urine of rats.

Methods: prodrugs dissolved in a mixture of 10% ethanol/90% polyethylene glycol (400 MB) and injected using a probe through the mouth at doses from 10 to 40 mg/kg parent compound equivalents rats Sprague Dawley (weighing 220-240 g)subjected to 6-hour fasting. The parent compound is usually dissolved in deionized water, neutralized with sodium hydroxide, and then injected rats that were shot with halothane gas (halothane)through the tail vein at a dose of ˜10 mg/kg Then rats placed in metabolic cages and urine collected for 24 hours. The amount of parent compound, isolated in the urine, determined by analysis with HPLC. The analysis is carried out, as described in the example is E. Oral bioavailability, expressed in %, determined by comparing the content in the urine of the parent compound formed from the prodrug, administered orally, with the content of the parent compound in the urine after intravenous unsubstituted parent compound.

Results: oral bioavailability, assessed in %for the selected prodrugs are presented below.

The prodrugThe original connectionOral bioavailability, %
50.23.111
50.33.17
50.43.117
50.53.122
50.63.1a 21.5
50.83.126
50.93.140
50.153.822
50.203.842
50.173.17
At 50.213.2645
51.23.137
52.129.116
52.43.2530
52.153.6 23
52.1845.122
52.2132.224
52.2236.118
52.323.5817
52.333.5819
52.3832.230
52.413.127
52.433.118
52.443.128
52.453.131
52.463.116

Example G. Oral pharmacokinetics in rats.

Objective: to determine the pharmacokinetic parameters and 50.6 50.9 (prodrugs 3.1)and 50.2 (prodrug 3.58) after oral administration to the rat.

Methods: prodrugs were administered orally at the dose of 10 mg/kg fed to rats, which were installed catheter in the caudal artery. At appropriate intervals after administration of medicines via catheters introduced into the tail vein, took blood samples. Of the samples received plasma by centrifugation and then laid siege to a plasma protein by the addition of methanol to 60%. Methanol extracts were osvetleni by centrifugation and then analyzed for the content of the prodrugs and the source is connected to the I by HPLC, as described in example E. pharmacokinetics Parameters were calculated from profiles "concentration in the plasma source connection-time" using compartmental analysis (WinNonLin v 1.1 software).

Results: prodrugs were not determined in plasma, indicating rapid in vivo into the corresponding parent compound. The pharmacokinetic parameters are summarized below.

The original connection
ConnectionWithmax(mg/ml)Tmax(h)Clearance (l/kg/h)The elimination half-life (h)
50.60,781,51,315,1
50.90,991,11,62,5
50.213,10,547,0

Example N. Acute oral efficacy in ZDF rats.

Objective: to determine the effect of reducing the level of glucose in the blood with the rapid introduction 50.6, and 50.9 50.2 in diabetic fatty rat line Zucker (ZDF rat).

Methods: ZDF rats were purchased from Genetics Inc (Indianapolis, Indiana) at the age of 8 weeks. Animals were kept under standard conditions and were provided food Purina 5008 and water (ad libitum). Rats were selected in who's who ACTE 10-12 weeks with levels of blood glucose > 500 mg/DL and was administered to them orally or filler (PEG 400)or prodrug (60 mg/kg). Glucose levels in the blood were monitored at regular intervals for 6 hours after dosing. Samples were taken of blood from the cut tail vein and analyzed by a glucose analyzer HemoCue (Hemocue, Mission Viejo, CA). Statistical analysis was performed using student's criterion. Presents averages ± standard error of the mean.

Results: three prodrugs were effective in oral introduction, which is confirmed by the observed effects of a significant reduction of the glucose level in the blood (see table).

The level of blood glucose, mg/DL
ProcessingBazovoeTC% change
Filler (n=8)562±38528±29-6%
50.6 (n=8)544±25406±12*-25%
50.9 (n=8)602±26410±18*-32%
50.2 (n=8)591±35415±15*-30%
*P<0,005 against filler

Example I. Chronic oral efficacy in ZDF rats.

Objective: to determine the influence of 50.6 to reduce the level of glucose in the blood in ZDF rats during 3 weeks of prolonged oral treatment.

Methods: ZDF rats (aged 10 weeks) contain or powdered feed rats Purina 5008 (n=10), or the same powder stern, supplemented with 0.4% 50.6 (n=8). Carry out the determination of glucose in the blood as described in example E, the base time and again a week later for a total of 3 weeks. Statistical analysis was performed using student's criterion. Shown are averages ± standard error of the mean.

Results: as shown in the table, the efficiency is maintained throughout the 3-week treatment period, with an obvious decrease in the level of glucose in the blood by 45% in the group treated with the medication (as filler), to the end of the study.

The level of blood glucose, mg/DL
ProcessingBazovoet21 day
Filler678±19776±28
50,6674+20436±41*
*p<0,0001 against filler

Example J. Identification of intermediate compounds formed during aktivacii.

Turning 50.6 were assessed in the plasma of rats, monkeys and humans by HPLC with a reversed phase column using Beckman Ultrasphere ODS (4,6×150 mm)equipped with a column Alltech All-Guard. The column was balanced 20 mm potassium phosphate, pH to 6.2, and suirable with a linear gradient of 0-60% acetonitrile for 20 minutes at a flow rate of 1.5 ml/min and at a temperature of 40°C. UV absorption was monitored at 300 nm. Exposure 50.6 (100 μm) in the plasma samples resulted in the formation of a single metabolite. Metabolite had the same retention time and UV spectrum of the product formed after incubation prodrugs with esterase pig liver (Sigma Chemical Co, MO), suggesting that it represents the product of the reaction catalyzed by esterase. The metabolite formed in the plasma of rats, collected and subjected to analysis by the method of mass spectrometry in Mass Consortium Corporation (San Diego. CA). The test gives a negative peak ion at 372, indicating that the formed metabolite has a molecular weight of 373. This molecular weight corresponds to the molecular mass monophosphorylated intermediate product. The intermediate product, probably formed in the reaction mechanism by which the prodrug first undergoes a full deesterification, and then intramolecular, hydrolytic cleavage of one of aminoaniline C is mustiala. Education postulated monophosphorylated intermediate product was confirmed by the subsequent synthesis of the synthetic standard (connection). The standard had a profile of HPLC and UV identical to the metabolite formed in the plasma samples.

Example K. Metabolism 50.6 in liver cells of humans.

Cryopreserved liver cells receive Vitro Technologies and defrost in accordance with the recommendations of the supplier. Cells are incubated at 37°in the buffer on the basis of Krebs-bicarbonate-containing 50.6 at 10 μm. At different points in time over 4 hours away aliquots of cells and extracted by the addition of methanol to 60%. Extracts of cells lighten by centrifugation and analyzed HPLC with reversed-phase column using Beckman Ultrasphere ODS (4,6×150 mm)equipped with a column Alltech All-Guard. Column offset of 20 mm potassium phosphate, pH to 6.2, and elute with a linear gradient of 0-60% acetonitrile for 20 minutes at a flow rate of 1.5 ml/min and at a temperature of 40°C. UV-absorption control at 300 nm. 50.6, connection and 3.1 determine quantitatively by comparison with authentic standards. The disappearance of 50.6 came quickly and almost completely within 60 minutes of incubation. Defined two metabolite 50.6: connection and 3.1. The initial rate of formation 3.1 was 24 pmol is/million cells/min. This study indicates that 50.6 transformed into an active inhibitor Fbpase, 3.1, in intact liver cells of humans.

Example L. the Relationship structure-activity phosphoramidate human liver.

The human liver, acquired from the Anatomic Gift Foundation (Laurel, MD), homogenized in Krebs-bicarbonate buffer and clarify by low-speed centrifugation. Metabolism of prodrugs appreciate in the reaction mixtures containing the homogenate human liver (4 mg protein), 50 mm Tris-HCl, pH 7.4, 10 mm MgCl2and 10 mm dithiothreitol. Through various time intervals over 2 hours of reaction mixtures selected aliquots and deproteinizing the addition of methanol to 60%. After clarification by centrifugation metabolites analyze HPLC with reversed-phase column using Beckman Ultrasphere ODS (4,6×150 mm)equipped with a column Alltech All-Guard. Column offset of 20 mm potassium phosphate, pH to 6.2, and elute with a linear gradient of 0-60% acetonitrile for 20 minutes at a flow rate of 1.5 ml/min and a temperature of 40°C. Control the UV absorption at 300 nm. A large part of the evaluated prodrugs were developed (within 5 minutes of incubation) through the stage, not limiting the speed of the process, catalyzed by esterase, monophosphorylated form. Therefore, the speed of phosphonic acid, essentially, assetcategory the rate of end-stage splitting, catalyzed phosphoramidates. Below are the results for typical prodrugs, for which phase catalyzed by esterase, is not a stage, limiting the speed of the process.

The prodrugPhosphoramidase activity (the rate of production of 3.1 or 3.58, nmol/min/mg protein liver)
50.60,022
50.80,019
50.100,005
50.120,022
50.200,085
50.190,029
52.80,025
52.12to 0.032
At 52.160,033

The results indicate that phosphoramidase human liver quickly breaks down communication phosphorus-nitrogen of a number of substrates phosphonic acid-monoamide, thereby releasing the inhibitor Fbpase - free phosphonic acid. The lowest rate of cleavage connection P-N observed in the case of a substrate containing a secondary amine, monophosphorylated 50.10. The first stage in the activation of prodrugs, deesterification catalyzed by esterase, is not a stage, limiting the speed of the process for most of the evaluated substrates.

While in accordance with patent Zack is the legislation in the description illustrates various options and technological conditions for carrying out the invention they should not be construed as limiting the scope of the present invention. For professionals in this field is obvious modifications and changes of the present invention, is not beyond the scope and substance of the present invention. Therefore understood that the scope of this invention should be determined by the following appended claims and not by the specific examples which have been presented to illustrate the invention.

1. The compound of formula IA

where the compounds of formula IA are converted in vivo or in vitro in M-RO3H2that is an inhibitor of fructose-1,6-bisphosphatase, and where

M is R5-X-,

where

R5selected from the group consisting of

and

where

each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may be O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G groups are N;

And selected from the group consisting of-H, -NR42, -CONR42, -CO2R3, halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, paraloid the La, haloalkyl, aryl, -CH2HE, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl,-C(O)R11, -C(O)SR3, SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H,-CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of N, or absent;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with the phosphorus atom is at the of Lerida, and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not replaced by a-COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of-R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aryl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms, selected from the group comprised the soup from Oh, N and S, with the formation of a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other17, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3; and provided that:

1) when G' is N, then the respective a, b, D or E is absent;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines the W hat as containing up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

2. Compounds according to claim 1, where M RHO3H2is IR50(IC50in relation to the enzyme Fbpase isolated from human liver, less than or equal to 10 microns.

3. Compounds according to claim 2, where the specified value IR50less than or equal to 1 micron.

4. Compounds according to claim 1, where R5selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazole, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazoline, each of which contains at least one Deputy.

5. Compounds according to claim 1, where a is selected from the group consisting of-H, -NR42, -CONR42, -CO2R3, halogen, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil,1-C6pergolide, C1-C6haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or lack the t; each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

E is selected from the group consisting of-H, C1-C6of alkyl, C2-C6alkenyl,2-C6the quinil, aryl, C4-C6alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -OR3, -SR3C1-C6pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted; and each R4independently selected from the group consisting of-H and C1-C2the alkyl.

6. The compound according to claim 1, where R5is

7. The compound according to claim 1, where R5is

8. The compound according to claim 1, where R5selected from the group consisting of

and

g is e And is selected from the group consisting of-H, -NR42, -CONR42, -CO2R3, halogen, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C1-C6pergolide,1-C6haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42and-NHAc;

" And D" are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R3, -S(O)R11, -CN, -NR92, -OR3, -SR3, pergolide and halogen, all except-H, -CN, pergolide and halogen, optionally substituted;

E is selected from the group consisting of-H, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, aryl, C4-C6alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -OR3, -SR3C1-C6pergolide and halogen, all except-H, -CN, pergolide and halogen, optionally substituted; and each R4independently selected from the group consisting of-H and C1-C2the alkyl.

9. Compounds according to claim 1, where X is selected from the group consisting of-heteroaryl-, -alkylcarboxylic-, -alkylaminocarbonyl - and-alkoxy is of arbonia-.

10. Compounds according to claim 1, where the specified connection represents the connection formulas II, III or IV

11. Connection of claim 8, where X is selected from the group consisting of-heteroaryl-, -alkoxyalkyl-, -alkylcarboxylic-alkylaminocarbonyl - and-alkoxycarbonyl-.

12. Compounds according to claim 1, where n is 1; R12and R13independently selected from the group consisting of-H, lower alkyl, lower pergolide and lower aryl, optionally substituted-OR19, -NR192, -SR192, -C(O)NR2R3, halogen, -CO2R2, 3-indolium, 4-imidazolyl or guanidinium, or R12and R13are connected via 2-5 carbon atoms, forming cycloalkyl group;

R14selected from the group consisting of-OR17, -SR17and-NR2OR19;

R15and R16independently selected from the group consisting of-H and C1-C6the alkyl, or R15and R16together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R17selected from the group consisting of C1-C7of alkyl, phenyl, indolyl, sesamol and benzyl, where the specified phenyl, indolyl, sesamol and benzyl can be long is Ino substituted by 1-3 groups selected from the group of-CO2R2, -OR2, -NHC(O)R3, halogen and lower alkyl; and R18selected from the group consisting of-H, C1-C6of alkyl and benzyl.

13. Compounds according to claim 1, where R18selected from the group consisting of-H, C1-C6the alkyl.

14. Compounds according to item 13, where R18selected from the group consisting of H and methyl.

15. Connection 14, where R18is N.

16. Compounds according to claim 1, where each R12and R13independently selected from the group consisting of-H, lower alkyl, lower pergolide, lower aralkyl, lower aryl, optionally substituted-OR19, -NR192, -SR19, -C(O)NR2R3, halogen, -CO2R2, 3-indolium, 4-imidazolyl or guanidinium, or R12and R13together are connected via 2-5 carbon atoms, forming cycloalkyl group.

17. Join on clause 16, where caandy R12and R13independently selected from the group consisting of-H, C1-C4of alkyl, -CH2O-C(CH3)3, phenyl and benzyl, or R12and R13are linked together via 2 or 4 carbon atoms, forming cyclopropyl or cyclopentyl group.

18. Connection 17, where each R12and R13independently selected from the group consisting of H and methyl, or R12and R13together connected through 4 carbon atoms, education is UYa cyclopentyloxy group.

19. Connection 17, where R12and R13are both-H, both methyl, or R12is N, and R13selected from the group consisting of methyl, isopropyl and benzyl.

20. Compounds according to claim 19, where n is 1 and R12is-H and the carbon associated with R12and R13has the stereochemistry S.

21. Compounds according to claim 1, where n is an integer 1 or 2.

22. Compounds according to item 21, where n is equal to 1.

23. Compounds according to claim 1, where each R14independently selected from the group consisting of-OR17, -SR17and-NR2OR19and R17selected from the group consisting of C1-C7of alkyl, phenyl, indolyl, sesamol and benzyl, where mentioned phenyl, indolyl, sesamol and benzyl may be optionally substituted by 1-3 groups selected from the group consisting of-CO2R2, -OR2, -NHC(O)R3, halogen and lower alkyl.

24. Compounds according to item 23, where R14is-OR17.

25. Connection point 24, where R17selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, t-butyl, isobutyl, neopentyl, cyclopentyl and unsubstituted benzyl.

26. Compounds according to claim 1, where R15and R16independently selected from the group consisting of-H and C1-C6the alkyl, or R15and R16together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting and what About, N and S.

27. Connection p where-NR15R16selected from the group consisting of morpholinyl and pyrrolidinyl.

28. Compounds according to claim 1, where R16is -(CR12R13)n-C(O)-R4and each n is equal to 1.

29. Compounds according to claim 1, where n is 1; R12and R13independently selected from the group consisting of-H, lower alkyl, lower pergolide and lower aryl, optionally substituted-OR19, -NR192-SR19, -C(O)NR2R3, halogen, -CO2R2, 3-indolium, 4-imidazolyl and guanidinium, or R12and R13are connected via 2-5 carbon atoms to form cycloalkyl group; R14selected from the group consisting of-OR17, -SR17and-NR2OR19; R15selected from the group consisting of-H and C1-C6of alkyl; R16selected from the group consisting of-H, C1-C6the alkyl and -(CR12R13)n-C(O)-R14; or R15and R16together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, O and S; R17selected from the group consisting of C1-C7of alkyl, phenyl, indolyl, sesamol and benzyl, where mentioned phenyl, indolyl, sesamol and benzyl may be optionally substituted by 1-3 groups selected from the group of-CO2R2, -OR3, -NHC(O)R3, halogen and lower the Lila; and R18selected from the group consisting of-H, C1-C6of alkyl and benzyl.

30. Join on clause 29, which have the formula

31. Compounds according to item 30, where n is equal to 1.

32. Connection p, where, when R12and R13are not the same, then R18HN-CR12R13-C(O)-R14represents an ester or thioether amino acids of natural origin; and R14selected from the group consisting of-OR17and-SR17.

33. Connection of claim 8, where a is selected from the group consisting of-NH2, -CONH2, halogen, -CH3, -CF3, -CH2-halogen, -CN, -och3, -SCH3and-N;

In" selected from the group consisting of-H, -C(O)R11, -C(O)SR3, alkyl, aryl, alicyclic, halogen, -CN, -SR3, -OR3and-NR92;

D is selected from the group consisting of-H, -C(O)R11, -C(O)SR3, -NR92, alkyl, aryl, alpicella, halogen, and-SR3;

E is selected from the group consisting of-H, C1-C6the alkyl, lower alicyclic, halogen, -CN, -C(O)OR3and-SR3;

X is selected from the group consisting of-heteroaryl-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of C1-the 4of alkyl, C4-C6aryl, C2-C7alicyclic and C5-C7aralkyl where these aryl, alicyclic and aralkyl can be optionally substituted with 1-2 heteroatoms;

each R12and R13independently selected from the group consisting of-H, C1-C4of alkyl, -CH2O-(CH3)3, phenyl and benzyl, or R12and R13together are connected via 2 or 4 carbon atoms, forming cyclopropyl or cyclopentyl group;

n = 1;

each R14independently selected from the group consisting of-OR17, -SR17and-NR2OR19;

R15selected from the group consisting of-H, methyl, ethyl, propyl;

R16is -(CR12R13)n-C(O)-R14;

R17selected from the group consisting of C1-C7of alkyl, phenyl, indolyl and benzyl, where mentioned phenyl, indolyl and benzyl may be optionally substituted by 1-3 groups selected from the group consisting of-CO2R2, -OR3, -NHC(O)R3, halogen and lower alkyl;

R18selected from the group consisting of H and methyl; and

R19selected from the group of-H, C1-C4of alkyl, C4-C6aryl, C2-C7alicyclic,5-C7aralkyl, -COR3.

34. Connection p, where

selected from the group consisting of

and

where R17selected from the group consisting of ethyl, isopropyl, n-propyl and neopentyl.

35. Connections 34, where S* is the stereochemistry S.

36. Connection p, where R5is

X is selected from the group consisting of methylisoxazole and furan-2,5-deila, and their pharmaceutically acceptable salts.

37. Connection p, where A" represents-NH2, X is furan-2,5-diyl, and" is-S(CH2)2CH3.

38. Connection p, where A" represents-NH2, X is furan-2,5-diyl, and" is-CH2-CH(CH3)2.

39. Connection p, where A" represents-NH2, X is furan-2,5-diyl, and" is-COOEt.

40. Connection p, where A" represents-NH2, X is furan-2,5-diyl, and" is-SMe.

41. Connection p, where A" represents-NH2X represents methylenecycloartanol, and" is-CH(CH3)2.

42. Join on clause 37, where

is

where R17selected from the group consisting of ethyl, isopropyl, which is cut and neopentyl.

43. Join on clause 37, where

is

where C* has S stereochemistry and where R17selected from the group consisting of ethyl, isopropyl, n-propyl and neopentyl.

44. Connections § 38, where

is

45. Connections § 38, where

is

where S* is the stereochemistry S.

46. Connections § 45, which is selected from the group consisting of cleaners containing hydrochloride salt, hydrobromide salts, acetic acid salts triperoxonane acids, salts of methansulfonate, salts of p-toluenesulfonic acid, and salts of maleic acid.

47. Connections § 38, where

selected from the group consisting of

and

where R17is ethyl, n-propylene, isopropyl and neopentyl and where S* is the stereochemistry S.

48. Connection p, which is selected from the group consisting of cleaners containing hydrochloride salt, hydrobromide salts, acetic acid salts triperoxonane acids, salts of methansulfonate, salt p-is toluolsulfonic and salts of maleic acid.

49. Connections § 38, where

is

where R12and R13together form cyclopentyloxy group.

50. Connections § 49, which is selected from the group consisting of cleaners containing hydrochloride salt, hydrobromide salts, acetic acid salts triperoxonane acids, salts of methansulfonate, salts of p-toluenesulfonic acid, and salts of maleic acid.

51. Connection p, where

is

where S* is the stereochemistry S.

52. Connections § 51, which is selected from the group consisting of cleaners containing hydrochloride salt, hydrobromide salts, acetic acid salts triperoxonane acids, salts of methansulfonate, salts of p-toluenesulfonic acid, and salts of maleic acid.

53. Connection p, where R5is

X is selected from the group consisting of furan-2,5-deila and methylisoxazole And"

represents-NH2,

and their pharmaceutically acceptable salts.

54. Compounds according to item 53, where X is furan-2,5-diyl and" is-SCH2CH2CH3.

55. Connection p, where R5is

A" represents-NH2, E" and D" represent-H, b" is selected from the group consisting of cyclopropyl and n-propyl, X is selected from the group consisting of methylisoxazole and furan-2,5-deila,

and their pharmaceutically acceptable salts.

56. Connection p, where R5is

A" represents-NH2D represents-H, b" is selected from the group consisting of n-propyl and cyclopropyl, X is selected from the group consisting of furan-2,5-deila and methylisoxazole,

and their pharmaceutically acceptable salts.

57. A method of treating diabetes or preventing diabetes in an animal at risk of developing diabetes, by introducing an animal in need of such treatment, a pharmaceutically effective amount of the compounds of formula (I)

where R5selected from the group consisting of:

and

where each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may represent O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G* groups are N;

And selected from the group consisting of-H, -NR42, -CONR4 , -CO2R3halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of N, or absent;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the cu is taysee the distance between R 5and the phosphorus atom, where the atom associated with the phosphorus is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not replaced by a-COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or R4and R4together form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 and the Ohm, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other172, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or associated with R121-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, nor is our aryl, lower alicyclic, lower aralkyl and COR3;

and provided that:

1) when G' is N, then the respective a, b, D or E is absent;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower", in contrast aemy in connection with organic radicals or compounds, respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

58. The method according to § 57, where these animals are at risk of developing diabetes have the disease or condition selected from the group including impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated gluconeogenesis and increased glucose production by the liver.

59. The method according to § 58, where the disease is an impaired glucose tolerance.

60. The method according to § 58, where the disease is a resistance to insulin.

61. The method according to p-60, where the disease is a hyperlipidemia, atherosclerosis, ischemic injury, and hypercholesterolemia.

62. The method of inhibition of fructose-1,6-bisphosphatase the animal, in need thereof, comprising the introduction of a pharmaceutically effective amount of the compounds of formula (I)

where R5selected from the group consisting of

and

where each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G can the t imagine About, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G' groups are N;

And selected from the group consisting of-H, -NR42, -CONR42, CO2R3, halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of-H, and missing;

X is optionally substituted by the second linking group, which links R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with the phosphorus is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not substituted -COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of and the Qila, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14selected independently from the group consisting of-OR17, -N(R17)2-The other172, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of - (CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R 18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or associated with R121-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

and provided that:

1) when G' is N, then the respective a, b, D or E is absent;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" means compounds that combine characteristicimpedance and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

63. A way of reducing glucose levels in the blood by injecting an animal in need this, pharmaceutically effective amount of the compounds of formula (I)

where R5selected from the group consisting of:

and

where

each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may represent O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G' groups are N;

And selected from the group consisting of-H, -NR42, -CONR42, -CO2R3halogen, -S(O)R3-SO2R3, alkyl, alkenyl, Alki the sludge, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of-H, and missing;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with fosforo is, is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not replaced by a-COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms, wybran the x group, consisting of O, N and S, to form a cyclic group;

each R14selected independently from the group consisting of-OR17, -N(R17)2-The other172, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or associated with R121-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

and provided that:

1) when G' is N, then the respective a, b, D or E is missing;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or connection of enemy, respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

64. A method of treatment of diseases associated with the deposition of glycogen by injection to a patient in need of such treatment, a pharmaceutically effective amount of the compounds of formula (I)

where R5selected from the group consisting of

and

where each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may represent O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G' groups are N;

And selected from the group consisting of-H, -NR42, CONR42, -CO2R3, halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, and the Qila, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR3, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of-H, and missing;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with the phosphorus is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -aldoxycarb the ILA, carbonylcyanide-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not replaced by a-COOR2, -SO3H or-PO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14selected independently from the group consisting of-OR17, -N(R17)2-The other172, -NR2OR19and-SR17;

R15selected from the group consisting of is-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

and provided that:

1) when G' is N, then the respective a, b, D or E is missing;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, have a look at the corresponding a or b is not halogen or a group, directly related to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

65. The method of inhibition of fructose-1,6-bisphosphatase the belly is wow, in need thereof, which includes the introduction of a pharmaceutically effective amount of the compounds of formula (X)

where

G is selected from the group consisting of-O - and-S-;

And2selected from the group consisting of-H, -NR42, -NHAc, -OR2, -SR2, -C(O)NR42, halogen, -COR11, -CN, pergolide, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil;

L2E2and J2selected from the group consisting of-NR42, -NHAc, -NO2, -H, -OR2, -SR2, -C(O)NR42, halogen, -COR11, SO2R3, guanidine, amidine, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHSO2R3, -SO2NR42, -CN, -S(O)R3, pergolide, pergolide, perhalogenated,1-C6alkyl (OH), C1-C6alkyl (SH), C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, heteroaryl and lower alicyclic, or together L2and E2or E2and J2form anilinophenol cyclic group;

X2selected from the group consisting of CR22-, -CF2-, -CR22-O-, -CR22-S-, -C(O)-O-, -C(O)-S-, -C(S)-O-, -CH2-C(O)-O -, and-CR22-NR20- igde atom, related to the phosphorus is a carbon atom; provided that X2not replaced by a-COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR2and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or together R12and R13are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other17, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12 R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

R20selected from the group consisting of lower alkyl, -h,- COR2;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, W is displaced aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication picoalgae connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

66. A method of treating diabetes by injecting an animal in need of such treatment, a pharmaceutically effective amount of an inhibitor Fbpase formula (X)

where

G is selected from the group consisting of-O - and-S-;

And2selected from the group consisting of-H, -NR42, -NHAc, -OR2, -SR2, -C(O)NR42halogen, -COR11, -CN, pergolide, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil;

L2E2and J selected from the group consisting of-NR42, -NHAc, -NO2, -H, -OR2, -SR2, -C(O)NR42, halogen, -COR11, SO2R3, guanidine, amidine, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHSO2R3, -SO2NR42, -CN, -S(O)R3, pergolide, pergolide, perhalogenated, C1-C6alkyl(OH), C1-C6alkyl(SH), C1-C6of alkyl, C2-C6alkenyl,2-C6the quinil, heteroaryl and lower alicyclic, or together L2and E2or E2and J2form anilinophenol cyclic group;

X2selected from the group consisting of CR22-, -CF2-, -CR22-O-, -CR22-S-, -C(O)-O-, -C(O)-S-, -C(S)-O-, -CH2-C(O)-O -, and-CR22-NR20and where the atom is related to the phosphorus is a carbon atom; provided that X2not replaced by a-COOR2, -SO3H or-PO3R22;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

R11SEL is an group, consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14selected independently from the group consisting of-OR17, -N(R17)2-The other17, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alikpala, lower aralkyl and COR3;

R20selected from the group consisting of lower alkyl, -h,- COR2;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to is in connection with organic radicals or compounds, respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

67. A method of treating an animal suffering from diabetes, including the introduction of a specified animal a therapeutically effective amount of the compounds of formula XI

where a3E3and L3selected from the group consisting of-NR82, -NO2, -H, -OR7-SR7, -C(O)NR42, halogen, -COR11, -SO2R3, guanidine, amidine, -NHSO2R3, -SO2NR42, -CN, sulfoxide, pergolide, pergolide, perhalogenated,1-C5of alkyl, C2-C5alkenyl, C2-C5

the quinil and lower alicyclic, or together And3and E3form a cyclic group, or together L3and E3form a cyclic group, or together E3and J3form a cyclic group including aryl, cycloalkyl and heterocyclic group;

J3selected from the group consisting of-NR82, -NO2, -H, -OR7, -SR7, -C(O)NR42, halogen, -COR11, -CN, sulfonyl, sulfoxide, is ergonomical, hydroxyalkyl, perhalogenated, alkyl, haloalkyl, aminoalkyl, alkenyl, quinil; alicyclic, aryl and aralkyl, or together with Y3forms a cyclic group including aryl, cycloalkyl and heteroseksualci;

X3selected from the group consisting of-alkyl(hydroxy)-, -alkyl-, -quinil-, -aryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-,

-alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alicyclic-aralkyl-,

-alkylaryl-, -alkoxycarbonyl-, -carbonyloxy-, -alkoxycarbonyl and

-alkylaminocarbonyl-, all optionally substituted; provided that X3not replaced by a-COOR2, -SO3H or RHO3R22;

Y3selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R3, -S(O)2R3, -C(O)-R11, -CONHR3, -NR22and

-OR3all, except H, are optionally substituted;

n is an integer from 1 to 3;

R2selected from the group consisting of R3and-N;

R3selected from the group consisting of alkyl, aryl, alicyclic and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4 form cycloalkyl group;

R7independently selected from the group consisting of-H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and-C(O)R10;

R8independently selected from the group consisting of-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R10or they together form a bidentate alkyl;

each R9independently selected from the group consisting of-H, -alkyl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R10selected from the group consisting of-H, lower alkyl,

-NH2, lower aryl, and lower pergolide;

R11selected from the group consisting of alkyl, aryl, NR22and-OR2;

each R12and R13independently selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other172, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, who schego aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye group, all of which can be optional is tion substituted, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.

68. Method of inhibiting gluconeogenesis in animal, in need thereof, comprising the introduction of a specified animal a pharmaceutically effective amount of a compound according to claim 1.

69. A pharmaceutical composition comprising a pharmaceutically effective amount of an inhibitor Fbpase formula IA:

where the compounds of formula IA are converted in vivo or in vitro in M-RO3sub> 2that

an inhibitor, a fructose-1,6-bisphosphatase, and where

M is R5-X-,

where

R5selected from the group consisting of

and

where

each G is independently selected from the group consisting of C, N, O, S and Se, and where only one G may be O, S or Se, and at most one G is N;

each G' is independently selected from the group consisting of C and N, and where no more than two G' groups are N;

And selected from the group consisting of-H, -NR42, -CONR42, -CO2R3, halogen, -S(O)R3, -SO2R3, alkyl, alkenyl, quinil, pergolide, haloalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or missing;

each b and D are independently selected from the group consisting of-H, alkyl, alkenyl, quinil, aryl, alicyclic, aralkyl, alkoxyalkyl,-C(O)R11, -C(O)SR3, SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, pergolide, halogen, -NO2or missing, all except-H, -CN, pergolide, -NO2and halogen, optionally substituted;

E is selected from the group consisting of-H, alkyl is, alkenyl, quinil, aryl, alicyclic, alkoxyalkyl, C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3-SR3, pergolide, halogen, or missing, all except-H, -CN, pergolide and halogen, optionally substituted;

J is selected from the group consisting of N, or absent;

X represents an optionally substituted linking group that binds R5with the phosphorus atom via 2-4 atoms, including 0-1 heteroatom selected from N, O and S, except that if X is urea or carbamate, then there is 2 heteroatoms, which determine the shortest distance between R5and the phosphorus atom, where the atom associated with the phosphorus is a carbon atom and where X is selected from the group consisting of-alkyl(hydroxy)-, -quinil-, -heteroaryl-, -carbonylethyl-, -1,1-dialogical-, -alkoxyalkyl-, -alkyloxy-, -alkyldimethyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarboxylic-, -alkoxycarbonyl-, -carbonyloxy-, -alkoxycarbonyl - and-alkylaminocarbonyl-, all optionally substituted; provided that X is not substituted -COOR2, -SO3N or RHO3R22;

n is an integer from 1 to 3;

R2selected from the group R3and-N;

R3selected from the group consisting of alkyl, aryl, Aliz is Lila and aralkyl;

each R4independently selected from the group consisting of-H and alkyl, or together R4and R4form cycloalkyl group;

each R9independently selected from the group consisting of-H, alkyl, aryl, aralkyl and alicyclic, or together R9and R9form cycloalkyl group;

R11selected from the group consisting of alkyl, aryl, -NR22and-OR2;

each R12and R13independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12and R13together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, with the formation of a cyclic group;

each R14independently selected from the group consisting of-OR17, -N(R17)2-The other17, -NR2OR19and-SR17;

R15selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R16connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R16selected from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15connected via 2-6 atoms, neobythites is but including 1 heteroatom, selected from the group consisting of O, N and S;

each R17independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or R17and R17N together are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R18independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12connected via 1-4 carbon atom, form a cyclic group;

each R19independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl and COR3; and provided that:

1) when G' is N, then the respective a, b, D or E is absent;

2) at least one of a and b, or a, b, D and E is not selected from the group consisting of N, or absent;

3) when G is N, then the respective a or b is not halogen or a group directly linked to G via a heteroatom;

where the term "aryl" refers to aromatic groups which have from 5 to 14 ring atoms and at least one ring having a conjugated PI electron system and includes carbocyclic aryl, heterocyclic aryl and burilnye groups, all of which may be optionally substituted by the YMI, preferably the phenyl and furan-2,5-Dyilo;

the term "aralkyl" refers to an alkyl group, substituted aryl group, suitable kalkilya groups include benzyl, picolyl and the like, and may be optionally substituted;

the term "alicyclic" refers to compounds which combine the characteristics of aliphatic and cyclic compounds, which include optionally substituted aromatic, cycloalkyl and the United bridging communication cycloalkyl connection, while cyclic compounds include heterocycles;

the term "lower"referred to in connection with organic radicals or compounds respectively, defines such with up to and including 10, or up to and including 6, or one to four carbon atoms, such groups may be straight chain, branched or cyclic;

and its pharmaceutically acceptable salts.



 

Same patents:
The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

FIELD: synthesis of lubricant oiliness addends.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-benzotriazol and O-(n-butyl)-O-(3,4,5-trithiatricyclodez-8-yl-methyl))-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product of general formula:

.

EFFECT: ash-free addend for lubricant oils processing under high pressure, in particular lubricant oiliness addend of improved antiscoring properties.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-benzotriazole salt of general formula 2 is disclosed. 1-(N,N-dimethylaminomethyl)-benzotriazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

The invention relates to new P,N-bidentate ligands of formula (I):

where a is S or NR,

where R represents a C1-C4alkyl,

R1and R2represent hydrogen, C1-C4alkyl, or R1and R2can be locked in the benzene ring,

R3and R4submit C1-C4alkyl or phenyl,

R5and R6submit C1-C4alkyl

The invention relates to new heteroaryl-alldifferent formulas (I) and (II) for compounds of formula (I) A=S if V=C; A=N, if B=N, R1is hydrogen or C1-C4alkyl, R2-R5-phenyl, R6and R7is hydrogen, n=0 or 1, R8-R11is hydrogen; compounds of f-crystals (II) A=N, if I=S, R1=C1-C4alkyl, A=C, if B= N, R1is hydrogen; A=N if I=N, R1=0; And=O, if=S, R1=0, R2-R5- phenyl, R8-R11is hydrogen or C1-C4alkyl

The invention relates to new heteroaryl-alldifferent formulas (I) and (II) for compounds of formula (I) A=S if V=C; A=N, if B=N, R1is hydrogen or C1-C4alkyl, R2-R5-phenyl, R6and R7is hydrogen, n=0 or 1, R8-R11is hydrogen; compounds of f-crystals (II) A=N, if I=S, R1=C1-C4alkyl, A=C, if B= N, R1is hydrogen; A=N if I=N, R1=0; And=O, if=S, R1=0, R2-R5- phenyl, R8-R11is hydrogen or C1-C4alkyl

The invention relates to new furifosmin formula I

< / BR>
where n denotes an integer of 1 or 2; R1denotes a hydrophilic group selected from the following groups: -SO2M, -SO3M, -CO2M, -PO3M, where M represents inorganic or organic cationic residue selected from a proton, cations, alkaline or alkaline earth metals, ammonium cations -- N(R)4where R denotes hydrogen or C1-C14alkyl, and the other cations are based on metals, salts with acids: fullsleeve, fullcarbon, fullsleeve or furylphosphonous soluble in water; m denotes an integer of 1; R2denotes a hydrophilic group,- SO2M, -SO3M, -CO2M, RHO3M, where M denotes hydrogen or an alkaline metal salt with the acid fullsleeve, fullcarbon, fullsleeve or fullfactorial soluble in water, R denotes an integer from 0 to 2

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds

The invention relates to chemistry fosforsodyerzhascikh heterocyclic compounds, and in particular to methods for obtaining compounds of formula

H3C -N(C2H5)2which is an effective postregulation some crops

The invention relates to the field of organofluorine compounds, particularly to a method of obtaining derivatives softinterface acid next строенияQ STN - RA , where R is--OR or NR-2; R is lower alkali

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition made mainly as solid medicinal formulations and comprising therapeutically effective amount of gliclazide and the special additive in the amount 4.65-6.70 mass. p. per mass unit of active substance. The additive comprises hydroxypropylmethylcellulose, microcrystalline cellulose, aerosil and stearate taken in the following ratio of components, mass. p. per 1 m. p. of active substance: hydroxypropylmethylcellulose, 2.50-3.50; microcrystalline cellulose, 2.12-3.00; aerosil, 0.01-0.05, and stearate, 0.02-0.15. Proposed pharmaceutical composition provides the sustained-release of gliclazide and high bioavailability of active substance, a simple method for its preparing as compared with solid medicinal formulation of gliclazide known from the prior art.

EFFECT: improved and valuable properties of composition.

3 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

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