Novel derivative vitronectin receptor antagonists, synthesis method thereof, use thereof as medicinal agent and pharmaceutical compositions containing said antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) in form of (R) or (S) isomers, separately or in a mixture, as well as their physiologically acceptable salts and hydrates, having vitronectin receptor antagonist properties. In formula (I)

G denotes Het-NH-CO-, Het-NH-CH2-, Het-; Het denotes a mono- or bicyclic system, where each ring is a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-2 nitrogen atoms as heteroatoms, where Het is unsubstituted or substituted with R9 groups; R1 denotes H, (C6-C14)-aryl, (C6-C14)aryl(C1-C4)alkyl; amino, unsubstituted, mono-or disubstituted with alkyl and/or acyl, containing 1-4 C atoms; R2 denotes H, halogen, nitro-group; alkyl containing 1-4 C atoms; amino, unsubstituted, mono- or disubstituted with alkyl and/or acyl containing 1-4 C atoms; a -(CH2)0-2-OR5 group; R3 denotes H, -CO2R5, -SO2R5 or mono- or bicyclic system, where each ring denotes a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-4 heteroatoms selected from N, O or S, unsubstituted or substituted with R9 radicals; R4 denotes OH, (C1-C8)alkoxy-; amino, unsubstituted, mono- or disubstituted with (C1-C4)alkyl; or an aminoacid residue; R5 denotes (C1-C8)alkyl; (C6-C14)aryl; (C6-C14)aryl(C1-C4)alkyl; (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bi- and tricycloalkyl(C1-C4)alkyl. Aryls, alkyls, cycloalkyls are not substituted or substituted with R9 groups; R9 denotes halogen, amino, nitro, hydroxyl, (C1-C4)alkyloxy-, carboxy, (C1-C4)alkyloxycarbonyl-, (C1-C8)alkyl, unsubstituted or substituted with halogen atoms; phenyl. The invention also relates to a methods for synthesis of formula (I) compounds, a medicinal agent and a pharmaceutical composition containing said compounds, as well as use thereof in preparing the medicinal agent.

EFFECT: improved properties of the compound.

21 cl, 41 ex

 

The present invention relates to new derivatives of antagonists of vitronectin receptor, the method of production thereof, their use as medicines and pharmaceutical compositions in which they are included.

The object inventions are the compounds of formula (I):

in which R1, R2, R3, R4and G have the meanings specified below, and also their physiologically acceptable salts. The compounds of formula (I) are compounds having pharmacological activity and, therefore, applicable in the quality of medicines. They are vitronectin receptor antagonists and inhibitors of cell adhesion, they also inhibit bone resorption mediated by osteoclasts. Therefore, they are suitable for therapeutic treatment and prevention of diseases caused at least partly undesirable increase in bone resorption, such as osteoporosis. In addition, the object of the invention are methods for producing compounds of formula (I), their use, in particular, as medicaments and pharmaceutical compositions containing them.

Bone is constantly exposed to a dynamic process that involves bone resorption and bone formation. These processes occur through special the x cells. The formation of bone is the result of deposition of mineral matrix by osteoblasts and bone resorption is the result of the decomposition of this bone matrix by osteoblasts. Bone disorders in most cases associated with the imbalance between bone formation and bone resorption. Osteoporosis is characterized by loss of dry weight of the bone matrix. Mature activated osteoblast Razorbill bone after adhesion to bone matrix by secreting proteolytic enzyme and protons within the zone of adhesion, causing indentation and the formation of depressions on the surface of the bone during the separation of osteoblasts from the bone.

Studies have shown that the attachment of osteoblasts to bone occurs via receptors - integrins. Integrins are a superfamily of receptors mediating the processes of cell adhesion/cell and more specifically the cell/matrix, to which, in particular, αIIbβ3as a receptor of platelets (fibrinogen) and αvβ3as vitronectin receptor. Peptides containing the link RGD, and anti-αvβ3antibodies are known for their ability to inhibit the resorption of dentin and to prevent the adhesion of osteoclasts to the mineralized matrix (Horton et al. Exp. Cell. Res. (1991), 195, 368). Peptide echistatin isolated from sneineh the poison, also contains a link RGD and described as an inhibitor of the adhesion of osteoclasts to the bone, is a potent inhibitor of bone resorption in tissue culture in vitro (Sato et al. J. Cell. Biol.(1990), 111, 1713) and in vivo in rats (Ficher et al. Endocrinology(1993), 132, 1411).

Receptor αvβ3is a transmembrane glycoprotein that is used by many cells, including endothelial cells, smooth muscle cells, osteoclast and cancer cells, therefore, the compounds of formula (1) according to the invention have a wide range of applications.

Indeed, receptors αvβ3with the expression level of the membrane of osteoclasts, are essential in the process of adhesion/absorption, contribute to the formation of the cellular cytoskeleton and are involved in the formation of osteoporosis. Receptors αvβ3with the expression level of the smooth muscle cells of the aorta, stimulate their migration to neointima, resulting in arteriosclerosis and postangioplasty restenosis (rown et al., cardiovascular Res. (1994), 28, 1815). Endothelium cells secrete growth factors that are mitogenic in relation to the endothelium, and may contribute to the formation of new blood vessels (angiogenesis).

Antagonists of integrin αvβ3can also reverse the development of malignant tumors by apoptosis of angiogenic blood vessels (Brook et al. Cel. (1994) 79, 1157).

Chresh et al. (Science 1995, 270, 1500) described anti-αvβ3antibodies or antagonists of receptor αvβ3inhibiting the process of angiogenesis induced bFGF in the rat eye, a property that can be used for the treatment of retinopathy, in particular, in patients with diabetes.

In the international patent application WO-A-12181 described substituted aromatic and non-aromatic system, and in WO-A-94/08577 described substituted heterocyclic compounds as antagonists of the receptor for fibrinogen and platelet aggregation inhibitors. In EP-A-528586 and EP-A-528587 described derivatives of phenylalanine, substituted aminoalkyl or heterocycle, and in WO-A-95/32710 described aryl derivatives as inhibitors of bone resorption by osteoclasts. In WO-A-96/00574 described benzodiazepines, and in WO-A-96/00730 described compounds inhibiting fibrinogen receptor, in particular, benzodiazepines associated with nitrogen-containing 5-membered cycle, as antagonists of the vitronectin receptor. In WO 9800395, WO 99/32457 and WO 99/37621 described antagonists of vitronectin receptor, which is derived from tyrosine. In EP 0820991 declared derivatives cycloalkyl as antagonists of vitronectin receptor.

Other studies have allowed to show that derivatives of the formula (I) have high activity as antagonists of the vitronectin receptor and bone resorption via OS is Eccleston.

The invention relates to compounds of formula (I):

in any of their isomeric forms, individually or in mixtures, as well as their physiologically acceptable additive salts, in which:

G means:

R7R8N-C(=NR6)-NH-CO-

Het-NH-CO-;

Het-NH-CH2-;

Het-;

Het thus denotes monocyclic or polycyclic system, where each cycle contains from 4 to 10 aromatic or non-aromatic units, cycle or at least one of the cycles containing from 1 to 4 nitrogen atoms, unsubstituted or substituted by one or more groups R9;

R1denotes a hydrogen atom; and (C5-C14)-aryl group; a (C5-C14)aryl((C1-C4)alkyl; an amino radical, unsubstituted or monosubstituted or disubstituted by alkyl and/or acyl containing from 1 to 4 carbon atoms;

R2denotes a hydrogen atom; a halogen atom; a nitro-group; alkyl containing from 1 to 4 carbon atoms; a radical of amino, unsubstituted or monosubstituted or disubstituted by alkyl and/or acyl containing from 1 to 4 carbon atoms; a group -(CH2)0-2-CO2R5or a group -(CH2)0-2-Or SIG5;

R3means:

a hydrogen atom;

the radical-CO2R5;

radical-SO2R5or

monocyclohexyl polycyclic system, each cycle contains from 4 to 10 aromatic or non-aromatic units, cycle or at least one of the cycles containing from 1 to 4 heteroatoms selected from N, O or S, unsubstituted or substituted by one or more radicals R9,

R4IT refers; and (C1-C8)alkoxy-; and (C5-C14)aryl(C1-C4)alkoxy-; and (C5-C14)aryloxy-; and (C3-C12)cycloalkane; and (C3-C12)cycloalkyl(C1-C4)alkyloxy-; and (C1-C8)alkylcarboxylic(C1-C4)alkyloxy-; and (C5-C14)aryl(C1-C4)alkylcarboxylic(C1-C4)alkyloxy-; and (C1-C8)dialkylaminomethylcalix-; and (C5-C14)aryl(C1-C4)dialkylaminomethylcalix-; an amino radical, unsubstituted or monosubstituted or disubstituted by (C1-C4)alkyl and/or (C5-C14)aryl and/or (C5-C14)aryl(C1-C4)alkyl and/or (C1-C5)acyl, or amino acid residue (D or L;

R5means (C1-C8)alkyl, (C5-C14)aryl; and (C5-C14)aryl(C1-C4)alkyl, (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bicycloalkyl(C1-C4)alkyl; tricyclohexyl(C1-C4)alkyl; and Azania radicals: arily, alkali, cycloalkyl, bicycloalkyl and critically not substituted or substituted by one or more selected groups of R9;

R6denotes a hydrogen atom, hydroxyl group, nitro, (C1-C6)alkyl-O-CO-; or (C1-C6)alkyl-O-CO-O-;

R7and R8independently from each other represent a hydrogen atom or a radical (C1-C6)alkyl, unsubstituted or substituted R9;

R9denotes halogen; amino; nitro; hydroxyl, (C1-C4)alkyloxy-; and (C1-C4)alkylthio-; carboxy; (C1-C4)allyloxycarbonyl-; and (C1-C8)alkyl, unsubstituted or substituted by one or more halogen atoms, (C5-C14)aryl; and (C5-C14)aryl(C1-C4)alkyl-.

All radicals, which can many times be included in the compounds of formula (I), as for example, the radical R9are independent from each other and can be identical or different.

The alkyl radicals can be linear or branched. This applies also to the case when they are replaced or are members of groups such as alkoxy, alkoxycarbonyl or aralkyl.

(C1-C8)-alkyl implies radicals: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, n-isomers of these radicals, isopropyl, isobutyl, isopentyl, n is opentel, isohexyl, 3-methylpentyl, 2,3,4-trimethylpentyl, verbatim, tertbutyl, treponti. Preferred radicals can be called the group: (C1-C4)alkali, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertbutyl. Preferably the alkyl represents methyl or ethyl.

Cycloalkyl can be monocyclic, bicyclic or tricyclic. We are talking about, for example, radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl, collateralized or cyclooctadiene, which if necessary can be substituted, such as alkyl containing from 1 to 4 carbon atoms. As substituted cycloalkyl can be called 4-methylcyclohexyl and 2,3-dimethylcyclohexyl.

Bicycloalkyl and critically can be substituted or unsubstituted at any position, for example, one or more oxo groups and/or 1 or more of the same or different alkyl groups such as methyl or isopropyl, and preferably the stands. The connecting link is bi - or tricyclic radical can contain in the molecule at any position. The connection can be made using the bridging carbon atom or one of the other carbon atoms. This link can also be in any position from the point of view stereohype is, for example, in the Exo - or endo-position. As examples bicycloalkyl or critically radicals can be called campanil, bornyl, substituted, such as 1-substituted or 2-substituted, carnil, apisalome, episomal, norbornyl or nobinary.

Halogen is fluorine, bromine or iodine.

The term (C5-C14)aryl includes:

or heterocyclic (C5-C14)arily (=(C5-C14)heteroaryl), in which one or more carbon atoms of the cycle is replaced by a heteroatom, such as nitrogen, oxygen or sulphur,

or carbocyclic (C6-C14)arily.

From carbocyclic (C6-C14)arilou can be called phenyl, naphthyl, biphenyl, antrel or fluorenyl and more specifically, 1-naphthyl, 2-naphthyl and phenyl.

Unless otherwise specified, aryl radicals, in particular phenyl can be unsubstituted or substituted by one or more identical or different radicals selected from (C1-C8)alkyl, in particular (C1-C4)alkyl, hydroxyl, (C1-C8)alkyloxy, (C1-C8)alkylthio, halogen, such as fluorine, chlorine and bromine, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, trifloromethyl, methylenedioxy, cyano, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl the La, carboxy, (C1-C4)alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy.

In the case of monosubstituted phenyl Deputy may be in position 2, 3 or 4 and preferably in position 3 or 4. In the case of a disubstituted phenyl, the substituents can be in position 2, 3 or 2, 4, or 2, 5, or 2, 6 or 3, 4, or 3, 5. Preferably disubstituted in Fadilah both Deputy are in position 3, 4. If this is phenyl tizamidine, provisions will be as follows: 2, 3, 4, or 2, 3, 5, or 2, 3, 6, or 2, 4, 5, or 2, 4, 6, or 3, 4, 5. Similarly, nattily or other arily can be substituted in any position, for example, the radical of 1-naphthyl in position 2-, 3-, 4-, 5-, 6-, 7 -, and 8, and the radical 2-naphthyl in position 1-, 3-, 4-, 5-, 6 - and 7-.

(C5-C14)aryl group can also refer to an aromatic monocyclic or polycyclic system, in which 1, 2, 3 or 4 carbon atoms, loop replaced by heteroatoms, in particular, the same or different, from the group consisting of nitrogen, oxygen, and sulfur. Of the heterocyclic (C5-C14)aryl groups (=(C5-C14)heteroaryl) include groups such radicals: 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazoles, talasani, chenail, ethanolic, honokalani, hintline, cinnoline-carbonyl or benzo-condensed, cyclopent-, cyclohexa or cyclohepta - condensed derivatives of such radicals. Heterocyclic system may be substituted by the same substituents as described above in relation to the carbocyclic system.

Optically active carbon atoms contained in the compounds of formula (I)can have the R configuration and the configuration of S independently from each other.

The compounds of formula (I) can be in the form of pure enantiomers or pure diastereoisomers or in the form of mixtures of enantiomers, for example, in the form of racemates or mixtures of diastereoisomers.

Thus the present invention relates to the pure enantiomers, mixtures of these enantiomers, pure diastereoisomers or mixtures of these diastereoisomers.

The invention relates to mixtures of two or more than two stereoisomers of formula (1) and all correlations between these stereoisomers in these mixtures.

The compounds of formula (1) can if necessary be present in the form of E isomers or z isomers Thus the invention relates to the pure isomers E, pure Z isomers and mixtures of E/Z in any proportion.

The invention relates to all tautomeric forms of the compounds of formula (1), for example, in the form expressed by the formula (I), RG is G = R 7R8N-C(=NR6)-NH-CO-, consider the form in which ALLROUNDER is present in the form of group -WITH-N=C(NR6)-NR7R8and to all the other forms in which a hydrogen atom is in a different position.

Diastereoisomer containing isomers E/Z, can be divided into the individual isomers, for example, chromatography. The racemates can be separated into two enantiomers by known methods, such as chromatography in a chiral phase or by means of splitting.

Physiologically acceptable salts of the compounds of formula (I) are, in particular, pharmaceutically acceptable or non-toxic or physiologically acceptable salt.

If the compounds of formula (I) contain an acid group such as carboxylic acid, it is, for example, salts of alkali or alkaline-earth metals such as sodium, potassium, magnesium, calcium, as well as physiologically acceptable salts formed ions, Quaternary ammonium, and additive, acid salts, such as ammonia, and physiologically acceptable amines have had, for example, triethylamine, ethanolamine or Tris(2-hydroxyethyl)Amina.

If the compounds of formula (I) include alkali group, they can form an additive, acid salts, for example, inorganic acids such as hydrochloric, sulphuric, phosphoric acid, or organic carboxylic acids, such as vinegar is Aya, triperoxonane, citric, benzoic, maleic, fumaric, tartaric, methansulfonate or paratoluenesulfonyl acid.

The compounds of formula (I)containing a basic group and an acidic group, such as guanidine or carboxyl group can be present in the form zwitterions (betaines), which also belong to the present invention.

If necessary, the compounds of formula (I)containing a charged ammonium group can contain physiologically acceptable anion Q-. Preferably this is a monovalent anion or an equivalent of a polyvalent anion of an organic or neorganicheskoi non-toxic physiologically acceptable and more particularly pharmaceutically acceptable acid, for example, anion or an equivalent of an anion of one of the above acids, suitable for receiving additive salts.

For example, Q-can be one of the anions (or equivalent anion) groups selected from chlorine, sulfate, phosphate, acetate, triptoreline, citrate, benzoate, maleate, fumarata, tartrate, methanesulfonate and paratoluolsulfonata.

Salts of compounds of formula (I) can be obtained by conventional methods known to the expert, for example, by combining the compound of formula (I) with organic or inorganic acid or base in a solvent or dispersant, or another salt by the of ationally or anyoneeven.

The invention also includes all salts of the compounds of formula (I), which due to their weak physiological suitability not suitable for direct use as drugs, but are suitable as intermediate products used for further chemical transformations of compounds of formula (I), or as a source of products to obtain physiologically acceptable salts.

The present invention includes all the solvate of the compounds of formula (I), for example hydrates, solvate formed by alcohols, and all derivatives of compounds of formula (I), for example esters, prodrugs and other physiologically acceptable derivatives and metabolites of the compounds of formula (I).

More specifically the invention relates to compounds of formula (I)in which G denotes the group Het, Het-NHCO-, or Het-NH-CH2-in which Het represents:

More specifically the invention relates to compounds of formula (1)above, in which R3means

a heterocycle selected from the

and their pharmaceutically acceptable additive salts.

More specifically the invention relates to the above compounds of formula (I)in which R3means benzyloxycarbonyloxy group, and their pharmaceutically preelimination salts.

More specifically the invention relates to the above compounds of formula (I)in which R2denotes hydrogen, an alkyl radical containing from 1 to 4 carbon atoms, and mainly methyl or ethyl or a fluorine atom, and their pharmaceutically acceptable additive salts.

More specifically the invention relates to the above compounds of formula (I), in which

G means:

and their pharmaceutically acceptable additive salts.

More specifically the invention relates to the above compounds of formula (I), in which

G means:

R1denotes a hydrogen atom

R2denotes a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical,

R3means benzyloxycarbonyloxy group

R4denotes hydroxy or (C1-C4)alkyloxy-group

and their pharmaceutically acceptable additive salts.

More specifically the invention relates to compounds of formula (1)with the following names:

3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

3-[[5-ethyl-6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

3-[[6-[4-(1,2,3,4-then it is carbonated the ro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

3-[[6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines

3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]Isopropylamine

(1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate

(1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate

(1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulfonyl)alaninate

with the configuration (R) or configuration (S) or their mixtures, and their additive salts.

The present invention relates also to a method for producing compounds of formula (I). Usually the connection can be obtained, for example, in the process of convergent synthesis by combining two or more fragments which can be obtained by reverse synatom from compounds of formula (I). To ensure that at each stage of the synthesis of functional groups does not lead to undesirable secondary reactions, it may be desirable or necessary in the IMO in the process of synthesis of compounds of formula (I) to introduce functional groups in the form of precursors, which then is converted into the desired functional groups, or to temporarily block these functional groups, using well-known specialist and acceptable for the synthesis strategy for the use of protection groups (Green, Wuts protective Group in Organic Synthesis, Willet 1991).

Thus the compounds of formula (I) can be obtained according to the following scheme:

Therefore the invention relates to a method for producing compounds of formula (I)in which:

lead in the interaction of the compound of formula (II)

in which R1, R2, R3and R4are as described above,

a) with the compound of the formula (III)

in which G corresponds described above, in the presence of a base or reagent that binds transition metal

b) then the compound of formula (I) may expose the splitting of the functional group, R3-NH - in order to restore the free amine, followed by or radicals R3structure-CO2-R5or-SO2-R5and/or, if necessary, hydrolysis and possibly the esterification or amidation and/or salt formation.

In the embodiment, the invention relates also to a method for producing compounds of formula (I), in which

a) lead in ot the activity of the compound of formula (II), the corresponding described above, with the compound of the formula (IIIA)

to obtain the intermediate compounds of formula (IV):

b) then bring in the interaction of the compound of the formula Het-NH2and get the connection formula (I), where G denotes the group Het-NH-,

C) then, the resulting compound of formula (I) may expose the splitting of the functional group, R3-NH - in order to restore the free amine, followed by or radicals R3structure-CO2-R5or-SO2-R5and/or, if necessary, the esterification or amidation and/or salt formation.

The combination of the compounds of formula (II) with a piperidine derivative of formula (III) or (IIIA) can be done by boiling under reflux in the presence of sterically constrained strong bases. More specifically, use diisopropylethylamine. The reaction may proceed under reflux for 4-12 hours.

As for the compounds of formula (IV), if OR represents hydroxyl, i.e. if the guanidine of the formula (Het-NH2) interacts with the carboxylic acid of formula (IV), carboxylic acid pre-trigger.

Activation can be performed, for example, using dicyclohexylcarbodiimide (DCCI) or O-((cyano(taxicab who yl)methylene)amino)-1,1,3,3-tetramethyluronium of tetrafluoroborate (TOTU; König et al, Proc. 21stEurop. Peptide Symp.1990 (Eds Giralt, Andreu, Escom, Leiden 1991, p.243) or other activating agents commonly used in peptide synthesis.

In addition to free guanidino formula (Het-NH2you can also use the salts of guanidine to interact with the compounds of the formula (IV), and available guanidine receive in situ or in a separate stage with the base.

The interaction of activated carboxylic acid derivative of the formula (IV) with guanidine (or derivative) of the formula (Het-NH2) is preferably carried out in a known manner in an organic proton or aprotic, but an inert solvent. In this case, use a solvent, such as methanol, isopropanol, tertbutanol, dimethylformamide, dichloromethane or tetrahydrofuran at a temperature from 0°C to the boiling temperature under reflux of these solvents, in particular, the complex interaction of the methyl or ethyl esters (OR denotes methoxy or ethoxy) guanidine.

Interaction of the compounds of the formula (IV) with free guanidine mainly carried out in inert aprotic solvent such as dimethylformamide, dichloromethane, tetrahydrofuran, dimethoxyethane or dioxane, if necessary, adding a base, such as, for example, tertbutoxide potassium methoxide, sodium or body of the economic base, such as N-methylmorpholine. However, as a solvent in the interaction of compounds of the formula (IV) with guanidine formula (Het-NH2you can also use water, for example, in the case of using such bases as sodium hydroxide.

Then the reaction mixture is treated and, if necessary, the reaction product is purified well-known specialist of ways.

The protective groups may be present in the compounds of formula (I)obtained from compounds of formula (IV) with amines or guanidines formula (Het-NH2) or from compounds of formula (II) with compounds of the formula (III), then remove by conventional methods, for example, the group of complex tertbutylamine transformed into a carboxylic acid by treatment triperoxonane acid, benzyl group is removed by hydrogenation or fluorenylmethoxycarbonyl group is removed in the presence of a secondary amine, used and other reaction carried out by known methods, for example by acylation.

Hydrolysis to obtain the derived acid (COR4= CO2H), esterification to obtain the complex ester or prodrug (mainly COR4= allyloxycarbonyl or aryloxyalkyl from the corresponding acid) or amidation (COR4= mono or disubstituted aminocarbonyl from the corresponding acid) spend a cent the traditional ways, well-known specialist.

In particular, the hydrolysis is carried out in an acid medium in the presence of triperoxonane acid, for example, in a halogenated organic solvent, such as, for example, dichloromethane.

In case you need translation in physiologically acceptable salts by prominent specialist methods.

The initial compounds of the formula (II) can be obtained are described in the literature methods or by analogy. Obtaining compounds of formula (II) illustrates the above-described scheme, provided that the present invention is not limited to such methods of synthesis or such original products. For professionals is not very difficult to modify described in this application, the methods of synthesis for the preparation of other compounds of formula (II) according to the invention.

Therefore the invention relates to a method for producing compounds of the formula (II), characterized in that it is injected into the interaction of the compound of formula (V):

in which R1and R2are as described above, and X denotes halogen, preferably chlorine,

with the compound of the formula (VI)

in which R3and R4are as described above, in the presence of a strong base.

Usually use steric shortness of strong base is s, such as diisopropylethylamine, well-known specialist of the reaction the condition of implementation of nucleophilic substitution. Preferably the reaction is carried out in the presence of dimethylformamide at the boiling temperature under reflux. In addition COR4 group preferably denotes a group steric obstruction of ester, such as tertbutyloxycarbonyl group.

In accordance with another variant of the invention, the products of formula (I) can also be obtained according to the following scheme:

In accordance with the invention, a method of obtaining compounds of formula (I) is that

a) result in the interaction of the compound of formula (IIA)

in which R1, R2, G, and X are as described above,

with the compound of the formula (VI)

in which R3and R4are as described above, or in the presence of a strong base, or by catalysis with palladium

b) then the compound of formula (I) may expose the splitting of the functional group, R3-NH - in order to restore the free amine with subsequent or radicals R3structure-CO2-R5or-SO2-R5and/or, if necessary, hydrolysis and possibly esterification, or amitirova the Yu, and/or salt formation.

The interaction of a pyrimidine of formula (IIa) with an amine of General formula (VI) is conducted under conditions similar to those described above in relation to the interaction between the pyrimidine of formula (V) with an amine of General formula (VI). In particular it is possible to carry out the process in diisopropylethylamine in an organic solvent such as an amide (dimethylacetamide, dimethylformamide, for example) at a temperature from 90°C to the boiling temperature under reflux the reaction mixture. You can also use the catalysis with palladium (for example, Tris(dibenzylideneacetone)diplodia) in the presence of cesium fluoride at the temperature of boiling under reflux the reaction mixture. It should be borne in mind that functional groups which are able to interfere in the reaction, are protected. Protection and transfer of these groups in the free state is carried out in traditional ways without changing the remainder of the molecule.

Condensation of the radicals R3structure-CO2-R5or-SO2-R5free Amina and hydrolysis were carried out as described above.

Derivatives of pyrimidine of formula (IIa) can be obtained by the coupling of compounds of formula (III)

in which G corresponds described above, with dehalogenating pyrimidine derivative of the formula (V)

in R 1, R2, G, and X are as described above.

The interaction mainly occurs in the presence of steric obstruction of a strong base at a temperature of boiling under reflux the reaction mixture. The process is carried out under the conditions described below in the examples, and, in particular, in the presence of sterically constrained amine, such as diisopropylethylamine in amide, such as dimethylacetamide. It should be borne in mind that functional groups which are able to interfere in the reaction, are protected. Protection and transfer of these groups in the free state is carried out in traditional ways without changing the remainder of the molecule.

The compounds of formula (I) are compounds having pharmacological activity and can thus be used, in particular, as medicaments, particularly for the treatment or prevention of bone diseases, neoplastic diseases, and cardiovascular diseases.

Thus the present invention relates to compounds of formula (I) and/or their physiologically acceptable salts as a drug.

The compounds of formula (I)and their physiologically acceptable salts and their prodrugs can be entered to animals, preferably mammals, and more specifically to a man as a drug who's funds for therapeutic or prophylactic purposes.

They can be used as such or in a mixture with one or more other compounds of formula (I) or in the form of a pharmaceutical preparation (pharmaceutical composition), which can be introduced through the small intestine or parenterally, and containing as active substance an effective amount of at least one of the compounds of formula (I) and/or its physiologically acceptable salts, as well as traditional and inert in medicinal respect to the fillers and/or auxiliaries.

The pharmaceutical compositions according to the invention, which can be introduced through the small intestine or parenteral, contain as active substance an effective amount of at least one of the compounds of formula (I) and/or its physiologically acceptable salts, and also typically used one or more fillers and/or one or more auxiliary substances.

Thus the present invention relates to pharmaceutical compositions containing a compound of the formula (I), such as described above, and one or more excipients.

Medicines can be administered orally, for example in the form of pills, tablets, coated tablets, coated with a thin film, granules, gelatin capsules and soft capsules, solutions, syrups, emulsions, suspensions or aerosol with the Yessei.

You can perform rectal administration, for example, in the form of a suppository, parenteral administration, for example, in the form of solutions for injection or infusion, microcapsules or implants for insertion through the skin, for example, in the form of ointments, solutions, pigments or dyes, through the dermis in the form of patches or other methods, for example, in the form of aerosols or nasal spray.

The pharmaceutical compositions according to the invention can be obtained by known methods, and the organic or inorganic inert in drug against the fillers added to the compounds of formula (I) and/or their physiologically acceptable salts.

To obtain pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Media acceptable for soft gelatin capsules or suppositories are, for example, fats, waxes, semi-solid or liquid polyols, natural or modified oils, etc. Carriers acceptable to obtain solutions, for example injection solutions, emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Carriers acceptable to the microcapsules or the implant is in, are, for example, copolymers glyoxalase acid and lactic acid. Usually medicines contain from 0.5 to 90 wt.% compounds of formula (I) and/or their physiologically acceptable salts.

In addition to the active ingredients and carriers medicines may contain auxiliary substances, such as, for example, diluents, disintegrators, binders, lubricants, surfactants, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, buffers, and solvents or solubilizing means or additives to achieve the effect of a slow-release, as well as salts for changing the osmotic pressure of the substance to the shell or antioxidants.

They can also contain two or more compounds of the formula (I) and/or their physiologically acceptable salts. In addition to at least one or more compounds of the formula (I) and/or their physiologically acceptable salts they may contain at least one or more other active substances, applicable in therapeutic or prophylactic purposes.

Pharmaceutical (pharmaceutical composition) typically contain from 0.2 to 500 mg and preferably from 1 to 200 mg of the compounds of formula (I) and/or its physiologically acceptable salts and/or prodrugs.

The compounds of formula (I) t is Auda, in particular, antagonists of the vitronectin receptor and is able, therefore, to inhibit the adhesion of osteoclasts to the bone surface and, therefore, bone resorption by osteoclasts.

The effect of the compounds of formula (I) can be demonstrated on the example test, which determine the inhibition of the binding of vitronectin with cells containing the receptor for vitronectin. More details on this test are described below. The compounds of formula (I) and/or their physiologically acceptable salts can be typically used as vitronectin receptor antagonists for the treatment or prevention of diseases associated with the interaction between vitronectin receptors and their ligands in the processes of interaction of cell-cell or cell-matrix or processes that may be influenced by the inhibition of interactions of this type to achieve remission or cure, if you want inhibition of interactions of this type. As mentioned above, this interaction plays an important role in bone resorption, angiogenesis or cell proliferation in vascular smooth muscle.

Bone diseases, treatment or prevention of which require the use of compounds of formula (I)are, in particular, osteoporosis, hypercalcemia, osteopenia caused, for example, bone metastases, oral diseases, such as periodontitis, hyperpure areas, particularlie erosion in rheumatoid arthritis and disease Paget. In addition, the compounds of formula (I) can be used to help prevent or treat bone disorders caused by treatment with corticosteroids, therapeutic treatment with steroids or corticosteroids or caused by lack of male or female sex hormones.

All these disorders are associated with bone loss in the result of the imbalance between the processes of bone formation and bone destruction, a beneficial effect on which has the inhibition of bone resorption by osteoclasts. Along with the specified application as an inhibitor of bone resorption by osteoclasts, the compounds of formula (I) and/or their physiologically acceptable salts are used as inhibitors of tumor growth and cancer metastasis, for treatment of inflammation, for the treatment or prevention of cardiovascular diseases such as arteriosclerosis or restenosis, or for the treatment or prevention of nephropathy or retinopathy, such as diabetic retinopathy.

Compounds according to the invention may also have activity against other integrins that interact with the ligand through Tripeptide sequence RGD (αvβ1αvβ5αIIbβ3,), p is alausa them pharmacological properties, suitable for the treatment of pathologies associated with these receptors.

Such activity against integrins makes the compounds of formula (I) are suitable for the prevention or treatment of some diseases, such as above or browse Dermot Cox DN§P 8(4) may 1995, 197-205, the content of which is incorporated into the present application.

Thus, more specifically, the present invention relates to the compound of formula (I) and/or its physiologically acceptable salts, such as described above, as a medicinal product with the activity of the vitronectin receptor antagonist.

Thus, more specifically, the present invention relates to the compound of formula (I) and/or its physiologically acceptable salts and/or prodrugs, as described above, as drugs having inhibitory activity against bone resorption, or for the treatment or prevention of osteoporosis.

Thus, more specifically, the present invention relates to the compound of formula (I) and/or its physiologically acceptable salts, such as described above, as drugs having inhibitory activity against the growth of tumors or cancer metastasis.

Thus, more specifically, the present invention relates to the compound of formula (I) and/or its physiologically acceptable is m salts, as described above, as a drug having anti-inflammatory activity or for the treatment or prevention of cardiovascular diseases, restenosis, arteriosclerosis, nephropathy or retinopathy.

Thus, the present invention also relates to the compound of formula (I) and/or its physiologically acceptable salts, such as described above, to obtain drugs designed to inhibit the growth of tumors or cancer metastasis.

Thus, the present invention also relates to the compound of formula (I) and/or its physiologically acceptable salts, such as described above, to obtain drugs intended for the treatment or prevention of cardiovascular diseases, restenosis, arteriosclerosis, nephropathy or retinopathy.

When using compounds of formula (I) dose can vary within wide limits and should be installed depending on the patient. For example, they depend on the connection you use, or the nature and severity of the disease, should be considered is whether the disease is acute or chronic illnesses or treatment is preventive.

By oral administration a daily dose of from 0.01 to 100 mg/kg and preferably from 0.1 to 50 mg/kg, in particular from 0.1 to 5 mg/kg, for Example, d is I an adult weighing 75 kg, the daily dose may be from 0.3 to 0.5 mg/kg

Intravenous daily dose is from about 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg

The daily dose may be divided, especially in the case of appointment of a large dose of the active substance, 2, 3 or 4 admission. If necessary, depending on individual tolerance can be assigned to different doses with their increase or decrease. In addition to the use of compounds of formula (I) in the quality of medicines, you can also use them as a carrier or support active substances for the implementation of specific delivery of such active substances on site activity (Drug targeting, see Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed. Born, G.V.R et al, Springer Verlag). Deliver active substances can be, in particular, substances used for the treatment or prevention of the above diseases.

The compounds of formula (I) and/or their salts can also be used as agents for the diagnosis of, for example, in methods in vitro or as auxiliary substances for biochemical studies, which require blocking of vitronectin receptor or impact on the interaction of cell-cell or cell-matrices. They can also be used as intermediates for other compounds, in particular, other active substances, which receive the compounds of formula (I), for example, by modification or by introducing radicals or functional groups.

Examples

The products were identified by infrared (IR) mass spectrum (MS) and/or NMR spectrum. Compounds that cleanse chromatography using eluent containing, for example, acetic or triperoxonane acid, and then dried, or using, for example, triperoxonane acid to remove the protective tertbutylphenol group at the last stage of the synthesis, sometimes contain, depending on the method used for drying the product, acid, originating from the eluent or the last stage of the synthesis, and therefore fully or partially are in the form of an acid salt used, for example, in the form of a salt or acetic triperoxonane acid. They can also be gidrirovanny to a greater or lesser extent.

Possibly used abbreviations/chemical name

AcOEt: ethyl acetate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; DMF: dimethylformamide; DIPEA: diisopropylethylamine; MeOH: methanol; TEA: triethylamine; TFA: triperoxonane acid; THF: tetrahydrofuran; MCPBA: a meta-chloroperoxybenzoic acid; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; APTS: paratoluenesulfonyl; DPPA: diphenylphosphoryl; DMSO: dimethyl sulfoxide; Pd/C: palladium on coal; Boc: tertbutoxycarbonyl; CBz: benzyloxy arbonyl; DCC: 1,3-dicyclohexylcarbodiimide; TMSBr: bromotrimethylsilane; TMSI: trimethylsilane iodide.

IR: infrared; RMN: nuclear magnetic resonance; SM: mass spectrum; ESP: Electrospray mode positif; EP.: shoulder; F: strong; s: singlet; d: doublet; t: triplet; q: quadruplet; Queen: quintet; ush: extended; m: multiplet or array; J: constant connection; Rf: retention index (chromatography).

It should be borne in mind that in the following examples, the products in examples 1-5 have the racemic form, the products in examples 6-9, 11 and 13-14, and their ester-precursors are of the form (S) in the asymmetric center 3-aminoadenine, and the products in examples 10 and 12 and, if necessary, their esters-predecessors are of the form (R) in the asymmetric center 3-aminoadenine.

Preparation 1

Synthesis of 4,6-dichloro-5-ethylpyrimidine (compound of formula (V)

A mixture of 5 g (35,7 mmol) of 5-ethyl-4,6-dihydroxypyrimidine (manufactured by Aldrich) in 30 ml of phosphorus oxychloride is refluxed for 1 hour. After cooling to ambient temperature is injected dropwise a mixture of 4 ml of N,N-diethylaniline in 10 ml of phosphorus oxychloride and the resulting heated under reflux for 4 hours. After cooling to ambient temperature the reaction medium is poured into a mixture of ice water. Extracted with ethyl acetate, the m washed the organic phase 2N hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. Receive 6 g (yield=95%) of the desired product in the form of oil chestnut colors used further as such.

SMS: Rf=0.5 (silica gel, eluent: dichloromethane-methanol 90-10).

Example 1

3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptorelin)

Stage a)

Synthesis of (1,1-dimethylethyl)-3-[(6-chloro-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

In a mixture of 3.8 g (21 mmol) of 4,6-dichloro-5-ethylpyrimidine and 4.4 g (15 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained by the method described in J.Med.Chem.(2001), 44(8), 1158-1176) in 50 ml of dimethylformamide injected 10 ml of diisopropylethylamine, then heated the mixture to 120°C for 6 hours. Then the dimethylformamide is removed under vacuum and treat the residue with a mixture of ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is decanted, dried on magnesium sulfate and the solvent is removed by evaporation in a vacuum. The remainder chromatographic on silica gel, elwira gradient from 100% heptane to heptane-ethyl acetate 50-50. Obtain 4.7 g (Yield=70%) of the desired product as oil.

SMS:Rf=0,2 (silicagel the ü, eluent: heptane-ethyl acetate 70-30)

IR (CHCl3):3411 (NH); 1718 (C=O); 1571; 1498 cm-1(Heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.02 (t, 3H, CH2-CH3); of 1.30 (s, 9H, tBu); to 2.57 (q, 2H,CH2-CH3); 3,74 (m, 2H, NH-CH2-CH-NH); 4,29 (ush. kV, 1H, NH-CH2-CH-NH); 5.00 and 5,06 (Syst. AB, 2H, O-CH2-Ph); 7,22 (ush. t, 1H,NH-CH2-CH-NH), 7,34 (m, 5H, Ph); to 7.64 (ush. d, 1H, NH-CH2-CH-NH), 8,16 h/m (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=26 min): 435 (MH+); 379 (MH-tBu+).

Stage b)

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

A mixture of 1.68 g (3 mmol) of 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthiridine, Tris(triptoreline) (obtained in accordance with the patents ER or WO 0078317) and 7.5 g (14.1 mmol equivalents of base) aminomethylpropanol (Polymer Labs 1.88 mmol/g) in 200 ml dichloromethane-methanol 50-50 shaken at ambient temperature for 1 hour. The mixture is filtered, the resin washed with methanol and dichloromethane and the filtrate concentrated to dryness in vacuo, and obtain 630 mg of the free amine. In the remainder enter 651 mg (1.5 mmol) of (1,1-dimethylethyl)-3-[(6-chloro-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 2 ml of diisopropylethylamine and heated with reverse Kholodilin the com within 8 hours. The reaction medium is evaporated in vacuum and treat the residue with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel, elwira consistently pure dichloromethane, a mixture of dichloromethane-methanol 90-10, then a mixture of dichloromethane-methanol-water-acetic acid 90-10-1-1. Obtain 115 mg (Yield=12%) of the desired product as oil. Get 280 mg (43%) source of chlorine-containing product.

SMS:Rf=0,55 (alumina, eluent: heptane-ethyl acetate 50-50)

IR (CHCl3):3438 (NH 1717 (C=O); 1583; 1500 cm-1(Heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.06 (t, 3H, CH2-CH3); to 1.31 (s, 9H, tBu); or 1.77 (m, 2H, CH2-CH2-CH2-NH); of 1.78 (m, 4H,CH2-CH-CH2); 2,43 (q, 2H,CH2-CH3); of 2.51 (m, 1H, CH2-CH-CH2); 2,61 (m, 2H,CH2-CH2-CH2-NH), 2,82 and 3,44 (2m, 4H,CH2-CH2-N-CH2-CH2); 3,23 (m, 2H, CH2-CH2-CH2-NH); and 3.72 (m, 2H, NH-CH2-CH-NH); to 4.23 (m, 1H, NH-CH2-CH-NH); 5,03 (ush. d, 2H,CH2-Ph); to 6.22 (m, 1H, CH2-CH2-CH2-NH); 6,30 and 7,05 (2m, 2H, H naphthiridine); 6,35 (m, 1H,NH-CH2-CH-NH); 7,34 (m, 5H, Ph); 7,60 (m, 1H, NH-CH2-CH-NH); 8,11 h/m (N=CH-N).

HPLC/mass spectrum:(tr=14 min) : 4616 (MH+).

Stage C)

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline).

Shake 110 mg (0.18 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 5 ml of dichloromethane with 1 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2CL2-Meon-N2On-Asón 90-10-1-1). Add toluene and the reaction medium is evaporated to dryness in a vacuum. The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 108 mg (Yield=76%) of the desired product as an amorphous solid.

SMS:Rf=0,33 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1))

IR (CHCl3):1677 (C=O); 1626; 1586; 1500 cm-1(Heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.07 (t, 3H, CH2-CH3); 1.77 and 1,94 (2m, 4H, N-CH2-CH2-CH-); of 1.84 (m, 2H, NH-CH2-CH2-CH2-); of 2.45 (q, 2H, CH2-CH3); to 2.75 (t, 2H, NH-CH2-CH2-CH2-); 2,85 (t, 1H, N-CH2-CH2-CH-), 2,98, and 3,53 (2 m, 4H, N-CH2-CH2-CH-);of 3.43 (m, 2H, N-CH2-CH2-CH2-); 3,61 and 3.85 (2 m, 2H, NH-CH2-CH-NH); 4,32 (kV, 1H, NH-CH2-CH-NH); 4.99 and 5,04 (Syst. AB, 2H, O-CH2-Ph); 6.67 (d, 1H, H naphthiridine); 7,22 (ush. s, 1H, NH-CH2-CH-NH); 7,35 (m, 5H, Ph); of 7.60 (d, 1H, NH-CH2-CH-NH); to 7.64 (d, 1H, H naphthiridine), compared to 8.26 (s, 1H, N=CH-N); 8,29 h/m (ush. s, 1H, NH-CH2-CH2-CH2-).

HPLC/mass spectrum: (tr=8,0 min): 560 (MH+); 427 (MH-naphthiridine+); 280 (M+2H++).

Microanalysis:

Theoretically,: With=51,84%; N=4,99%; N=12,45%;

Found: C=52,0%; N=5,2%; N=12,4%;

Example 2

3-[[5-ethyl-6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy) carbonyl]alanine

Stage a)

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(methoxycarbonyl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

A mixture of 1.2 g (2.8 mmol) of (1,1-dimethylethyl)-3-[(6-chloro-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate, 5 ml of methyl-4-piperidinecarboxylate and 1 ml of isopropylethylene heated to a temperature of from 110 to 120°C for 4 hours. After cooling to ambient temperature the reaction medium is treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, then concentrated to dryness in vacuo. The remainder chromatographic on silica gel, elwira gradient from pure heptane to pure this is lazette. Obtain 260 mg (Yield=17%) of the desired product as oil.

SMS:Rf=0.36 and (silica gel, eluent: heptane-ethyl acetate 50-50)

IR (CHCl3):3422 (NH); 1725 (C=O); 1582; 1499 cm-1(Heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.05 (t, 3H, CH2-CH3); of 1.30 (s, 9H, tBu); 1,67 and a 1.88 (2m, 4H, N-CH2-CH2-CH); 2.40 a (q, 2H,CH2-CH3); of 2.50 (m, 1H, N-CH2-CH2-CH); 2,81 and 3.33 (2m, 4H, N-CH2-CH2-CH); 3,62 (s, 3H, O-CH3); 3,71 (m, 2H, NH-CH2-CH-NH); 4,22 (kV, 1H, NH-CH2-CH-NH); 5,02 (s, 2H, O-CH2-Ph); 6,36 (t, 1H,NH-CH2-CH-NH); 7,34 (m, 5H, Ph); to 7.64 (d, 1H, NH-CH2-CH-NH); 8,10 h/m (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=12 min) : 564 (MNa+); 542 (MH+); 486 (MN-tBu+).

Stage b)

Synthesis of 3-[[5-ethyl-6-[4-[(1,2,3,4-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

A mixture of 250 mg (0.46 mmol) of 3-[[5-ethyl-6-[4-(methoxycarbonyl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 200 mg (2.0 mmol) 2-amino-1,4,5,6-tetrahydropyrimidine (obtained in accordance with R.F.Evans J.Chem.Soc. 1964, 2450-2455)) in 15 ml of dichloromethane is shaken at ambient temperature for 24 hours. After evaporation to dryness the residue chromatographic on silica gel, elwira gradienta from pure dichloromethane to a mixture of dichloromethane-the ethanol-water-acetic acid 85-15-2-2. After evaporation of the solvent the desired fractions, the residue is treated with a minimum amount of methanol-dichloromethane 50-50 and the acid is precipitated by adding a simple ethyl ester. Filtered, dried to dryness in a vacuum and get 18 mg (Yield=7%) of the desired product in the form of a solid amorphous substance.

SMS:Rf=0.5 (silica gel, eluent: dichloromethane-methanol-acetic acid 70-20-10)

IR (CHCl3):3287 (HE/NH); 1700; 1600 (C=O); 1582; 1499 cm-1(Heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.05 (t, 3H, CH2-CH3); 1,67 and 1.86 (2m, 4H, N-CH2-CH2-CH-); of 1.80 (m, 2H, NH-CH2-CH2-CH2-NH); and 2.26 (m, 1H, N-CH2-CH2-CH-); of 2.38 (m, 2H,CH2-CH3); 2,78 and 3.33 (2m, 4H, N-CH2-CH2-CH-), 3,24 (m, 4H, NH-CH2-CH2-CH2-NH); 3,42 and 3.75 (2m, 2H, NH-CH2-CH-NH); 4,08 (m, 1H, NH-CH2-CH-NH), and 5,00 4,95 (Syst AB, 2H, O-CH2-Ph); 6,10 (ush. t, 1H,NH-CH2-CH-NH); 6,74 (ush. s, 1H, NH-CH2-CH-NH); 7,30 (m, 5H, Ph); with 8.05 (s, 1H, N=CHN); 8,55 h/m (ush. s, 2H,NH-CH2-CH2-CH2-NH).

HPLC/mass spectrum:(tr=6 min): 553(MH+); 364 (MH-tBu-PhCH2+); 320 (MH-tBu-Z+).

Example 3

3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

Stage a)

Synthesis of (1,1-dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimido the yl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated to 120°With a mixture of 325 mg (2 mmol) of 4,6-dichloro-5-methylpyrimidine (manufactured SPECS), 600 mg (2 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176) in 3 ml of dimethylformamide and 3 ml of diisopropylethylamine during the night. Reaction medium was concentrated to dryness in vacuo and the residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated in vacuum. The remainder chromatographic on silica gel, elwira gradient from heptane (100%) to a mixture of heptane-ethyl acetate (50-50). Receive 450 mg (Yield=53%) of the desired product as oil.

SMS:Rf=0.5 (silica gel, eluent: ethyl acetate-heptane 25-75)

1H-NMR (CDCl3):δ to 1.48 (s, 9H, tBu); of 2.08 (s, 3H,CH3); 3,80 and 3.97 (2m, 2H, NH-CH2-CH-NH); 4,50 (m, 1H, NH-CH2-CH-NH); 5,08 and 5,15 (Syst AB, 2H, O-CH2-Ph); 5,86 (ush. d, 1H, NH-CH2-CH-NH); 6,12 (ush. s, 1H,NH-CH2-CH-NH); 7,35 (m, 5H, Ph); 8,30 h/m (s, 1H, N=CH-N).

Mass spectrum (FAB): 421 (MH+); 365 (MH-tBu).

Stage b)

Synthesis of (1,1-dimethylethyl)-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate/p>

A mixture of 370 mg (0.88 mmol) of (1,1-dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 1.0 g (1,79 mmol) 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthiridine, Tris(triptorelin) (obtained in accordance with patineta ER or WO 0078317) in 1 ml of diisopropylethylamine heated to 120°C for 2 hours. Then injected 10 ml of xylene and heated environment under reflux for 4 hours. The reaction medium is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then evaporated to dryness in vacuo and the residue chromatographic on silica gel, elwira gradient from ethyl acetate to 100% to a mixture of ethyl acetate-methanol-triethylamine-dichloromethane 50-10-10-50. Obtain 32 mg (yield=6%) of the target product, and 200 mg (54%) of the original chlorine-containing product.

SMS:Rf=0.6 (silica gel, eluent: ethyl acetate-dichloromethane-methanol 50-40-10)

1H-NMR (CDCl3):δ for 1.49 (s, 9H, tBu); of 1.97 (m, 2H, NH-CH2-CH2-CH2); a 2.01 (s, 3H,CH3); to 2.18 (m, 4H, N-CH2-CH2-CH); and 2.79 (m, 2H, NH-CH2-CH2-CH2); 2,98 (m, 1H, N-CH2-CH2-CH); 3,39 and the 3.89 (2m, 4H, N-CH2-CH2-CH); to 3.52 (m, 2H, NH-CH2-CH2-CH ); of 3.77 and 4.09 to (2m, 2H, NH-CH2-CH-NH); 4,47 (m, 1H, NH-CH2-CH-NH); 5,13 (ush. s, 2H, O-CH2-Ph); of 5.92 (ush. s, 1H, NH-CH2-CH-NH); 6,47 (ush. d, 1H, H naphthiridine); 7,37 (m, 5H, Ph); 7,38 (m, 1H, H naphthiridine); to 8.41; 8,68 and 14,80 h/m (WS. s, 3H, N=CH-N and mobile).

Mass spectrum:602(MH+); 546 (MH-tBu +).

Stage C)

Synthesis of 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

When the ambient temperature is shaken mixture of 38 mg (0.06 mmol) of (1,1-dimethylethyl)-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 2 ml triperoxonane acid in 10 ml of dichloromethane for 3 hours. Then injected 5 ml of toluene and the mixture is evaporated to dryness. Get 26 mg (Yield=76%) of the desired product in the form of a solid amorphous substance.

SMS:Rf=0.8 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1)

1H-NMR (DSO-d6):δ of 1.84 (m, 2H, NH-CH2-CH2-CH2); of 1.92 (s, 3H),CH3); 1,75 and 1,91 (2m, 4H, N-CH2-CH2-CH); is 2.74 (m, 2H, NH-CH2-CH2-CH2); 2,84 (m, 1H, N-CH2-CH2-CH); 2,92 and 3.67 (2m, 4H, N-CH2-CH2-CH); 3,44 (m, 2H, NH-CH2-CH2-CH2); 3,63 and 3,82 (2m, 2H, NH-CH2-CH-NH); the 4.29 (m, 1H, NH-CH2-CH-NH); 5,02 (ush. s, 2H, O-CH2-Ph); and 6.6 (d, 1H, H naphthiridine); 7,20-7,40 (m, 5H, Ph); to 7.64 (ush. d, 1H, NH-CH2-CH-NH); the 7.65 (d, 1H, H naphthiridine); 7,82 and 8,21 h/m (WS. s, 3H, N=CH-N and mobile).

HPLC/mass spectrum:(tr=7 min), 546(MH+); 273 (MH+2H++).

Example 4

3-[[6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine

Stage a)

Synthesis of (1,1-dimethylethyl)-3-[[6-[4-(methoxycarbonyl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux a mixture of 80 mg (0,19 mmol) of (1,1-dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate and 3 ml of 4-methylpiperidine for 3 hours. After cooling, the reaction medium is treated with water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated to dryness in a vacuum. The remainder chromatographic on silica gel, elwira gradient from heptane (100%) to a mixture of heptane-ethyl acetate (50-50). Receive 25 mg (Yield=25%) of the desired product as oil.

SMS:Rf=0,3 (silica gel, eluent: ethyl acetate-heptane 50-50)

IR (CHCl3):3421 (NH); 1724 (C=O); 1585; 1501 cm-1(C=C, C=N).

1H-NMR (D the SO-d6): δ is 1.31 (s, 9H, tBu); 1,68 (ush. kV, 2H,CH2-CH(C=O)); to 1.87 (m, 2H,CH2-CH(C=O)); to 1.87 (s, 3H,CH3-C=); of 2.51 (hidden, 1H, -CH2-CH-CH2-); 2,80 (ush. t, 2H, -N- (CH2)2-(CH2)2-); 3,44 (ush. d, 2H, -N-(CH2)2-(CH2)2-); 3,62 (s, 3H,CH3-Oh); 3,71 (m, 2H, NH-CH2-CH-NH-); 4,22 (m, 1H, NH-CH2-CH-NH-); 5,03 (ush. s, 2H, O-CH2-Ph); 6,35 (ush. s, 1H,NH-CH2-CH-NH-); 7,34 (m, 5H, Ph); 7,63 (ush. d, 1H, NH-CH2-CH-NH-); 8,08 h/m (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=17 min) 528 (MH+); 472 (MH-tBu+).

Stage b)

Synthesis of 3-[[6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl]aminocarbonyl]-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine.

When the ambient temperature is shaken mixture of 100 mg (0,19 mmol) of (1,1-dimethylethyl)-3-[[6-[4-(methoxycarbonyl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 150 mg (1.5 mmol) 2-amino-1,4,5,6-tetrahydropyrimidine (obtained in accordance with R.F.Evans J.Chem.Soc. 1964, 2450-2455)) in 10 ml of dichloromethane for 5 hours. The reaction mixture is evaporated to dryness and the residue chromatographic on silica gel, elwira a mixture of dichloromethane-methanol-water-acetic acid 85-15-2-2.

Receive 10 mg (Yield=10%) of the desired product in the form of a solid amorphous substance.

SMS:Rf=0,4 (silica gel, eluent: dichloromethane-m is thanol-water-acetic acid 85-15-2-2).

1H-NMR (DSO-d6):δ 1.64 and of 1.74 (2m, 4H, N-CH2-CH2-CH); 1.77 in (m, 2H, NH-CH2-CH2-CH2-NH); of 1.85 (s, 3H),CH3); 2,11 (m, 1H, N-CH2-CH2-CH);. 3,17 (m, 4H, NH-CH2-CH2-CH2-NH); 2,68 and 3,42 (2m, 4H, N-CH2-CH2-CH); 3.30, and 3,62 (2m, 2H, HN-CH2-CH-NH); to 3.73 (m, 1H, N-CH2-CH-NH); 5,00 (m, 2H, O-CH2-Ph); 6,54 (ush. d, 1H, NH-CH2-CH-NH); 6,77 (ush. s, 1H,NH-CH2-CH-NH); 7,33 (m, 5H, Ph); 8,04 h/m (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=min 1,9) 1077 (2MH+); 539 (MH+); 440 (MN-aminotetrahydrofuran+).

Example 5

3-[[5-ethyl-6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines, dichlorhydrate

In 4 ml of ethanol, cooled to -12°C. in a nitrogen atmosphere, enter 160 ál (2,19 mmol) of thionyl chloride and the mixture is shaken for 30 minutes. Then introduce a solution of 354 mg (0.45 mmol) of 3-[[5-ethyl-6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline) in 13 ml of ethanol. The mixture was shaken for 30 min at -12°C., then left to warm to ambient temperature and finally heated to 40°C for 4 hours in nitrogen atmosphere. The reaction mixture is evaporated to dryness in vacuo and the residue is crystallized in a mixture of simple diisopropanolamine and pentane and the solid is filtered. Obtain 284 mg (Yield=95%) of the desired product in the form of a solid amorphous material, beige color.

SMS:Rf=0,4 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

IR (CHCl3):3400-3000 (HE, NH); 1719 (C=O); 1654; 1623; 1580; 1504 cm-1(C=C, C=N, aromatic)

1H-NMR (DSO-d6):δ of 1.09 (t, 3H, CH2-CH3); to 1.14 (t, 3H, O-CH2-CH3); of 1.85 (m, 2H, NH-CH2-CH2-CH2); of 1.85 and 2.00 (2m, 4H, N-CH2-CH2-CH); 2,48 (m, 2H,CH2-CH3); to 2.75 (t, 2H, NH-CH2-CH2-CH2); 2,92 (m, 1H, N-CH2-CH2-CH); 3,03 and 3.57 (2m, 4H, N-CH2-CH2-CH); 3,44 (t, 2H, N-CH2-CH2-CH2); 3,76 and a 3.87 (2m, 2H, NH-CH2-CH-NH); 4,07 (kV, 2H, O-CH2-CH3); 4,39 (kV, 1H, NH-CH2-CH-NH); to 5.03 (s, 2H, O-CH2-Ph); 6,62 (d, 1H, H naphthiridine); 6,86 (ush. s, 1H,NH-CH2-CH-NH); 7,30 (m, 5H, Ph); 7,33 (ush. s, 1H, NH-CH2-CH-NH); 7,58 (d, 1H, H naphthiridine); 8,20 h/m (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=6.2 min) 588 (MH+); 454 (MH-SOON2PH+); 437 (MH-NHCOOCH2Ph+).

Example 6

Synthesis of 4,6-dihydroxy-5-methylpyrimidine.

In a solution of 7.5 g (94 mmol) of formamidopyrimidine in 250 ml of ethanol, cooled to 0°C, enter 102 ml (282 mmol) of a 21% solution of ateleta sodium in ethanol and the mixture is shaken for 30 minutes, then injected a solution of 13 ml (94 mmol) diethylamine is onata in 50 ml of ethanol and shaken overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and treat the residue with ethyl acetate, water and acetic acid to obtain a pH equal to 6. The precipitate is filtered, then washed successively with water, isopropanol, simple diethyl ether and finally with pentane. Get 7 g (Yield=60%) of the desired product in the form of a solid beige color.

SMS:Rf=0,20 (silica gel, eluent: ethyl acetate-dichloromethane-methanol 50-40-10).

1H-NMR (DSO-d6):δ h/million of 1.73 (s, 3H, C-CH3); 7,88 (C, N=CH-N).

Mass spectrum:127(MH+); 125 (M-N).

Synthesis of 4,6-dibromo-5-methylpyrimidine.

A mixture of 6 g (47,6 mmol) 5-methyl-4,6-dihydroxypyrimidine in 18 g of oxybromide phosphorus is heated to 200°C for 3 hours. After cooling to ambient temperature the reaction mixture is treated with a mixture of ice water and sodium bicarbonate and extracted with ethyl acetate, wash the organic phase with water, dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). Get 9 g (Yield=75%) solid beige color.

SMS:Rf=a 0.27 (silica gel, eluent: dichloromethane-pentane 50-50).

1H-NMR (CDCl3):δ h/million of 2.58 (s, 3H, C-CH3); 8,51 (C, N=CH-N).

Mass spectrum:253-255 (MH+).

Synthesis of 6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-bromopyrimidine:

In odnogolosy flask containing 8 g cases (36.8 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-pyrimidine obtained from its salts, enter 70 ml of dimethylacetamide, 7,56 g (30 mmol) of 4,6-dibromo-5-methylpyrimidine in solution in 40 ml of dimethylacetamide and 14 ml of diisopropylethylamine. This mixture is heated to 140°C for 4 hours, then concentrated to dryness under reduced pressure (kPa). The resulting residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated under reduced pressure (kPa). The obtained solid is washed repeatedly simple diisopropyl ether and then with pentane and get to 7.7 g of the desired product in the form of powder light brown. The filtrate is concentrated to dryness, then chromatographic on silica gel, elwira with a gradient of ethyl acetate (100%), then a mixture of ethyl acetate-methanol (95-5). Get 533 mg of the desired product as a yellow powder (total yield = 70%).

Getting naphthiridine in the form of free amine:

22 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, with shaking for 30 minutes. The resin beforehand about what to see and leave for 20 minutes for swelling in the mixture solvent. This operation was repeated 3 times to complete exclusion of salt. After filtration of the resin and evaporation of the solvents receive 8 g cases (36.8 mmol) of free naphthiridine.

SMS:Rf=0,33 (silica gel, eluent: ethyl acetate (100%)).

1H-NMR (DSO-d6):δ from 1.7 to 1.85 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); of 2.23 (s, 3H, CH3-); 2,60 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 3,23 (m, 2H, NH-CH2-CH2-CH2); 2,97 and to 3.92 (2m, 4H, CH2-CH2-NCH2-CH2); 6.3 and 7,05 (2D, 2H,CH=CHthe naphthiridine); of 8.28 (s, 1H, N=CH-N).

Mass spectrum (FAB):388 (M); 389 (MH+).

Synthesis of (1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux 620 mg (1.6 mmol) 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 565 mg (1.92 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 340 mg (2.25 mol) of cesium fluoride, 73 mg (0.08 mmol) of Tris(dibenzylideneacetone)diplegia(0), 100 mg (0.16 mmol) of S(-)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 50 ml of dioxane for 5 hours. Cool, then re-injected 280 mg (0.96 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy carb the Nile]alaninate, 340 mg (2.25 mmol) of cesium fluoride, 73 mg (0.08 mmol) of Tris(dibenzylideneacetone)diplegia(0), 100 mg (0.16 mmol) of S(-)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and heated under reflux for 5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic first time on silica gel, elwira gradient ethyl acetate-methylene chloride-triethylamine-methanol from 50-50-0-0 to 50-50-2-2. The resulting product again chromatographic aluminum oxide, elwira a mixture of heptane-methylene chloride 50-50, then ethyl acetate-simple diisopropyl ether 50-50. Get 360 mg (Yield=37%) of the desired product in the form of a solid amorphous substance of white color.

SMS:Rf=0,20 (silica gel, eluent: methylene chloride-methanol 95-5).

IR (CHCl3):3435 (NH); 1717 (C=O); 1583; 1555; 1501 cm-1(heterocycle+aromatic+amide).

1H-NMR (CDCl3):δ of 1.47 (s, 9H, tBu); of 1.94 (s, 3H, C-CH3); 1,75-2,05 (m, 6N, CH2-CH2-CH2-NH andCH2-CH-CH2); 2,60-2,77 (m, 3H, CH2-CH-CH2andCH2-CH2-CH2-NH); 2,93 and 3,90 (2m, 4H, CH2-CH2-NCH2-CH2); of 3.42 (m, 2H, CH2-CH2 -CH2-NH); 3,66 (t, 2H, NH-CH2-CH-NH), of 4.45 (m, 1H, NH-CH2-CH-NH); 4,95, and a 5.25 6,20 (3M, 3H, CH2-CH2-CH2-NHNH-CH2-CH-NH,NH-CH2-CH-NH); 5,12 (s, 2H,CH2-Ph); 7,35 (m, 5H, Ph); 8,29 h/m (C, N=CH-N).

Mass spectrum:602 (MH+); 546 (MH-tBu+); 412 (MH-COOCH2Ph+).

D](of 0.625% EtOH): -4,5.

Synthesis of 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline).

Shake 350 mg (of 0.58 mmol) of (1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 15 ml of dichloromethane with 3 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get 330 mg (Yield=73%, expressed in DATEFORMAT) of the target product in a solid white color.

SMS:Rf=0,44 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (CDCl3: δ a 1.96 (s, 3H,-CH3); 1,80-2,05 (m, 6H, CH2-CH2-CH2-NH and CH2-CH-CH2); was 2.76 (t, 2H, NH-CH2-CH2-CH2-); 2,96 (t, 1H, N-CH2-CH2-CH-); 3,21 and 3,83 (2m, 4H, N-CH2-CH2-CH-); 3,50 (m, 2H, N-CH2-CH2-CH2-); 3,83 and of 4.05 (2m, 2H, NH-CH2-CH-NH); 4,54 (kV, 1H, NH-CH2-CH-NH); of 5.50 (s, 2H, O-CH2-Ph); 6,40 (d, 1H, H naphthiridine); 6,55 (ush. d, 1H, NH); 7,28 (m, 5H, Ph), 7,45 (ush. m, 1H, NH); by 8.22 (d, 1H, H naphthiridine), by 8.22 (s, 1H, N=CH-N); 9,62 h/m (ush. s, 1H).

Mass spectrum:546 (MH+); 412 (MH-COOCH2Ph+); 544- (M-N); 436- (544-och2RH-); 1089- (2M-N).

D](0,60% Meon): -14,0.

Example 7

Getting naphthiridine in the form of a free amine:

22 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent. This operation was repeated 3 times to complete exclusion of salt. After filtration of the resin and evaporation of the solvents receive 8 g cases (36.8 mmol) of free naphthiridine.

SMS:Rf=0,33 (silica gel, eluent: ethyl acetate (100%)).

1H-NMR (DSO-d6):δ from 1.7 to 1.85 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); of 2.23 (s, 3H, CH3-); 2,60 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 3,23 (m, 2H, NH-C 2-CH2-CH2); 2,97 and to 3.92 (2m, 4H, CH2-CH2-NCH2-CH2); 6.3 and 7,05 (2D, 2H,CH=CHthe naphthiridine); of 8.28 (s, 1H, N=CH-N).

Mass spectrum (FAB):(tr=0,50 min and 2,80 min): 388 (M); 389 (MH+).

Synthesis of N-(alpha)-Z-L,2-3-ethyldiethanolamine.

In odnogolosy flask containing 26 ml of absolute ethanol, injected dropwise at 0°With 12 ml (168 mmol) of thionyl chloride. This mixture is shaken for approximately 20 minutes at ambient temperature, then it is injected in small portions 2 g (8.4 mmol) of N-(alpha)-Z-L,2-3-diaminopropionic acid, a white mist.

Then the reaction mixture is heated under reflux (78°C.) for 2 hours (after heating for several minutes the solution becomes transparent).

After cooling, the solution is concentrated to dryness, get a yellow liquid, which is injected a simple isopropyl ether. Formed target product, then remove the pooled liquid and the residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated in vacuum. Obtain 1.4 g of a light yellow oil, or ester in the form of free amine (yield =63%).

<> SMS:Rf=0,41 (silica gel, eluent: methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1)).

1H-NMR (CDCl3):δ of 1.33 (t, 3H,CH3-CH2-Oh); 2,53 (m, 2H,NH2-CH2-CH) a 3.15 (m, 2H, NH2-CH2-CH); 4,22 (kV, 2H, CH3-CH2-Oh); was 4.42 (m, 1H, NH2-CH2-CH-NH); to 5.85 (m, 1H, CH-NH-CO)of 5.15 (s, 2H, O-CH2-Ph); 7,35 (m, 5H, Ph)

Mass spectrum (FAB):(tr=0,51 min and 1.2 min): 267 (MH+); 533 (2MH+).

D](CHCl3)=+6,336.

Synthesis of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines.

A mixture of 1.9 g (4.9 mmol) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-bromopyrimidine and of 1.62 g (between 6.08 mmol) 3-amino-N-[(phenylmethoxy)carbonyl]acylalanines in the presence of 1.06 g (6,86 mmol) of cesium fluoride, 310 mg (490 mmol) of (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 230 mg (245 mmol) of Tris(dibenzylideneacetone)diplegia(0) in 40 ml of 1,2-dimethoxyethane heated under reflux for 4 hours. The reaction mixture is then brought to the temperature for the introduction of 230 mg (245 mmol) of Tris(dibenzylideneacetone)diplegia(0), then heated under reflux for 16 hours.

After cooling, the solution is concentrated to dryness, then treated with a mixture of water, ethyl acetate and a saturated solution of BIC is rbonate sodium. The organic phase is decanted and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate and evaporated to dryness in a vacuum. The remainder chromatographic on silica gel using 100% ethyl acetate. Get to 1.15 g of the desired product as a solid light-yellow oil (yield = 40%).

SMS:Rf=0,16 (silica gel, eluent: ethyl acetate 100%).

1H-NMR (CDCl3):δ of 1.25 (t, 3H),CH3-CH2-Oh); 1,80-2,05 (m, N, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2CH3-C=C-); of 2.72 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 2,95 and 3,93 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.45 (m, 2H, NH-CH2-CH2-CH2); 3,68 (d, 2H, NH-CH2-CH-NH) to 4.23 (t, 2H, CH3-CH2-Oh)of 4.45 (m, 1H, NH-CH2-CH-NH); 5,10 and 5.17 (Syst AB, 2H, O-CH2-Ph); -6,41 and to 7.18 (2D, 2H,CH=CHthe naphthiridine); 7,35 (m, 5H, Ph); of 8.27 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=0,48 min and 2.9 min): 574 (MH+); 440 [MN-Z+]; 287[MH-(tBu-Z+)].

D](CHCl3): +0,788.

Obtaining hydrochloride:

of 1.15 g of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines dissolved in a minimum amount of methylene chloride. This solution was poured on a simple ethyl ether, the solution to the wives to remain transparent. Then dropwise with shaking pour in to 2.65 ml of 2N HCl, diluted in a small amount of simple ethyl ester. Formed hydrochloride, the pooled liquid is removed, then the residue is crystallized in a simple isopropyl ether. Get solid, which was filtered, washed with simple ether, then with pentane. After drying obtain 890 mg of a light yellow powder (yield=73%).

Example 8

Getting naphthiridine in the form of a free amine:

22 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, with shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent. This operation was repeated 3 times to complete exclusion of salt. After filtration of the resin and evaporation of the solvents receive 8 g cases (36.8 mmol) of free naphthiridine.

SMS:Rf=0,33 (silica gel, eluent: ethyl acetate (100%)).

1H-NMR (DMSO-d6):δ from 1.7 to 1.85 (m, 6N, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); of 2.23 (s, 3H, CH3-); 2,60 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 3,23 (m, 2H, NH-CH2-CH2-CH2); 2,97 and to 3.92 (2m, 4H, CH2-CH2-NCH2-CH2); 6.3 and 7,05 (2D, 2H,CH=CHthe naphthiridine); of 8.28 (s, 1H, N=CH-N).

Mass spectrum (FAB):(tr=0,50 min and 2,80 min): 388 (M); 389 (MH+).

Synthesis of N-(alpha)-Z-L,2-3-isopropylcarbonate.

In odnogolosy flask containing 125 ml of isopropanol, injected dropwise at 0°46 ml (840 mmol) of thionyl chloride. This mixture is shaken for approximately 20 minutes at ambient temperature, then it is injected in small portions 10 g (42 mmol) of N-(alpha)-Z-L,2-3-diaminopropionic acid, a white mist.

Then the reaction mixture is heated under reflux (78°C.) for 2 hours (after heating for several minutes the solution becomes transparent).

After cooling, the solution is concentrated to dryness, get a yellow liquid, which is injected a simple isopropyl ether. Formed target product, then remove the pooled liquid and the residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated in vacuum. Gain of 7.4 g of a white powder, this ester in the form of free amine (yield =42%).

SMS:Rf=0.5 (silica gel, eluent: methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1)).

1H-NMR (CDCl3):δ of 1.25 (d, 6H,CH3CH-CH3 )and 1.60 (m, 2H,NH2-CH2-CH) 3,10 (m, 2H, NH2-CH2-CH); of 4.35 (m, 1H, NH2-CH2-CH-NH) to 5.10 (m, 1H, CH3-CH-CH3); further 5.15 (s, 2H, O-CH2-Ph); and 5.2 (m, 1H, CH-NH-CO), 7,37 (m, 5H, Ph).

Mass spectrum (FAB):(tr=0,52 min and 2,09 min): 281 (MH+); 239 (MH-ipr+).

D](CHCl3)=+15,02.

Synthesis of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]isopropylaniline.

A mixture of 1.5 g (to 3.89 mmol) 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-bromopyrimidine and 1.30 grams (4,63 mmol) 3-amino-N-[(phenylmethoxy)carbonyl]Isopropylamine in the presence of 825 mg (5.41 mmol) of cesium fluoride, 241 mg (386 mmol) of (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 180 mg (193 mmol) of Tris(dibenzylideneacetone)diplegia(0) in 40 ml of 1,2-dimethoxyethane heated under reflux for 5 hours and 30 minutes. The reaction mixture is then brought to the temperature for injection of 180 mg (245 mmol) of Tris(dibenzylideneacetone)diplegia(0), then heated under reflux for 16 hours.

The next day heated for 9 hours after addition of 180 mg (193 mmol) of Tris(dibenzylideneacetone)diplegia(0). After cooling, the solution is concentrated to dryness, then treated with a mixture of water, ethyl acetate and a saturated solution of bicarbonate NAT the Oia. The organic phase is decanted and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate and evaporated to dryness in a vacuum. The remainder chromatographic on silica gel using 100% ethyl acetate. Get to 1.15 g of the desired product as a crystalline light yellow substance (yield = 50%).

SMS:Rf=0,18 (silica gel, eluent: ethyl acetate 100%).

1H-NMR (CDCl3):δ of 1.27 (d, 6N, CH3-CH-CH3); 1,83-2,05 (m, 9H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2,CH3-C=C-); of 2.72 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 2,95 and 3,93 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.45 (m, 2H, NH-CH2-CH2-CH2); 3,68 (d, 2H, NH-CH2-CH-NH), 4,50 (m, 1H, NH-CH2-CH-NH); 5,07 (m, 1H, CH3-CH-CH3); 5,12 (s, 2H, O-CH2-Ph); 6.42 per 7,18 and (2D, 2H,CH=CHthe naphthiridine); 7,35 (m, 5H, Ph); of 8.28 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=0,48 min and 3,03 min): 588 (MH+); 454 [MN-Z+]; 412[MH-(ipr-Z+)].

D](CHCl3): +0,7655.

Obtaining hydrochloride:

3.8 g of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]isopropylaniline dissolved in 20 ml of methylene chloride. This solution was poured on a simple ethyl ether, a solution should the n to remain transparent. Then dropwise with shaking enter 3,23 ml of 2N HCl, diluted in a small amount of simple ethyl ester. Formed hydrochloride, the pooled liquid is removed, then the residue is crystallized in a simple isopropyl ether. Get solid, which was filtered, washed with simple ether, then with pentane. After drying receive 3,44 g of white powder (yield=85%).

Example 9

Synthesis of 4,6-dibromo-5-ethylpyrimidine.

A mixture of 2.8 g (20 mmol) of 5-ethyl-4,6-dihydroxypyrimidine (available from Aldrich) and cent to 8.85 g (31 mmol) of oxybromide phosphorus is heated to 160°C for 1 hour. After cooling to ambient temperature the reaction medium is poured into a mixture of ice and saturated sodium bicarbonate solution and ethyl acetate. Decanted, the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient from heptane to 100% to heptane-ethyl acetate 50-50. Get to 3.92 g (Yield=74%) solid light brown color, used as such in the following stage.

SMS:Rf=0.5 (silica gel, eluent: heptane-ethyl acetate 90-10).

IR (CHCl3):1538; 1503 (C=C, C=N).

1H-NMR (DMSO-d6):δ of 1.16 (t, 3H, CH2-CH3); of 2.86 (q, 2H,CH2CH 3); 8,63 h/m (s, 1H, N=CH-N).

Mass spectrum:266 (MH+); 249 (MH-CH3+); 184 (MN-NVG+).

Synthesis of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine.

The mixture to 3.67 g (6,45 mmol) 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthiridine, Tris(triptoreline) (obtained in accordance with ER or WO 0078317) and 25 g of resin Amberlyst A-21 (Fluka production 06424, pre-washed with a solution of dichloromethane-ethyl acetate-methanol 1-1-1) in 150 ml dichloromethane-ethyl acetate-methanol 1-1-1, shaken at ambient temperature for 1 hour. The mixture is filtered, the resin washed three-component solution. The obtained filtrate is shaken at ambient temperature for 1 hour in the presence of 25 g of resin Amberlyst A-21, processed as described above; this operation is repeated for the third time. The resulting filtrate is concentrated to dryness under reduced pressure (2 kPa) and obtain 1.4 g of the free amine. In this remainder is injected to 2.06 g (7,74 mmol) of 4,6-dibromo-5-ethylpyrimidine, 200 ml of dimethylacetamide and 5 ml of diisopropylethylamine and heated to 100°C. for 3.5 hours. The reaction mixture is evaporated under reduced pressure (2 kPa) and treat the residue with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated at below the nom pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient from 100% heptane to heptane-ethyl acetate 50-50. Obtain 1.5 g (Yield=58%) of the desired product in the form of a solid beige color.

SMS:Rf=0.5 (aluminium oxide, eluent: heptane-ethyl acetate 50-50).

IR (CHCl3):3440 (NH); 1596; 1586; 1547; 1508; 1480 cm-1(Heterocycle+aromatic).

1H-NMR (DSO-d6):δ of 1.23 (t, 3H, CH2-CH3); to 1.75 (m, 6H, CH2-CH2-CH2-NH,CH2-CH-CH2); to 2.67 (m, 5H,CH2-CH3CH2-CH-CH2,CH2-CH2-CH2-NH); to 3.02 (t, 2H, CH2-CH2N); 3,23 (m, 2H, CH2-CH2-CH2-NH); 3,90 (m, 2H, CH2-CH2N); of 6.20 (s, 1H, CH2-CH2-CH2-NH); 6,30 and 7.04 (2D, 2H, H naphthiridine); 8,27 h/m (C, N=CH-N).

Mass spectrum:403(MH+).

Synthesis of (1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux a mixture of 317 mg (0,79 mmol) 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 279 mg (0.95 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 168 mg (1.11 mol) of cesium fluoride, 36 mg (0.04 mmol) of Tris(dibenzylideneacetone)dialled is I(0), 49 mg (0.08 mmol) of S(-)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 11 ml of dioxane for 21 hours. Cool, then re-enter 140 mg (0.48 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 168 mg (1.11 mmol) of cesium fluoride, 36 mg (0.04 mmol) of Tris(dibenzylideneacetone)diplegia(0), 49 mg (0.08 mmol) of S(-)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 2 ml of dioxane and heated under reflux for 3.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient heptane-ethyl acetate-methylene chloride-methanol 50-50-0, 25-75-0, 0-100-0 and finally 0-100-3. Obtain 400 mg (Yield=83%) of the desired product as oil.

SMS:Rf=0,55 (silica gel, eluent: ethyl acetate-methanol-triethylamine 95-2-2).

IR (CHCl3):3435 (NH); 1717 (C=O); 1583; 1555; 1501 cm-1(heterocycle+aromatic+amide)

1H-NMR (DSO-d6):δ of 1.06 (t, 3H, CH2-CH3); to 1.31 (s, 9H, tBu); to 1.75 (m, 2H, CH2-CH2-CH2-NH); or 1.77 (m, 4H,CH2-CH-CH2); the 2.46 (m, 2H,CH2-CH3); 2,53 (m, 1H, CH2-CH-CH2); 2,62 (t, 2H,CH2-CH2-CH2-NH); 2,83 and 3,44 (2m, 4H, CH2-CH2 -NCH2-CH2); 3,24 (m, 2H, CH2-CH2-CH2-NH); and 3.72 (m, 2H, NH-CH2-CH-NH); to 4.23 (q, 1H, NH-CH2-CH-NH); 5,02 (s, 2H,CH2-Ph), 6,24 (s, 1H, CH2-CH2-CH2-NH); 6,30 and 7,06 (2D, 2H, H naphthiridine); 6,36 (m, 1H,NH-CH2-CH-NH); 7,34 (m, 5H, Ph); a 7.62 (d, 1H, NH-CH2-CH-NH); 8,11 h/m (C, N=CH-N).

Mass spectrum:616 (MH+); 560 (MH-tBu+); 426 (MH-COOCH2Ph+).

D](1,05% EtOH): -6,1.

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline).

Shake 475 mg (0.77 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 15 ml of dichloromethane with 3.5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get 368 mg (Yield=61%, expressed in DATEFORMAT) of the desired product as an amorphous substance.

SMS:Rf=0,33 (silica gel, eluent: what harmatan-methanol-water-acetic acid 90-10-1-1).

IR (CHCl3): 1677 (C=0); 1625; 1587; 1492 cm-1(conjugated system + aromatic).

1H-NMR (DSO-d6):δ was 1.04 (t, 3H, CH2-CH3); 1.77 and 1,90 (2m, 4H, N-CH2-CH2-CH -),;is 1.81 (m, 2H, NH-CH2-CH2-CH2-); of 2.45 (q, 2H,CH2-CH3);by 2.73 (t, 2H, NH-CH2-CH2-CH2-); 2,78 (t, 1H, N-CH2-CH2-CH-); 2,87 and 3,48 (2m, 4H, N-CH2-CH2-CH-); of 3.23 (m, 2H, N-CH2-CH2-CH2-); 3.58 and 3,83 (2m, 2H, NH-CH2-CH-NH); 4,28 (kV, 1H, NH-CH2-CH-NH); 5,01 (Syst AB, 2H, O-CH2-Ph); of 6.65 (d, 1H, H naphthiridine); 6,55 (ush. s, 1H,NH-CH2-CH-NH); 7,33 (m, 5H, Ph); to 7.68 (d, 1H, NH-CH2-CH-NH); 7,58 (d, 1H, H naphthiridine); 8,15 (s, 1H, N=CHN); 6,24 h/m (ush. s, 1H,NH-CH2-CH2-CH2-).

Mass spectrum:560 (MH+); 426 (MH-COOCH2Ph+); 558- (M-N); 450- (558-och2RH-); 1117- (2M-N).

D](1% CHCl3): +2,4.

Example 10

(1,1-dimethylethyl)-N-[(phenylmethoxy)carbonyl]alaninate

480 mg (2 mmol) N-[(phenylmethoxy)carbonyl]alanine acid in 15 ml of tributylamine injected dropwise 1 ml perchloro acid. A two-phase mixture is shaken for 24 hours. The mixture is treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated to dryness under reduced d is the pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient heptane-ethyl acetate-methanol 100-0-0, 0-100-0, and finally, 0-95-05. Obtain 50 mg (Yield=10%) of the desired product as oil.

SMS:Rf=0,20 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

D](1,25% CHCl3): -9,0.

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux 200 mg (0.5 mmol) 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidine, 50 g (0,17 mmol) (D)(1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 40 mg (0.26 mol) of cesium fluoride, 15 mg (0,016 mmol) of Tris(dibenzylideneacetone)diplegia(0), 20 mg (to 0.032 mmol) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 20 ml of dioxane for 5 hours. Cool, then re-enter 15 mg (0,016 mmol) of Tris(dibenzylideneacetone)diplegia(0) and heated under reflux for 15 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic first time on the oxide and uminia, elwira gradient ethyl acetate-simple diisopropyl ether-methylene chloride from 50-50-50, 10-50-50 and, finally, 10-20-70, then on silica gel, elwira with ethyl acetate. Obtain 40 mg (Yield=38%) of the desired product as oil.

SMS:Rf=0.25 in (silica gel, eluent: ethyl acetate).

Mass spectrum:616 (MH+); 560 (MH-tBu+).

D](1,0% l3): -2,4.

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline).

Shake 40 mg (0.77 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 10 ml of dichloromethane with 1 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira a mixture of CH2Cl2-MeOH-H2O-AcOH 90-10-1-1. Receive 25 mg (Yield=48%, expressed in DATEFORMAT) of the target product in the form of a solid amorphous substance.

SMS:Rf=0,10 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

Mass spectrum:560 (MH+); 426 (MH-COOCH2Ph+); 558- (M-N); 450- (558-och2PH); 1117- (2M-N).

D](1,75% CHCl3): -6,0.

Example 11

Dichlorhydrate 3-[[5-ethyl-6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines

In 5 ml of ethanol, cooled to -12°C. in a nitrogen atmosphere, enter 160 ál (2,19 mmol) of thionyl chloride and the mixture is shaken for 30 minutes. Then introduce a solution of 354 mg (0.45 mmol) of 3-[[5-ethyl-6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptoreline) in 13 ml of ethanol. The mixture was shaken for 30 min at -12°C., then left to warm to ambient temperature and finally heated to 40°C for 4 hours in nitrogen atmosphere. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is crystallized in a mixture of simple diisopropyl ether and pentane and the solid is filtered off. Obtain 284 mg (Yield=95%) of the desired product in the form of a solid amorphous material, beige color.

SMS:Rf=0,4 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

IR (CHCl3):3400-3000 (HE, NH); 1719 (C=O); 1654; 1623; 1580; 1504 cm-1(C=C, C=N, aromatic)

1H-NMR (DSO-d6):δ of 1.09 (t, 3H, CH2-CH3); to 1.14 (t, 3H,-CH2-CH3); of 1.85 (m, 2H, NH-CH2-CH 2-CH2); of 1.85 and 2.00 (2m, 4H, N-CH2-CH2-CH); 2,48 (m, 2H,CH2-CH3); to 2.75 (t, 2H, NH-CH2-CH2-CH2); 2,92 (m, 1H, N-CH2-CH2-CH); 3,03 and 3.57 (2m, 4H, N-CH2-CH2-CH); 3,44 (t, 2H, N-CH2-CH2-CH2); 3,76 and a 3.87 (2m, 2H, NH-CH2-CH-NH); 4,07 (kV, 2H, O-CH2-CH3); 4,39 (kV, 1H, NH-CH2-CH-NH); to 5.03 (s, 2H, O-CH2-Ph); 6,62 (d, 1H, H naphthiridine); 6,86 (ush. s, 1H, NH-CH2-CH-NH), 7,30 (m, 5H, Ph); 7,33 (ush. s, 1H, NH-CH2-CH-NH); 7,58 (d, 1H, H naphthiridine); 8,20 h/m (s, 1H, N=CH-N).

Mass spectrum:588 (MH+); 454 (MH-SOON2PH); 426 (MH-NHCOOCH2Ph+).

D](1% CHCl3): +4.

Example 12

N-[(phenylmethoxy)carbonyl]acylalanines

In 12 ml of ethanol, cooled to 0°C. in a nitrogen atmosphere, enter 6 ml (63 mmol) of thionyl chloride and the mixture is shaken for 20 minutes at ambient temperature. Then introduce a solution of 950 mg (4 mmol) N-[(phenylmethoxy)carbonyl]alanine acid in 5 ml of ethanol. Shake mixture by heating under reflux for 1 hour in nitrogen atmosphere. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is crystallized in a mixture of simple diisopropyl ether and pentane and the solid is filtered off. The obtained solid is treated with ethyl acetate, water and saturated sodium bicarbonate solution. Get 535 mg (Yield=50%) of the desired product as a colourless oil.

SMS:Rf=0,4 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

HPLC/mass spectrum: (tr=0.5 and 1,4 min) 267 (MH+).

D](1,0% CHCl3): -11,2.

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]acylalanines.

Heated under reflux 320 mg (0.8 mmol) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 215 mg (0.14 mmol) (D) 3-amino-N-[(phenylmethoxy)carbonyl]acylalanines, 190 mg (1.25 mmol) of cesium fluoride, 37 mg (0.04 mmol) of Tris(dibenzylideneacetone)diplegia(0), 50 mg (0.08 mmol) of S(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 15 ml of dioxane for 5 hours. Cool, then re-enter 37 mg (0.04 mmol) of Tris(dibenzylideneacetone)diplegia(0) and heated under reflux for 7 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient ethyl acetate-simple diisopropyl ether-methylene chloride 50-50-50, 10-50-5 and finally 10-20-70. Obtain 260 mg (Yield=55%) of the desired product as oil.

SMS:Rf=0.25 in (silica gel, eluent: ethyl acetate).

1H-NMR (CDCl3): δ of 1.16 (t, 3H, CH2-CH3); of 1.27 (t, 3H, O-CH2-CH3); 1.85 to 2,00 (m, 6H, N-CH2-CH2-CH and NH-CH2-CH2-CH2); the 2.46 (m, 2H,CH2-CH3); 2,75 (t, 3H, NH-CH2-CH2-CH2and N-CH2-CH2-CH); the 3.89 (t, 2H, N-CH2-CH2-CH2); 3,47 and 3,61 (2m, 4H, N-CH2-CH2-CH); 3.00 and 3,98 (2m, 2H, NH-CH2-CH-NH); 4,22 (m, 2H, O-CH2-CH3); of 4.54 (m, 1H, NH-CH2-CH-NH); to 5.13 (s, 2H, O-CH2-Ph); to 6.43 (d, 1H, H naphthiridine); 7,22 (d, 1H, H naphthiridine); 7,35 (m, 5H, Ph); 8,27 h/m (s, 1H, N=CH-N).

Mass spectrum:558 (MH+); 454 (MH-SOON2RH+).

D](1,3% l3): -6,0.

Example 13

Synthesis of 6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-chloropyrimidine:

In odnogolosy flask containing 12.5 g (57.5 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidine, obtained from its salts, enter 80 ml of dimethylacetamide, and 11.8 g (30 mmol) of 4,6-dichloro-5-ethylpyrimidine in solution in 40 ml of dimethylacetamide and 24 ml of diisopropylethylamine. This mixture is heated to 140°C for 5 hours, then concentrated to dryness in vacuo. The resulting residue is treated with a mixture of water, ethyl acetate and us the seal sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated to dryness in a vacuum and obtain 15.5 g of orange oil. This oil is dissolved in a minimum amount of methylene chloride and precipitated in a simple isopropyl ether, to obtain 9 g of the desired product in the form of a powder beige. The filtrate is concentrated to dryness, then chromatographic on silica gel, elwira gradient cyclohexane (100%), ethyl acetate-cyclohexane (50-50), then ethyl acetate-cyclohexane (70-30).

Get 3 g of the target product as a pale yellow powder (total yield = 58%).

Getting naphthiridine in the form of free amine:

28.5 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent.

This operation was repeated 3 times to complete exclusion of salt.

After filtration of the resin and evaporation of the solvents to obtain 12.5 g (57.5 mmol) of free naphthiridine.

SMS:Rf=0,32 (silica gel, eluent: ethyl acetate (100%)).

1H-NMR ():δ of 1.32 (t, 3H),CH3-CH2); 1,81-2,05 (m, 6H, NH-CH2-CH2-CH2N-CH2-C 2-CH-CH2); 2,70 (m, 5H, CH2-CH-CH2, NH-CH2-CH2-CH2CH3-CH2); of 3.43 (m, 2H, NH-CH2-CH2-CH2); 3,05 and 3.97 (2m, 4H, CH2-CH2-NCH2-CH2); 6.4 and for 7.12 (2D, 2H,CH=CHthe naphthiridine); of 8.37 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr= 0.51 and at 2.93 min); 358 (MH+).

Synthesis of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]isopropylaniline.

A mixture of 1 g (2,79 mmol) 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-chloropyrimidine and 940 mg (3.35 mmol) of 3-amino-N-[(phenylmethoxy)carbonyl]Isopropylamine in the presence of 594 mg (3,91 mmol) of cesium fluoride, 174 mg (279 mmol) of (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 130 mg (140 mmol) of Tris(dibenzylideneacetone)diplegia(0) in 35 ml of 1,2-dimethoxyethane heated under reflux for 5 hours. The reaction mixture is then brought to the temperature for injection of 180 mg (140 mmol) of Tris(dibenzylideneacetone)diplegia(0), then heated under reflux for 16 hours.

After cooling, the solution is concentrated to dryness, then treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted and the aqueous phase extracted with ethyl acetate. United organic the ski phases are dried on magnesium sulfate and evaporated to dryness in a vacuum. The remainder chromatographic on silica gel using 100% ethyl acetate. Obtain 1.07 g of the desired product as a crystalline light yellow substance (yield = 64%).

SMS:Rf=0,20 (silica gel, eluent: ethyl acetate 100%).

1H-NMR (CDCl3):δ of 1.18 (t, 3H,CH3-CH2); to 1.25 (d, 6H, CH3-CH-CH3);1,83-2,05 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); at 2.45 (q, 2H, CH3-CH2); 2,72 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); 2,97 and 3,93 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.45 (m, 2H, NH-CH2-CH2-CH2); of 3.60 (d, 2H, NH-CH2-CH-NH), 4,50 (m, 1H, NH-CH2-CH-NH); equal to 4.97-5,20 (m, 3H, CH3-CH-CH3O-CH2-Ph); to 6.43 and to 7.18 (2D, 2H,CH=CHthe naphthiridine); 7,35 (m, 5H, Ph); of 8.28 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=0,50 min 3.14 min): 602(MH+); 468 [MN-Z+]; 426 [MH-(ipr-Z)+].

D](CHCl3): +2,175.

Obtaining hydrochloride:

3.2 g (5.3 mmol) of 3-[[-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]isopropylaniline dissolved in a minimum amount of methylene chloride. This solution was poured on a simple ethyl ether, the solution should be transparent. Then dropwise with shaking enter to 2.65 ml of 2N HCl in simple Atila the second ether. Formed hydrochloride, the pooled liquid is removed, then the residue is re-crystallized in a simple isopropyl ether. Get solid, which was filtered, washed with simple ether, then with pentane. After drying obtain 3.5 g of powder off-white color (yield = quantitative)

Example 14

Synthesis of 2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]-naphthiridine-2-yl)-piperidine-1-yl]- pyrimidine-4-ylamino}propylamino)-tributyltinchloride

Shaken 80 mg (0.15 mmol) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, 45 mg (0.20 mmol) tertbutyl-L-Latinate-hydrochloride, 22 mg (0.16 mmol) 1-hydroxybenzotriazole, 30 mg (0.16 mmol) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 0,050 ml (0.45 mmol) of N-methylmorpholine and 0,070 ml (0.50 mmol) of triethylamine in 5 ml of dimethylformamide for 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). Sediment chromatographic, elwira gradient etelaat-methylene chloride-methanol from 50-50-0 to 50-45-5. Receive 60 mg Yield=55%) of the desired product in the form of a solid white color.

SMS:Rf=0,66 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (CDCl3):δ of 0.91 (t, 3H, CH2-CH3); to 1.16 (d, 6H, CHCH2CH(CH3)2); 1.28 (in ush. t, 2H, CHCH2CH(CH3)2); 1,41-of 1.57 (m, 1H, CHCH2CH(CH3)2); to 1.48 (s, 9H, tBu); 1,80-2,05 (m, 6H, CH2-CH2-CH2-NH,CH2-CH-CH2); 2,49 (m, 2H,CH2-CH3); 2,67 (TT, 1H, CH2-CH-CH2); by 2.73 (t, 2H,CH2-CH2-CH2-NH); 2,98 and 3,66 (ush. kV and m, 4H, CH2-CH2-NCH2-CH2); of 3.43 (m, 2H, CH2-CH2-CH2-NH); 3,70 and 4,16 (2m, 2H, NH-CH2-CH-NH); 4,32 (m, 1H, NH-CH2-CH-NH); of 4.49 (m, 1H, CONH-CHCH2CH(CH3)2)-CO)to 5.13 (m, 2H,CH2-Ph); 5,42, 6.83 and a 7.92 (3H, N mobile); to 6.43 and to 7.15 (2D, 2H, H naphthiridine); 7,37 (m, 5H, Ph); to 8.2 ppm (s, 1H, N=CH-N).

Mass spectrum: 729 (MH+).

Synthesis of 2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[5,6,7,8-tetrahydro-[1,8]naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)-4-methylvaleramide acid

Shake 60 mg (0,083 mmol) tertbutyl-2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[5,6,7,8-tetrahydro-[1,8]naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)-4-methylpentanoate in 5 ml of dichloromethane with 0.5 ml triperoxonane acid at the temperature of the environment and the surrounding environment to the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get 55 mg (Yield=74%, expressed in DATEFORMAT) of the target product in a solid white color.

SMS:Rf=0.52 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

Mass spectrum:673 (MH+).

Example 15

Synthesis of 4,6-dihydroxy-5-propylpyrimidine

In a solution of 7.5 g(94 mmol) of formamidopyrimidine in 200 ml of ethanol, cooled to 0°C, enter 102 ml (282 mmol) of a 21% solution of ateleta sodium in ethanol and shake the mixture for 30 minutes; then introduce a solution of 19.5 ml (94 mmol) of diethylpropion in 50 ml of ethanol and shaken overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is treated with 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phase is dried on sodium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). Gain of 7.3 g (Yield=50%) of the desired product in the form of a solid beige color.

1H-NMR (DMSO d6):δ of 0.85(t, 3H, CH2-CH2-CH3); 1,39 (Sextus, 2H, CH2-CH2-CH3); of 2.23 (t, 2H,CH2-CH2-CH3); a 7.85 h/m (C, N=CH-N).

Mass spectrum: 155 (MH+); 159 (M-N).

Synthesis of 4,6-dichloro-5-propylpyrimidine.

A mixture of 3 g (of 19.5 mmol) of 5-propyl-4,6-dihydroxypyrimidine 20 g of phosphorus oxychloride is heated under reflux for 1 hour. After cooling to ambient temperature is injected dropwise a mixture of 3 ml of N,N-diethylaniline in 10 ml of phosphorus oxychloride and heated received under reflux for 4 hours. After cooling to ambient temperature the reaction mixture was poured into a mixture of ice and water, then gradually introducing sodium bicarbonate to obtain an alkaline pH. Extracted with ethyl acetate, dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient heptane-methylene chloride from 100-0 to 80-20. Get 2 g (Yield=54%) as a solid blue color.

SMS:Rf=0.35 in (silica gel, eluent: heptane-ethyl acetate 90-10).

Synthesis of 6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-propyl-4-chloropyrimidine:

In odnogolosy flask containing 1.6 g (7.4 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidine, the scientists of its salts, introduce 50 ml of dimethylacetamide, 2 g (10.5 mmol) of 4,6-dichloro-5-propylpyrimidine and 4 ml of diisopropylethylamine. This mixture is heated to 140°C for 5 hours, then concentrated to dryness under reduced pressure (2 kPa). The resulting residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient heptane-methylene chloride-ethyl acetate from 50-50-0 to 0-0-100. Get 875 mg of the desired product in the form of a solid amorphous substance (yield=50%).

SMS:Rf=0.25 in (silica gel, eluent: ethyl acetate (100%)).

1H-NMR (CDCl3):δ of 1.02 (t, 3H,-CH2-CH2-CH3); 1,72 (Sextus, 2H,-CH2-CH2-CH3); 1,81-2,07 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); to 2.64 (t, 2H,-CH2-CH2-CH3); 2,73 (m, 3H, CH2-CH-CH2, NH-CH2-CH2-CH2); of 3.46 (t, 2H, NH-CH2-CH2-CH2); 3,06 vs. 3.96 (m and d, 4H, CH2-CH2-NCH2-CH2); 5,00 (m, 2H,NH-CH2-CH2-CH2); 6,40 and 7,14 (2D, 2H,CH=CHthe naphthiridine); scored 8.38 (s, 1H, N=CH-N).

Mass spectrum:372 374 (MH+).

Synthesis of (1,1-dimethylethyl)-3-[[5-propyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux 600 mg (of 1.62 mmol) 4-chloro-5-propyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 590 mg (2 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 380 mg (2.51 mmol) of cesium fluoride, 76 mg (0,083 mmol) of Tris(dibenzylideneacetone)diplegia(0), 102 mg (0,163 mmol) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 50 ml of dioxane for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient of methylene chloride-simple diisopropyl ether-ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0, then 0-0-100-0 and finally 0-0-90-10. Obtain 620 mg (Yield=61%) of the desired product in the form of a solid amorphous yellow substance.

SMS:Rf=0,12 (silica gel, eluent: ethyl acetate).

1H-NMR (CDCl3):δ of 0.90 (t, 2H,-CH2-CH2-CH3); a 1.01 (t, 3H, C-CH2-CH2-CH3); 1,48, 9H, tBu); 1,81-2,07 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); 2,39 (t, 2H,-CH2-CH2-CH3); 2,65 (ush. t, 1H, CH2-CH-CH2); by 2.73 (t, 2H, NH-CH2-CH2-CH2); 2,97 and 3,55 (ush. t and ush. d, 4H, CH2-CH2-NCH2-CH2); 3,44 (m, 2H, NH-CH2-CH2-CH2); 3,85 and 3,93 (2m, 2H, NH-CH2-CH-NH); to 4.46 (m, 1H, NH-CH2-CH-NH); 5,14 (s, 2H,CH2-Ph); 6,16 (d, 1H, CH2-CH2-CH2-NH); 6,44 (d, 1H, H naphthiridine); to 7.15 (d, 1H, H naphthiridine), 7,37 (m, 5H, CH2Ph); 8,29 (s, 1H, N=CH-N).

Mass spectrum:630 (MH+); 574 (MH-tBu+); 440 (MH-COOCH2Ph+).

Synthesis of bis(triptorelin) 3-[[5-propyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine.

Shake 610 mg (0.97 mmol) of (1,1-dimethylethyl)-3-[[5-propyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 50 ml of dichloromethane and 5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methane is a, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 400 mg (Yield=51%, expressed in DATEFORMAT) of the target product in a solid beige color.

SMS:Rf=0.40 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (DSO d6):δ of 0.93 (t, 3H,-CH2-CH2-CH3); l,48 (m, 2H,-CH2-CH2-CH3); 1,67-2,00 (m, 6H, CH2-CH2-CH2-NN andCH2-CH-CH2); 2.40 a (t, 2H,-CH2-CH2-CH3); 2,65-2,96 (m, 5H, NH-CH2-CH2-CH2-, N-CH2-CH2-CH-, N-CH2-CH2-CH-); 3,32-3,51 (m, 4H, N-CH2-CH2-CH - and NH-CH2-CH2-CH2-); 3,56 and 3,84 (2m, 2H, NH-CH2-CH-NH); or 4.31 (q, 1H, NH-CH2-CH-NH); 5,02 (s, 2H, O-CH2-Ph); of 6.68 (d, 1H, H naphthiridine); 7,33 (m, 5H, Ph); to 7.61 (m, 1H, H naphthiridine); to 8.20 (s, 1H, N=CH-N).

Mass spectrum:574 (MH+); 440 (MH-COOCH2Ph+); 572- (M-N); 464- (572-och2RH-); 1145- (2M-N).

D](1,20% CHCl3) 17, 7C.

Example 16

Synthesis of 4,6-dihydroxy-5-isobutylpyrazine

In a solution of 7.5 g (94 mmol) of formamidopyrimidine in 200 ml of ethanol, cooled to 0°C, enter 102 ml (282 mmol) of a 21% solution of ateleta sodium in ethanol and shake the mixture for 30 minutes; then introduce a solution of 20.6 ml (94 mmol) of diethylpropion 50 metanol and shaken overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is treated with 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phase is dried on sodium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). Gain of 13.7 g (Yield=86%) of the desired product in the form of a solid beige color.

SMS:Rf=0,53 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (DMSO d6):δ 0,81 (d, 6N, CH2CH-(CH3)2); of 1.85 (m, 1H, -CH2-CH-(CH3)2); 2,13 (d, 2H, -CH2-CH-(CH3)2); 7,81 h/m (C, N=CH-N).

Mass spectrum: 169 (MH+); 167 (M-N).

Synthesis of 4,6-dichloro-5-isobutylpyrazine.

A mixture of 3 g (to 17.9 mmol) 5-isobutyl-4,6-dihydroxypyrimidine 20 g of phosphorus oxychloride is heated under reflux for 1 hour. After cooling to ambient temperature is injected dropwise a mixture of 3 ml of N,N-diethylaniline in 10 ml of phosphorus oxychloride and heated received under reflux for 4 hours. After cooling to ambient temperature the reaction mixture was poured into a mixture of ice and water, then gradually introducing sodium bicarbonate to obtain an alkaline pH. Extracted with ethyl acetate, dried on magnesium sulfate and evaporated of Dosh is under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient heptane-methylene chloride from 100-0 to 80-20. Obtain 0.9 g (Yield=25%) brown oil.

SMS:Rf=0.25 in (silica gel, eluent: heptane-ethyl acetate 95-5).

Synthesis of 6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-isobutyl-4-chloropyrimidine:

In odnogolosy flask containing 0.95 g (4.4 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidine, obtained from its salts, enter 25 ml of dimethylacetamide, 0.9 g (4.4 mmol) of 4,6-dichloro-5-isobutylpyrazine and 2 ml of diisopropylethylamine. This mixture is heated to 120°C for 5 hours, then concentrated to dryness under reduced pressure (2 kPa). The resulting residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient heptane-methylene chloride-ethyl acetate from 50-50-0 to 0-0-100. Receive 1 g of the target product in a solid beige color (yield=60%).

SMS:Rf=0.25 in (silica gel, eluent: ethyl acetate (100%)).

1H-NMR (CDCl3):δ 0,89 (d, CH2-CH2CH-(CH3)2); 1,77-2,12 (m, 7H, NH-CH2- CH2-CH2N-CH2-CH2-CH-CH2and CH2-CH-(CH3)2); to 2.66 (d, 2H, -CH2-CH-(CH3)2); by 2.73 (t, 2H, NH-CH2-CH2-CH2); 2,61-2,77 (1H, hidden, CH2-CH-CH2); 3,44 (m, 2H, NH-CH2-CH2-CH2); 3,03 and a 3.87 (t and d, 4H, CH2-CH2-NCH2-CH2); 5,11 (m, 2H,NH-CH2-CH2-CH2); 6,41 and to 7.15 (2D, 2H,CH=CHthe naphthiridine); to 8.40 (s, 1H, N=CH-N).

Mass spectrum:386, 388 (MH+).

Synthesis of (1,1-dimethylethyl)-3-[[5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux 450 mg (1,17 mmol) 4-chloro-5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 413 mg (1.4 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 275 mg (1,81 mmol) of cesium fluoride, 55 mg (to 0.060 mmol) of Tris(dibenzylideneacetone)diplegia(0), 75 mg (0.12 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 35 ml of dioxane for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated the ri reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient of methylene chloride-simple diisopropyl ether-ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0, then 0-0-100-0 and finally 0-0-90-10. Obtain 630 mg (Yield=83%) of the desired product in the form of a solid amorphous yellow substance.

SMS:Rf=0,12 (silica gel, eluent: ethyl acetate).

1H-NMR (CDCl3):δ of 0.91 (d, 6H, CH2-CH-(CH3)2); for 1.49 (s, 9H, tBu); 1,77-2,07 (m, 7H, -CH2-CH-(CH3)2), NH-CH2-CH2-CH2and N-CH2-CH2-CH-CH2); 2,32 (d, 2H, -CH2-CH-(CH3)2); 2,65 (ush. t, 1H, CH2-CH-CH2); by 2.73 (t, 2H, NH-CH2-CH2-CH2); 2,95 (ush. t, 2H, CH2-CH2-N-CH2-CH2); 3,44 (m, 4H, CH2-CH2-N-CH2-CH2and NH-CH2-CH2-CH2); of 3.85 to 3.92 and (2m, 2H, NH-CH2-CH-NH); of 4.45 (m, 1H, NH-CH2-CH-NH); 5,14 (s, 2H,CH2-Ph); 6,12 (d, 1H, CH2-CH2-CH2-NH); to 6.43 (d,1H, H naphthiridine); 7,16 (d, 1H, H naphthiridine), 7,37 (m, 5H, CH2Ph); 8,31 (s, 1H, N=CH-N).

Mass spectrum:644 (MH+); 588 (MH-tBu+); 454 (MH-COOCH2Ph+).

Synthesis of 3-[[5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptorelin).

Shake 620 mg (0.96 mmol) of (1,1-dimethylethyl)-3-[[5-and butil-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 50 ml of dichloromethane and 5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get 525 mg (Yield=67%, expressed in DATEFORMAT) of the target product in a solid beige color.

SMS:Rf=0.40 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (DSO d6):of 0.83 (d, 6H, CH2-CH-(CH3)2); 1,60-2,05 (m, 7H, CH2-CH-(CH3)2), NH-CH2-CH2-CH2and N-CH2-CH2-CH-CH2); to 2.35 (m, 2H, -CH2-CH-(CH3)2); 2,65-2,87 (m, 3H, CH2-CH-CH2and NH-CH2-CH2-CH2); 2.91 in (ush. t, 2H, CH2-CH2-N-CH2-CH2); of 3.42 (m, 4H, CH2-CH2-N-CH2-CH2and NH-CH2-CH2-CH2); 3.57 and 3,84 (2m, 2H, NH-CH2-CH-NH); 4,32 (m, 1H, NH-CH2-CH-NH); 5,0 (s, 2H,CH2-Ph); of 6.68 (d, 1H, H naphthiridine); 7,37 (m, 5H, CH2Ph); 7,66 (d, 1H, H naphthiridine); to 7.59 (d, 1H of CH2-CH2-CH2-NN); of 8.27 (s, 1H, N=CH-N).

Mass spectrum:588 (MH+); 454 (MH-COOCH2Ph+); 586- (M-N); 478- (586-och2RH-); 1173- (2M-N).

D](0,75% CHCl3 ): +1,0.

Example 17

Synthesis of 5-methoxy-4,6-dihydroxypyrimidine

In odnogolosy flask containing 30 ml of absolute ethanol and 90 ml of ateleta sodium in ethanol concentratie 1.7 mol/l, administered at 0°C in small portions 5 g (6.2 mmol) of formamidopyrimidine. Shaken at ambient temperature for about 20 minutes, then injected dropwise to 8.5 ml of dimethylethoxysilane. Continue to shake for 16 hours. After this reaction medium was acidified with pure acetic acid to obtain a pH of from 4 to 5, then concentrate to dryness in the presence of cyclohexane. The resulting crude substance chromatographic on silica gel after separation, using as elution solvent a mixture of methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1). Obtain 9.5 g of the desired product containing small amounts of salts of sodium acetate.

SMS:Rf=0 (silica gel, eluent: methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1).

1H-NMR (eOD):δ to 3.67 (s, CH3-Oh); 7,73 (s, 1H, N=CHN); 2,00 (s, 3H, CH3-COO-).

HPLC/mass spectrum:(tr=0.5 min).

Synthesis of 4,6-dichloro-5-methoxypyridazine.

A mixture of 5 g (of 35.2 mmol) 5-methoxy-4,6-dihydroxypyrimidine and 40 g of phosphorus oxychloride is heated under reflux for 1 hour. After cooling to the fact the temperature of the environment is injected dropwise a mixture of 4.8 ml of N,N-diethylaniline and 18 ml of phosphorus oxychloride.

Received re-heated under reflux for 4 hours 30 minutes After cooling, the reaction mixture is slowly poured into a mixture of ice and water, then neutralize with saturated sodium bicarbonate solution. This aqueous phase is further extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate and evaporated to dryness in a vacuum.

The obtained residue is purified on silica, elwira with a mixture of cyclohexane and acetate (95-5).

Obtain 2.5 g (Yield=40%) of the desired product as white powder.

SMS:Rf=0,48 (silica gel, eluent: cyclohexane-ethyl acetate (80-20)).

1H-NMR (eOD):δ of 4.00 (s, CH3-Oh); 8,55 (s, 1H, N=CH-N).

HPLC/mass spectrum:tr = 1,3 minutes

Synthesis of 6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methoxy-4-chloropyrimidine:

In odnogolosy flask containing 800 mg (3,68 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidine, obtained from its salts, introducing 2.2 g (12.3 mmol) of 4,6-dichloro-5-methoxypyridine in solution in 25 ml of dimethylacetamide and 3640 ál diisopropylethylamine. This mixture is heated to 130°C for 2 hours, then concentrated to dryness in vacuo. The resulting residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. Unite the military organic phases are dried on magnesium sulfate, then the solvent is evaporated in vacuum. The remainder chromatographic aluminum oxide, elwira with a mixture of cyclohexane and acetate (80-20). Receive 900 mg (yield = 68%) of the desired product as a yellow powder.

Getting naphthiridine in the form of free amine:

2.4 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent. This operation is repeated 3 times to complete exclusion of salt. After filtration of the resin and evaporation of the solvents receive 800 mg (3,68 mmol) of free naphthiridine (yield = 88%).

SMS:Rf=0.4 (of alumina, eluent: ethyl acetate-cyclohexane (30-70)).

1H-NMR (eOD):δ 1,75-of 1.95 (m, 6H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2); 2,70 (t, 1H, CH2-CH-CH2); 2,8 (m, 2H, NH-CH2-CH2-CH2); 3,15 and 3.75 (2m, 4H, CH2-CH2-NCH2-CH2); of 3.75 (s, CH3-Oh); 6.4 and to 7.15 (2D, 2H,CH=CHthe naphthiridine); and 8.1 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr= 0.53 and 2,56 min); 359 (M); 360 (MH+); 361 (M+2H++).

Synthesis of (1,1-dimethylethyl)-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methoxy-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

A mixture of 300 mg (0.83 mmol) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methoxy-4-chloropyrimidine and 295 mg (1 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176) in the presence of 177 mg (1,17 mmol) of cesium fluoride, 52 mg (83 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 40 mg (42 μmol) of Tris(dibenzylideneacetone)diplegia(0) in 10 ml of dioxane is heated under reflux for 3 hours 30 minutes the Reaction mixture is cooled. Then enter 0.5 mmol (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate and at 1.17 mmol of cesium fluoride, 83 mmol 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 42 μmol of Tris(dibenzylideneacetone)diplegia(0), then the reaction mixture is heated under reflux for a further 8 hours.

After cooling, the solution is concentrated to dryness and treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate and evaporated to dryness in a vacuum. The remainder chromatographic aluminum oxide gradient of isopropyl ether and ethyl acetate (70-30, 60-40, 50-50)to ethyl acetate 100%. The fractions containing the desired product are pooled for re-purification on silica gel with a gradient of 100% ethyl acetate. Get t the left the product as a pale yellow oil, which is treated with a simple mixture of isopropyl ether and pentane and obtain 220 mg (yield=43%) of white powder.

SMS:Rf=0,3 (alumina, eluent: simple isopropyl ether-ethyl acetate 60-40).

1H-NMR (eOD):δ of 1.46 (s, 9H, tBu); of 1.80 (m, 2H, NH-CH2-CH2-CH2); 1,90 (m, 4H, N-CH2-CH2-CH-CH2); to 2.65 (m, 1H, CH2-CH-CH2); 2,69 (t, 2H, NH-CH2-CH2-CH2); 2,95 and of 3.78 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.38 (t, 2H, NH-CH2-CH2-CH2); 3,59 (s, CH3-Oh); of 4.35 (m, 1H, NH-CH2-CH-NH); of 4.45 (d, 2H, NH-CH2-CH-NH); 5.03 and 5,12 (Syst. AB, 2H, O-CH2-Ph); 6,38 and to 7.15 (2D, 2H,CH=CHthe naphthiridine); 7,32 (m, 5H, Ph); of 7.90 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=3,4 min): 618(MH+); 562 (MH-tBu); 428 [(MH-tBu-Z+)].

The synthesis of the appropriate acid:

Shaken at ambient temperature of 200 mg (0.32 mmol) of (1,1-dimethylethyl)-3-[[5-methoxy-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 1.5 ml triperoxonane acid in 15 ml of dichloromethane for 8 hours. Add toluene and the mixture is evaporated to dryness. Obtain 350 mg of a yellow oil, this oil is treated with a minimal amount of methylene chloride, precipitated simple isopropyl ether and thus receive the crude salt is of referencedata. Re-precipitated in a simple ether before purification (control via SMS). Finally obtain 156 mg of the target product (Yield=71%) as a white powder.

SMS:Rf=0,4 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (eOD):δ of 1.85 (m, 2H, NH-CH2-CH2-CH2); 2,00 (m, 4H, N-CH2-CH2-CH-CH2); and 2.83 (t, 2H, NH-CH2-CH2-CH2); 3,90 (m, 1H, CH2-CH-CH2); 3,12 and 3,72 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.52 (t, 2H, NH-CH2-CH2-CH2); 3,62 (s, 3H, CH3-About); to 4.52 (m, 2H, NH-CH2-CH-NH); 4,60 (m, 1H, NH-CH2-CH-NH); 5,06 and 5,10 (Syst. AB, 2H, O-CH2-Ph); -6,65 and 7.62 (2D, 2H,CH=CHthe naphthiridine); the 7.43 (m, 5H, Ph); 8,00 (s, 1H, N=CH-N).

HPLC/mass spectrum:(tr=0.5 min and 2.75 min): 562 (MH+); 428 [MH-(tBu-Z+)]; 428.

Example 18

Synthesis of 4,6-dibromo-5-ftorpirimidinu

1. In a solution of 5.83 g (56 mmol) of formamidine in 300 ml of ethanol, cooled to 0°C, injected 60,7 ml (168 mmol) of a 21% solution of ateleta sodium in ethanol and shake the mixture for 30 minutes; then introduce a solution of 10 g (56 mmol) of diethylphosphonate in 25 ml of ethanol and shaken overnight at ambient temperature. The mixture is cooled to 0°C, then enter 17,85 ml of concentrated hydrochloric acid to obtain a pH of 6. The precipitate is filtered, then the follower is about washed with water, isopropanol, simple diethyl ether and finally with pentane. Obtain 14.2 g (theoretically of 7.3 g) of the target product and mineral salts, used as such in the future.

2. A mixture of 14.2 g (56 mmol) of 5-fluoro-4,6-dihydroxypyrimidine in 21 g of oxybromide phosphorus is heated to 200°C for 3 hours. After cooling to ambient temperature the reaction mixture is treated with a mixture of ice water and sodium bicarbonate and extracted with ethyl acetate, wash the organic phase with water, dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient of methylene chloride-heptane from 0-100 to 100-0. Get 850 mg (Yield=0,6%) of the desired product in the form of a solid beige color used as such in the future.

SMS:Rf=0.50 in (silica gel, eluent: dichloromethane-heptane 50-50).

Synthesis of 4-bromo-5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine.

A mixture of 840 mg (1.5 mmol) of 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthiridine, Tris(triptoreline) (obtained in accordance with ER or WO 0078317) and 5 g of resin Amberlyst A-21 (Fluka production 06424, pre-washed with a solution of dichloromethane-ethyl acetate-methanol 1-1-1) in 100 ml dichloromethane-ethyl acetate-methanol 1-1-1 shaken at ambient temperature for 1 hour. The mixture is filtered, the resin is washed with three-component solution. The obtained filtrate is shaken at ambient temperature for 1 hour in the presence of 5 g of resin Amberlyst A-21, processed as described above. The resulting filtrate is concentrated to dryness under reduced pressure (2 kPa) and obtain 320 mg of the free amine. In the remainder of the injected 384 mg (1.5 mmol) of 4,6-dibromo-5-ftorpirimidinu, 6 ml of dimethylacetamide and 1.5 ml of diisopropylethylamine and heated to 130°C. for 1.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and treat the residue with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira heptane-ethyl acetate 50-50. Obtain 300 mg (Yield=52%) of the desired product as an amorphous solid.

SMS:Rf=0.15 in (silica gel, eluent: heptane-ethyl acetate 50-50).

IR (CHCl3):3440 (NH); 1573; 1542; 1503; cm-1(Heterocycle).

1H-NMR (CDCl3):δ 1,82, 1,92 and 2.02 (dt, t and d 6H, CH2-CH2-CH2-NH andCH2CH-CH2); of 2.72 (t, 2H,CH2-CH2-CH2-NH); 2,80 (ush. t, 1H, CH2-CH-CH2); 3,13 and 4,68 (ush. t and d, 4H, CH2-CH2-NCH2-CH2); of 3.42 (m, 2H, CH2-CH2-CH2-NH); 5,00 (m, 1HNH); 6,37 (d, 1H, naphthiridine); 7,14 (d, 1H, h is pteridine); 8,11 h/m (C, N=CH-N).

Mass spectrum:392(MH+).

Synthesis of (1,1-dimethylethyl)-3-[[5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate.

Heated under reflux a mixture of 280 mg (0,72 mmol) 4-bromo-5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]pyrimidine, 253 mg (0.86 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 152 mg (1.00 mol) of cesium fluoride, 33 mg (being 0.036 mmol) of Tris(dibenzylideneacetone)diplegia(0), 45 mg (0,072 mmol) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 50 ml of dioxane for 6 hours. Cool, then re-injected 125 mg (0.43 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 152 mg (1.0 mmol) of cesium fluoride, 33 mg (being 0.036 mmol) of Tris(dibenzylideneacetone)diplegia(0), 45 mg (0,072 mmol) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and heated under reflux for 4 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient heptane-ethyl acetate-methanol from 100-0-0 to 0100-0 and finally 0-95-5. The resulting product again chromatographic aluminum oxide, elwira a mixture of heptane-methylene chloride 50-50, then ethyl acetate-simple diisopropyl ether 50-50. Obtain 300 mg (Yield=70%) of the desired product as yellow oil.

SMS:Rf=0.35 in (silica gel, eluent: ethyl acetate).

IR (CHCl3):3439 (NH); 1718 (C=O); 1609; 1503 cm-1(heterocycle+aromatic+amide)

1H-NMR (CDCl3):δ of 1.47 (s, S, tBu); 1.70 to 2.05 is (m, 6N, CH2-CH2-CH2-NH andCH2CH-CH2); by 2.73 (t, 2H,CH2-CH2-CH2-NH); 2,80 (ush. t, 1H, CH2-CH-CH2); 3,01 and 3,90 (ush. t and m, 4H, CH2-CH2-NCH2-CH2); of 3.43 (m, 2H, CH2-CH2-CH2-NH); was 4.42 (m, 1H, NH-CH2-CH-NH); 4,51 (ush. d, 2H, NH-CH2-CH-NH); 5,11 (m, 1HNH); 5,14 (s, 2H,CH2-Ph); 6,12 (m, 1H of CH2-CH2-CH2-NH); 6,37 (d, 1H, naphthiridine); 7,16 (d, 1H, naphthiridine); 7,35 (m, 5H, Ph); 7,98 h/m (C, N=CH-N).

Mass spectrum:606 (MH+); 550 (MH-tBu+); 416 (550-COOCH2Ph+), 604-[(M-H)], 650-[(604+HCOOH)]-, 496-[(604-OCH2Ph)]-.

D](1,0% CHCl3): +4,4.

Synthesis of bis(triptorelin) 3-[[5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine.

Shake 290 mg (0.48 mmol) of (1,1-dimethylethyl)-3-[[5-ftor-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 40 ml of dichloromethane and 4 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 310 mg (Yield=83%, expressed in DATEFORMAT) of the desired product as a white solid.

SMS:Rf=0,44 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

Mass spectrum:550 (MH+); 416 (MN-COOCH2Ph+), 548-[(M-H)], 440-[(548-OCH2Ph)]-, 1097-(2M-N).

D](0,30%Meon): -9,3.

Example 19

Synthesis of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino] alaninate.

In odnogolosy flask containing 3 g (4,87 mmol) 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, enter 150 ml of 100% acetic acid and 300 mg of palladium on activated coal (5-10%). This mixture is purified by reduced pressure (2 kPa), and then shaken at ambient temperature and under pressure in a nitrogen atmosphere for 22 hours.

Received a heterogeneous environment is filtered through clarcel. The filtrate is concentrated to dryness, then treated with a mixture of water, e is racette and saturated sodium bicarbonate solution. The organic phase is extracted with ethyl acetate and dried on magnesium sulfate, then the solvent is evaporated under reduced pressure (2 kPa). Get 1,95 mg of pale yellow oil.

SMS:Rf=0,65 (silica gel, eluent: ethyl acetate-methanol-triethylamine 90-5-5).

1H-NMR (CDCl3):δ of 1.09 (t, 3H, CH2-CH3); to 1.35 (s, 9H, tBu); to 1.75 (m, 6H,CH2-CH-CH2and CH2-CH2-CH2-NH); 2,44 (m, 2H,CH2-CH3);2,60 (t, 2H,CH2-CH2-CH2-NH); of 2.81 (m, 2H, CH2-CH-CH2and NH-CH2-CH-NH); 3,23 (m, 2H, CH2-CH2-CH2-NH); to 3.41 (m, 4H, CH2-CH2-NCH2-CH2); 3,42 and 3.57 (2m, 2H, NH-CH2-CH-NH); and 6.25 (m, 2H, CH2-CH2-CH2-NHandNH-CH2-CH-NH); 6,30 and 7.04 (2D, 2H, H naphthiridine); 8,08 h/m (s, 1H, N=CH-N).

IR (CHCl3):3439 (NH); 1726 (C=)0; 1580, 1502 cm-1(heterocycle).

Mass spectrum:482+(MN)+; 426+[MH+-tBu]+; 339+[MH+-CH2CH(NH2)CO2tBu]+; 241,7+, [M+2H]2.

D]:-3(1% CHCl3).

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(adamantylidene)carbonyl]alaninate.

A mixture of 239 mg (0.49 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-after the DIN-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate, 152 mg (0.49 mmol) of N-adamantanecarboxylic and 0.104 g ml (0.75 mmol) of triethylamine in 50 ml of methylene chloride is shaken for 5 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwira gradient of 100% methylene chloride to methylene chloride-methanol 90-10. Get 77 mg (Yield=17%) of the desired product in the form of a solid beige color.

SMS:Rf=0.45 in (silica gel, eluent: methylene chloride-methanol-acetic acid-water 90-10-1-1).

IR (CHCl3):3437 (NH); 1711 (C=O); 1583; 1556; 1501 cm-1(heterocycle).

1H-NMR (DSO-d6):δ a 1.08 (t, 3H, CH2-CH3); 1,45-of 1.92 (m, 15H, substituted); to 1.32 (s, 9H, tBu); or 1.77 (m, 6H,CH2-CH-CH2and CH2-CH2-CH2-NH); is 2.44 (q, 2H,CH2-CH3); of 2.50 (m, 1H, CH2-CH-CH2); 2,61 (t, 2H,CH2-CH2-CH2-NH); 2,82 and 3,44 (2m, 4H, CH2-CH2-NCH2-CH2); up 3.22 (m, 2H, CH2-CH2-CH2-NH); of 3.56 (s, 2H, O-CH2-substituted); 3,66 (m, 2H, NH-CH2-CH-NH); 4,17 (kV, 1H, NH-CH2-CH-NH); 6,24 (s, 1H, CH2-CH2-CH2- ); 6,30 and 7,05 (2D, 2H, H naphthiridine); 6,37 (t, 1H,NH-CH2-CH-NH); 7,44 (d, 1H, NH-CH2-CH-NH); 8,10 h/m (C, N=CH-N).

Mass spectrum:674 (MH+); 618 (MH-tBu+); 426 (618-COOCH2adam+); 337,7 (M2H++); 718-(M-H-HCOOH); 672-(M-H).

D]:+2,5 (1% CHCl3).

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(adamantylidene)carbonyl]alanine

Shake 130 mg (0,19 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(adamantylidene)carbonyl]alaninate in 20 ml of dichloromethane and 2 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get 368 mg (Yield=61%, expressed in DATEFORMAT) of the desired product as an amorphous solid.

SMS:Rf=0.35 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

IR (CHCl3):3401 (NH); 1668 (C=O); 1581; 1492 cm-1(heterocycle).

1H-NMR (DSO-d6):δ a 1.08 (t, 3H, CH2-CH3); 1,5-of 1.92 (m, 15H, the substituted); to 1.76 (m, 6N,CH2-CH-CH2CH2-CH2-CH2-NH); 2,43 (q, 2H,CH2-CH3); of 2.50 (m, 1H, CH2-CH-CH2); 2,60 (t, 2H,CH2-CH2-CH2-NH); 2,82 and 3.45 (2m, 4H, CH2-CH2-NCH2-CH2); 3,23 (m, 2H, CH2-CH2-CH2-NH); 3.49 and to 3.58 (m, 2H, O-CH2-substituted); 3,56 and 3.76 (m, 2H, NH-CH2-CH-NH); 4,18 (m, 1H, NH-CH2-CH-NH); of 6.26 (s, 1H, CH2-CH2-CH2-NH); 6,30 and 7,05 (2D, 2H, H naphthiridine); 6,44 (m, 1H,NH-CH2-CH-NH); to 7.25 (d, 1H, NH-CH2-CH-NH); 8,11 h/m (C, N=CH-N).

Mass spectrum:618 (MH+); 426 (MN-COOCH2Ph+), 1235 (2MH+), 309,8 (MN++); 616-(M-N).

D]:(0.7% of CH3HE): -2,8.

Example 20

Synthesis of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate

In odnogolosy flask containing 3 g (4,87 mmol) 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, enter 150 ml of 100% acetic acid and 300 mg of palladium on activated coal (5-10%). This mixture is purified by reduced pressure (2 kPa), and then shaken under pressure in a nitrogen atmosphere for 22 hours.

Received a heterogeneous environment is filtered through clarcel. The filtrate is concentrated to dryness under reduced pressure (2 kPa), the ATEM is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is extracted with ethyl acetate and dried on magnesium sulfate, then the solvent is evaporated under reduced pressure (2 kPa). Get 1,95 g of pale yellow oil.

SMS:Rf=0,65 (silica gel, eluent: t-MeOH-TEA=90-5-5).

αD=-3 (1% CHCl3).

1H-NMR (CDCl3):δ of 1.09 (t, 3H, CH2-CH3); to 1.35 (s, S, tBu); to 1.75 (m, 6H,CH2-CH-CH2and CH2-CH2-CH2-NH); 2,44 (m, 2H,CH2-CH3); 2,60 (t, 2H,CH2-CH2-CH2-NH); of 2.81 (m, 2H, CH2-CH-CH2and NH-CH2-CH-NH); 3,23 (m, 2H, CH2-CH2-CH2-NH); to 3.41 (m, 4H, CH2-CH2-NCH2-CH2); 3,42 and 3.57 (2m, 2H, NH-CH2-CH-NH); and 6.25 (m, 2H, CH2-CH2-CH2-NHandNN-CH2-CH-NH); 6,30 and 7.04 (2D, 2H, H naphthiridine); 8,08 h/m (s, 1H, N=CH-N).

IR (CHCl3)3439 (NH); 1726 (C=0); 1580-1502 (heterocycle).

HPLC/mass spectrum:482+(MN)+; 426+[MH+-tBu]+; 339+[MH+-CH2CH(NH2)CO2tBu]+; 241,7+[M+2H]2.

Examples 21 to 31

Example 28

Stage a)

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(4-methoxybenzenesulfonyl)alaninate.

In a mixture of 150 mg (0.31 mmol) of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate in solution in 6 ml dichloromethane and 650 μl of pyridine enter and 64.3 mg (0.31 mmol) of 4-methoxybenzenesulfonamide in solution in 3 ml of dichloromethane. The reaction mixture is shaken at ambient temperature for 5 hours. Then the solvent is evaporated under reduced pressure (2 kPa) and the residue chromatographic on silica gel using the following eluent: ethyl acetate-dichloromethane/methanol (95-5) 50-50 to ethyl acetate-methanol 90-10. Get to 55.8 mg (Yield=28%) of the target product.

SMS:Rf=0,63 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (CDCl3):δ to 1.21 (t, 3H, CH2-CH3); of 1.30 (s, 9H, tBu); 1,92 and 2.02 (2m, 6H, N-CH2-CH2-CH-CH2-CH2CH2-CH2-CH2-NH); 2,48 (q, 2H,CH2-CH3); 2,72 (m, 3H, N-CH2-CH2-CH-CH2-CH2,CH2-CH2-CH2-NH); 2,97 and 3,61 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); to 3.45 (m, 2H, CH2-CH2-CH2-NH); 3,74 and 3,86, and 3.95 (3M, 6H, NH-CH2-CH-NH, co3); of 4.95 (t, 1H,NHmobile); of 5.92 (d, 1H, NH mobile); to 6.43 and 7,20 (2D, 2H, CH=CH naphthiridine); 6,95 and 7,79 (2D, 4H, CH=CH benzene); 8,29 (s, 1H, N=CH-N).

Mass spectrum:652 (MH+).

Stage b)

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(4-methoxybenzenesulfonyl)alanine

Shake to 55.8 mg (0,086 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-n is pteridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[4-(methoxybenzenesulfonyl)alaninate in 5 ml of dichloromethane with 0.5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 85-15-2-2). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get to 59.8 mg (Yield=85%, expressed in DATEFORMAT) of the target product.

SMS:Rf=0,33 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (eOD):δ to 1.22 (t, 3H, CH2-CH3); 1,96 and 2.10 (2m, 6H, N-CH2-CH2-CH-CH2-CH2CH2-CH2-CH2-NH); to 2.55 (q, 2H,CH2-CH3); to 2.85 (t, 2H,CH2-CH2-CH2-NH); 2,95 (m, 1H, N-CH2-CH2-CH-CH2-CH2); 3,20 and 3.67 and to 3.92 (3M, 6H, N-CH2-CH2-CH-CH2-CH2, NH-CH2-CH-NH); 3,51 (m, 2H, CH2-CH2-CH2-NH); 4,24 (m, 1H, NH-CH2-CH-NH); of 6.71 and to 7.64 (2D, 2H, CH=CH naphthiridine); £ 6.99 and 7,74 (2D, 4H, CH=CH benzene); of 8.27 (s, 1H, N=CH-N).

Mass spectrum:596 (MH+).

A General method of polucheniya sulfonamides

Stage a)

In a mixture of 150 mg (0.31 mmol) of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate in solution in 6 ml dichloromethane and 650 μl of pyridine enter 0.31 mmol (mass mx) sulfon is chloride in 3 ml of dichloromethane. The reaction mixture is shaken at ambient temperature for 5 hours. Then the solvent is evaporated under reduced pressure (2 kPa) and the residue chromatographic on silica gel using the following eluent: ethyl acetate-dichloromethane/methanol (95-5) 50-50 to ethyl acetate-methanol 90-10. Get a mass mythe target product.

SMS:Rf (eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

Stage b)

Shake the mass my(1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(R-sulfonyl)alaninate in 5 ml of dichloromethane with 0.5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 85-15-2-2). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Get a mass mzthe target product.

SMS:Rf (eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

Sulphonylchloridemx (mg)The obtained estermy
(mg)
OutletMass spectrum
(MN+)
Rf
Example 2147,130226720,61
Example 2240,438,7296400,63
Example 2359,348246360,69
Example 2455,1 18,410622-6240,65
Example 2565,657,628656-6580,67
Example 2678,670326980,67
Example 2773,0to 49.3236800,67
Example 2976,163,430690063
Example 3081,721,4107080,63
Example 3162,756,3286470,65
Mx: put a lot of sulphonylchloride
My: the weight of ester

The obtained acidFW (free base)Free. Base +2TFAmz
(mg)
Mass spectrum
(MN+)
Rf
Example 21615,76843,7620,8 6160,4
Example 22583,69811,6931,25840,33
Example 23579,73807,73to 45.45800,3
Example 24566,13794,13the 11.6566-5680,26
Example 25600,14828,1458,3600-6010,3
Example 26641,8869,856,66420,37
Example 27623,74851,7441,26240,37
Example 29633,7861,759,86340,33
Example 30651,79879,7948,56520,35
Example 31590,71818,71285910,26
Mz: the mass of the obtained acid

Example 32

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulfonyl)alaninate.

A mixture of 239 mg (0.49 mmol) of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinamine]alaninate, 113 mg (0.5 mmol) of 1-naphthalenesulfonate and 0.104 g ml (0.75 mmol) of triethylamine in 50 ml of tetrahydrofuran shaken for 5 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira gradient heptane-ethyl acetate from 75-25 to 0-100. Obtain 220 mg (Yield=67%) of the desired product as white solid.

SMS:Rf=0,10 (silica gel, eluent: methylene chloride-methanol-acetic acid-water 90-10-1-1).

IR (CHCl3):3440 (NH); 1728 (C=O); 1583; 1555; 1503 cm-1(heterocycle+aromatic).

1H-NMR (CDCl3):δ of 1.02 (t, 3H, CH2CH3);to 1.15 (s, S, tBu); 1,81-2,03 (m, 6H,CH2-CH-CH2and CH2-CH2-CH2-NH); 2,23 and 2,31 (2Q, 2H,CH2-CH3); to 2.67 (t, 1H, CH2-CH-CH2); of 2.72 (t, 2H,CH2-CH2-CH2-NH); 2,93 and 3,56 (ush. t and ush. d, 4H, CH2-CH2-NCH2-CH2); 3,43 (m,2H, CH2-CH2-CH2-NH); 3,66 and 3.76 (2m, 2H, NH-CH2-CH-NH); of 3.97 (m, 1H, NH-CH2-CH-NH); to 4.73 (t, 1H, t, 1H,NH-CH2-CH-NH); 6,55 (s, 1H, CH2-CH2-CH2-NH); 6.4 and 7,05 (2D, 2H, H naphthiridine); 7,51 (t, 1H, H3 1-SO2naphthyl); and 7.62 EUR 7.57 (2T, 2H, h6 and H7 1-SO2naphthyl); of 7.90 (d, 1H, H2 1-SO2naphthyl); 8,02 (d, 1H, H4 1-SO2naphthyl); by 8.22 (m, 2H, N=CH-N and N5 1-SO2naphthyl); 8,61 h/m (m, 1H, H8 1-SO2).

Mass spectrum:672 (MH+); 426 (616-SOOnapht+); 670(M-H).

D]:+3,3 (1% CHCl3).

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulfonyl)alanine

Shake 220 mg (0.33 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulfonyl)alaninate in 20 ml of dichloromethane and 2 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 230 mg (Yield=82%, expressed in DATEFORMAT) of the desired product as white solid.

SMS:Rf=0,10 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

IR (CHCl3):3412-3257 (HE, NH); 1668 (C=O); 1628; 1582, 1505 cm-1(C=C, C=N, aromaticheski is)).

1H-NMR (DSO-d6):δ of 0.87 (t, 3H, CH2-CH3); to 1.77 (m, 6H,CH2-CH-CH2CH2-CH2-CH2-NH); 2,05 (kV, 1H,CH2-CH3); 2,16 (kV, 1H,CH2-CH3); 2,62 (t, 2H,CH2-CH2-CH2-NH); 2,73 and 3,50 (2m, 4H, CH2-CH2-NCH2-CH2); 2,80 (m, 1H, CH2-CH-CH2); 3,20 (m, 2H, CH2-CH2-CH2-NH); 3,50 (m, 2H, CH-CH2-CH2N); 3,66 and 3.76 (2m, 2H, NH-CH2-CH-NH); of 3.97 (t, 1H, NH-CH2-CH-NH); of 6.26 (s, 1H, CH2-CH2-CH2-NH); of 6.31 and 7,06 (2D, 2H, H naphthiridine); at 7.55 (t, 1H, H3 1-SO2naphthyl); a 7.62 (m, 2H, h6 and H7 1-SO2naphthyl); of 7.96 h/m (C, N=CHN); 8,02 (m, 1H, H5 1-SO2naphthyl); 8,08 (d, 1H, H2 1-SO2naphthyl); to 8.14 (d, 1H, H4 1-SO2naphthyl); 8,58 (m, 1H, H8 1-SO2naphthyl).

Mass spectrum:616 (MH+); 426 (MN-SOOnapht+), 1231 (2MH+), 308,8 (MN++); 616-(M-N).

D](0.4% of CH3HE): +7,0.

Example 33

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl)alaninate.

A mixture of 240 mg (0.50 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate and 3 ml of 2-herperidin shaken for 24 hours under reflux. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the OS is atok treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira a mixture of ethyl acetate-methylene chloride-methanol 80-16-4. 13 mg (Yield=0,5%) of the desired product as oil.

SMS:Rf=0.40 in (silica gel, eluent: methylene chloride-methanol 90-10).

Mass spectrum:559 (MH+).

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl)alanine

Shake 13 mg (0.23 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl)alaninate in 2 ml of dichloromethane with 0.2 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane and then poured on a simple diisopropyl ether. The precipitate is filtered. 13 mg (Yield=76%, expressed in DATEFORMAT) of the desired product as beige solid substance.

SMS:Rf=0.35 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

Mass when ECTR: 503 (MH+); 501- (M-N).

Example 34

Synthesis of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-benzothiazolyl)alaninate.

A mixture of 200 mg (0.42 mmol) of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate and 90 mg (0.6 mmol) of 2-perbenzoate in 5 ml of pyridine is shaken for 2 hours at a temperature of 100°C. the Reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic first time on silica gel, elwira gradient of methylene chloride-ethyl acetate-methanol from 100-0-0 to 0-100-0, then 0-95-5; the second time on reverse phase R8, elwira gradient of methanol-water from 80-20 to 100-0. Obtain 50 mg (Yield=19%) of the target product in a solid pink color.

SMS:Rf=0,20 (silica gel, eluent: ethyl acetate-methanol 98-2).

1H-NMR (CDCl3):δ of 1.06 (t, 3H, CH2CH3); for 1.49 (s, S, tBu); 1,77 is 2.01 (m, 6H,CH2-CH-CH2and CH2-CH2-C2-NH); to 2.41 (q, 2H,CH2-CH3); 2,61 (t, 1H, CH2-CH-CH2); of 2.72 (t, 2H,CH2-CH2CH 2-NH); 2,92 and 3,51 (ush. kV and ush. t, 4H, CH2-CH2-NCH2-CH2); of 3.42 (m, 2H, CH2-CH2-CH2-NH); 3,95 and 4.09 to (2m, 2H, NH-CH2-CH-NH); 4,88 (m, 1H, NH-CH2-CH-NH); 4,98 and 5.63 (m, t, 2H,NH-CH2-CH-NH and NH-CH2-CH-NH); 6,67 (ush. s, 1H, CH2-CH2-CH2-NH); 6,41 and 7,13 (2D, 2H, H naphthiridine); 7,12, 7,31 and EUR 7.57 (t hidden, T. and ush. t, 4H, H benzothiazole); 8,32 h/m (s, 1H, N=CH-N).

Mass spectrum:615 (MN+), 559 (MH-tBu+); 613- (M-N).

Synthesis of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-benzothiazolyl)alanine

Shake 45 mg (0,073 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-benzothiazolyl)alaninate in 10 ml of dichloromethane with 1 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Receive 60 mg (Yield=97%, expressed in DATEFORMAT) of the desired product as white solid.

SMS:Rf=0.45 in (silica gel, eluent: dihl rmean-methanol-water-acetic acid 85-15-2-2).

1H-NMR (CDCl3):δ of 1.15 (t, 3H, CH2-CH3); 1,75-2,07 (m, 6N,CH2-CH-CH2CH2-CH2-CH2-NH); of 2.51 (q, 1H,CH2-CH3); was 2.76 (ush. t, 2H,CH2-CH2-CH2-NH); 2,96 (m, 1H, CH2-CH-CH2); 3,20 and to 3.73 (2m, 4H, CH2-CH2-NCH2-CH2); 3,51 (m, 2H, CH2-CH2-CH2-NH); to 4.23 (m, 2H, NH-CH2-CH-NH); of 4.67 (m, 1H, NH-CH2-CH-NH); 6,38 and 7.35 (2D, 2H, H naphthiridine); 7,20, 7,35, 7,47 and rate of 7.54 (t, t hidden, ush. d and ush. d 4H, H benzothiazole); 7,73 and of 10.05 (2m, 2H, H mobile); at 8.36 PM/m (s, 1H, N=CH-N).

Mass spectrum:559 (MH+); 557- (M-N).

Example 35

By analogy with example 34 (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]alaninate receive 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[2-(4-methoxybenzimidazole)]alanine in the form of a beige solid substance.

SMS:Rf=0.40 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (CDCl3):δ of 1.12 (m, 3H, CH2CH3); 1,65-2,07 (m, 6N,CH2-CH-CH2and CH2-CH2-CH2-NH); 2,47 (m, 2H,CH2-CH3); to 2.74 (m, 2H,CH2-CH2-CH2-NH); 2,92 (m, 1H, CH2-CH-CH2); 3,17 and to 3.73 (2m, 4H, CH2-CH2-NCH2-CH2) to 3.52 (m, 2H, CH2-CH2-CH2-NH); 3,79 (s, 1H, OCH3); 4,18 (m, 2H, NH-CH2-CH-NH); to 4.81 (m, 1H, NH-CH2-CH-NH); 6,35 and 7,36C (2D, 2H, H naphthiridine); 6,72 and to 7.18 (2D, 2H, NC(C)CHCHC(CH)OCH3); 6.87 in (s, 1H, NC(C)CHC(CH)OCH3); 6,37, 7,70 and 9,84 (mobile 3H); 8,32 h/m (s, 1H, N=CH-N).

Mass spectrum:572 (MH+); 570- (M-N).

Example 36

Synthesis tertbutyl-2-(2-benzyloxycarbonylamino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]-naphthiridine-2-yl)-piperidine-1-yl]- pyrimidine-4-ylamino}propylamino)propionate

Shake 170 mg (0.30 mmol) 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, 150 mg (1.0 mmol) tertbutyl-L-alaninate, 66 mg (0.48 mmol) of 1-hydroxybenzotriazole, 90 mg (0.48 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 0,015 ml (is 0.135 mmol) N-methylmorpholine and 0,210 ml (1.50 mmol) of triethylamine in 10 ml of dimethylformamide for 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). Sediment chromatographic on silica gel, elwira a mixture of ethyl acetate-methylene chloride-methanol 50-50-10. Obtain 120 mg (Yield=60%,the target p is oduct in a solid white color.

SMS:Rf=0.40 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

Mass spectrum: 673 (MH+).

Synthesis of 2-(2-benzyloxycarbonylamino-3-{5-methyl-6-[5,6,7,8-tetrahydro-[1,8]naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)propionic acid

Shake 120 mg (0,179 mmol) tertbutyl-2-(2-benzyloxycarbonylamino-3-{5-methyl-6-[4-[5,6,7,8-tetrahydro-[1,8]naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)propionate in 5 ml of dichloromethane with 1 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 95 mg (Yield=63%, expressed in DATEFORMAT) of the target product in a solid white color.

SMS:Rf=0.45 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

Mass spectrum:616 (MH+).

Example 37

Synthesis tertbutyl-2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]-naphthiridine-2-yl)-piperidine-1-yl]pyrimidine-4-ylamino}propylamino)propionate

p>

Shaken 80 mg (0.15 mmol) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, 32 mg (0.20 mmol) tertbutyl-L-alaninate, 22 mg (0.16 mmol) 1-hydroxybenzotriazole, 30 mg (0.16 mmol) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 0,050 ml (0.45 mmol) of N-methylmorpholine and 0,070 ml (0.50 mmol) of triethylamine in 5 ml of dimethylformamide for 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue treated with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). Sediment chromatographic on silica gel, elwira a mixture etelaat-methylene chloride-methanol from 50-50-0 to 50-45-5. Get 55 mg (Yield=53%) of the desired product in the form of a solid white color.

SMS:Rf=0,30 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (CDCl3):δ of 0.91 (t, 3H, CH2-CH3); to 1.38 (d, 3H, CONH-CH(CH3)-CO)to 1.48 (s, 9H, tBu); 1,79-2,07 (m, 6H, CH2-CH2-CH2-NH,CH2-CH-CH2); 2,49 (m, 2H,CH2-CH3); to 2.66 (m, 1H, CH2-CH-CH2); by 2.73 (t, 2H,CH2-CH2-CH2-NH); 2,97 and 3,63 (2m, 4H, CH2-CH 2-NCH2-CH2); of 3.42 (m, 2H, CH2-CH2-CH2-NH); to 3.73 and 4,14 (2m, 2H, NH-CH2-CH-NH); or 4.31 (m, 1H, NH-CH2-CH-NH); of 4.44 (q, 1H, CONH-CH(CH3)-CO); 5,14 (m, 2H,CH2-Ph); 5,35, 6,92 and 7,89 (3H, H mobile); and 6.42 per 7,14 (2D, 2H, H naphthiridine); of 7.36 (m, 5H, Ph); 8,29 h/m (s, 1H, N=CH-N).

Mass spectrum: 687 (MH+).

Synthesis of 2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]-naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)propionic acid

Shake 50 mg (0,073 mmol) tertbutyl-2-(2-benzyloxycarbonylamino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]-naphthiridine-2-yl)piperidine-1-yl]pyrimidine-4-ylamino}propylamino)propionate in 5 ml of dichloromethane with 0.5 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: CH2Cl2-MeOH-H2O-AcOH 90-10-1-1). Add toluene and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 53 mg (Yield=85%, expressed in DATEFORMAT) of the target product in a solid white color.

SMS:Rf=0,12 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (CDC 3):δ of 1.16 (t, 3H, CH2-CH3); of 1.41 (d, 3H, CONH-CH(CH3)-CO); 1,80-2,10 (m, 6H, CH2-CH2-CH2-NH,CH2-CH-CH2); 2,48 (m, 2H,CH2-CH3); and 2.79 (m, 2H,CH2-CH2-CH2-NH); 3,00 (ush. t, 1H, CH2-CH-CH2); 3.28 and 3,84 (2m, 4H, CH2-CH2-NCH2-CH2); to 3.52 (m, 2H, CH2-CH2-CH2-NH); 3,78 and 4.13 (2m, 2H, NH-CH2-CH-NH); to 4.46 (m, 1H, NH-CH2-CH-NH); 4,59 (m, 1H, CONH-CH(CH3)-CO); of 5.05 (m, 2H,CH2-Ph); 6,41 and 7,38 (2D, 2H, H naphthiridine); 6,68, 7,20, 7.95 and 9,68 (4H, H mobile); 7,31 (m, 5H, Ph); 8,28 h/m (s, 1H, N=CH-N).

Mass spectrum:631 (MH+).

Example 38

1) Synthesis of tertbutyl-4-hydroxy-1-piperidinecarboxylate 1:

Dissolve 1 g (5 mmol) tertbutyl-4-oxo-1-piperidinecarboxylate (manufactured by Aldrich) in 5 ml of ethanol. This solution is cooled to 0°C in an ice bath, introducing portion 200 mg (7.56 mmol) of tetraborate sodium and shaken for 4 hours at ambient temperature. The reaction mixture was added saturated aqueous solution of ammonium chloride. Evaporate the ethanol under reduced pressure (2 kPa), then treat the reaction mixture with ethyl acetate. Separate the organic phase from the aqueous phase. Carry out this extraction one more time and then combine the organic phases and dry on sulfate m is fester. Concentrate under reduced pressure (2 kPa) and the gain of 1.05 g (Yield=100%) colorless oil.

SMS:Rf=0.5 (silica gel, eluent: CH2Cl2/MeOH 90:10).

1H-NMR (CDCl3):δ of 1.47 (s, 9H, tBu) and (m, 2H; CHH-CH2-N-CH2-CHH-); to 1.87 (m, 2H, -CHH-CH2-N-CH2-CHH-); 3.04 from (m, 2H, -CHH-N-CHH-); of 3.85 (m, 2H, -CHH-N-CHH-) and (m, 1H, -CH-OH).

2) Synthesis of tertbutyl-4-iodine-1 piperidinecarboxylate 2:

Dissolve 2.15 g of triphenylphosphine (8,2 mmol) and of 2.08 g of iodine (8,2 mmol) in 30 ml of acetonitrile.

Shake for 10 minutes at ambient temperature, then injected 918 mg of imidazole (13.5 mmol) and shaken for 10 min at ambient temperature. Then enter 1 g (5 mmol) tertbutyl-4-hydroxy-1-piperidinecarboxylate obtained at the previous stage, and shaken for 24 hours at ambient temperature. The reaction mixture was added saturated aqueous sodium thiosulfate solution and acetonitrile is evaporated under reduced pressure (2 kPa). Treated with ethyl acetate, extracted and washed with aqueous sodium thiosulfate solution. The organic phase is dried MgSO4filter and evaporate the ethyl acetate under reduced pressure (2 kPa). Chromatographic on silica gel, elwira dichloromethane, then dichloromethane/methanol 90/10.

Obtain 1.1 g (Yield=70%) is escitalo oil.

SMS:Rf=0.8 in (silica gel, eluent: CH2Cl2/MeOH 90/10).

1H-NMR (CDCl3):δ of 1.47 (s, 9H, tBu); 2,03 (m, 4H,- N2-CHI-CH2-); 3.30, and of 3.60 (2m, 4H, -CH2-N-CH2-); to 4.46 (m, 1H,- CHI-).

3) Synthesis of 2-bromo-6-(2,5-dimethylpyrazol-1-yl)pyridine 3:

In a flask with a volume of 100 ml, to which is attached ustroystvo Dean Stark, enter 1 g (5,78 mmol) 2-amino-6-bromopyridine, manufactured by Aldrich, 30 ml of toluene. Add 0.3 ml of acetic acid and 0.8 ml (of 6.78 mmol) of acetonylacetone, manufactured by Aldrich. Heated for 5 hours until the condensation of toluene. Cooled to ambient temperature and is evaporated with toluene under reduced pressure (2 kPa). Injected water and extracted with ethyl acetate. Combine the organic phases and dry obtained with magnesium sulfate. Evaporate the ethyl acetate under reduced pressure (2 kPa) and the crude residue purified by chromatography on silica gel, elwira dichloromethane.

Get 1 g (Yield=90%) yellow powder.

SMS:Rf=0,7 (silica gel, eluent: CH2Cl2).

1H-NMR (CDCl3):δ of 2.20 (s, 6H,- N3C=CH-CH=SSN3-); 5,90 (s, 2H, -CH3C=CN- N=CLO3-); was 7.08 (d, 1H, H3 or H5 ); 7,16 (d, 1H, H3 or H5); 7,29(m, 1H, H4).

4) Synthesis of butyl ester 6-(2,5-dimethylpyrrole-1-yl)-3',4',5',6'-tetrahydro-2 N-[2,4']bipyridinyl-1'-carboxylic acid is 4:

In an argon atmosphere suspended 284 mg (4,34 mmol) of electrolytic zinc, to which is added 0,033 ml 1-2-dibromoethane and 1 ml of tetrahydrofuran.

Shake for 3 min at 60°C and cooled to ambient temperature. Enter 0,047 ml trimethylsilylpropyne and shaken for 30 min at ambient temperature. Enter 1 g (3.2 mmol) of 2, pre-dissolved in 2 ml of tetrahydrofuran. This reaction mixture was shaken for 45 min at ambient temperature and give it a solution containing 30 mg (to 0.032 mmol) of Tris(dibenzylideneacetone)diplodia, manufactured by Aldrich, and 30 mg (0.13 mmol) of Tris(2-furyl)phosphine, manufactured by LANCASTER. Then enter 1 g (4 mmol) of 3, pre-dissolved in 10 ml of tetrahydrofuran. Perform magnetic stirring the reaction mixture at 60°C for 2 hours. Cooled to ambient temperature and filtered through clarcel and extracted, distributing between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase is twice extracted with ethyl acetate, then the combined organic phases are dried obtained with magnesium sulfate. Evaporate the ethyl acetate under reduced pressure (2 kPa) and the crude residue purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 4:1. Obtain 350 mg (Yield=30%) the target issue for lighting the th product as a yellow oil.

SMS:Rf=0.2 (silica gel, eluent: heptane/ethyl acetate 90:10).

1H-NMR (CDCl3):δ of 1.50 (s, 9H, tBu); 1.78, and of 1.97 (m, 4H, -CH2-CH2-N-CH2-CH2-); to 2.18 (s, 6H, -CH3C=CH-CH=CCH3-); to 2.85 and 2.95 (m, 3H, CH-CH2-CHH-N-CHH-CH2-); to 4.28 (m, 2H, -CH2-CHH-N-CHN-CH2-); of 5.92 (s, 2H, -CH3C=CH-CH=CCH3-); was 7.08 (d, 1H, H3 or H5); 7,16 (d, 1H, H3 or H5 ); 7,29 (m, 1H, H4).

5) Synthesis of 6-(2,5-dimethylpyrrole-1-yl)-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl

Dissolve 330 mg (0,928 mmol) 4 in 3 ml of dichloromethane and injected with 0.3 ml triperoxonane acid. Shake for 2 hours at ambient temperature. Evaporate dichloromethane under reduced pressure (2 kPa). Processed the remainder water, alkalinized to pH 10 with concentrated ammonia and extracted the product with dichloromethane. The organic phase is dried on magnesium sulfate and the dichloromethane is evaporated under reduced pressure (2 kPa). Obtain 220 mg (Yield=92%) yellow oil.

SMS:Rf=0,3 (silica gel, eluent: CH2Cl2/MeOH 90:10).

1H-NMR (CDCl3):δ 1,90 and of 2.08 (m, 4H, -CH2-CH2-N-CH2-CH2-); to 2.18 (s, 6H, -CH3C=CH-CH=SSH3-); 2,88 and to 3.34 (m, 4H, -CH2-CH2-N-CH2-CH2-); 2,95 (m, 1H,N-CH2-CH2-N-CH2-); 4,10 (m, 1H, NH); of 5.92 (who, 2H, -CH3C=CH-CH=CCH3-); was 7.08 (d, 1H, H3 or H5); 7,16 (d, 1H, H3 or H5); 7,29 (m, 1H, H4).

Mass spectrum: 256 (MH+)

6) Synthesis of 1'-(6-chloro-5-methylpyrimidin-4-yl)-6-(2,5 dimethylpyrrole-1-yl)-1',2',3',4',5',6'-hexahydro[2,4']bipyridinyl

Dissolved 220 mg (0,860 mmol) of 5 in 2 ml of dimethylacetamide and administered 140 mg (0,860 mmol) of 4,6-dichloro-5-methylpyrimidine manufactured by SPECS, and 0.2 ml of diisopropylethylamine. The mixture is heated to 110°C With magnetic stirring for 1 hour. Cooled to ambient temperature and dimethylacetamide is evaporated under reduced pressure (2 kPa). The crude residue is treated with ethyl acetate and washed with water. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried on magnesium sulfate. Evaporate the ethyl acetate under reduced pressure (2 kPa) and obtain 330 mg of a brown resin used in the next stage without purification.

SMS:Rf=0,4 (silica gel, eluent: CH2Cl2).

1H-NMR (CDCl3):δ 2,02 and 2.10 (m,4H, -CH2-CH2-N-CH2-CH2-); to 2.18 (s, 6H,- N3C=CH-CH=SSN3-); of 2.30 (s, 3H, CH3); is 3.08 and 4,01 (m,4H, -CH2-CH2-N-CH2-CH2-); to 3.02 (m, 1H, CH-CH2-CH2-N-CH2-); of 5.92 (s, 2H, -CH3C=N-CH=CCH3-); to 7.09 (d, 1H, H3 or H5); then 7.20 (d, 1H, H3 or H5 ); 7,29 (m, 1H, H4) to 8.41 (s, 1H, =N-CH=N)

7) Synthesis of butyl ether 2-benzyloxycarbonylamino-3-{6-[6-(2,5-dimethylpyrrole-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl]-5-methylpyrimidin-4-ylamino}-propionic acid 7:

330 mg (0,866 mmol) of the substance obtained in the preceding stage, dissolved in 5 ml of dimethoxyethane. Consistently give 286 mg (1 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176), 184 mg (1,21 mol) of cesium fluoride, 54 mg (10 mol%) rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, manufactured by Aldrich, and 40 mg (5 mol%) Tris(dibenzylideneacetone)diplodia manufactured by Aldrich. This mixture is heated to 100°C for 18 hours under magnetic stirring. Re-enter 54 mg (10 mol%) rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 40 mg (5 mol%) Tris(dibenzylideneacetone)diplodia and heated for 2 hours to 100°C. Ohlala to ambient temperature and evaporate dimethoxyethane under reduced pressure (2 kPa). The resulting residue is treated with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate, the combined organic phases are dried on magnesium sulfate. Evaporate the ethyl acetate under reduced pressure (2 kPa). The resulting residue is purified by chromatography on silica gel, elwira a mixture of heptane-ethyl shall zitat 1:1. Receive 200 mg solid yellow color.

SMS:Rf=0.2 (silica gel, eluent: heptane/ethyl acetate 1:1).

1H-NMR (CDCl3):δ of 1.50 (s, 9H, tBu); of 1.97 (s, 3H, CH3); 2,02 is 2.10 (m, 4H, -CH2-CH2-N-CH2-CH2-); to 2.18 (s, 6H, -CH3C=CH-CH=SSN3-); 3,20 and of 3.78 (m, 4H, -CH2- N2-N-CH2-CH2-); 3,00 (m, 1H,N-CH2-CH2-N-CH2-); from 3.85 to 4.00 (m, 2H, NH-CH2-CHCOOtBuNH); 4,47 (m, 1H, NH-CH2CH-COOtBuNH); 5,12 (2H, -O-CH2-phenyl); of 5.92 (s, 2H, -CH3C=CH-CH=CCH3-); 6,12 (m, 1H mobile); to 7.09 (d, 1H, H3 or H5); 7,21 (d, 1H, H3 or H5); for 7.78 (t, 1H, H4); was 7.45 (m, 5H, aromatic); 8,32 (s, 1H, =N-CH=N).

Mass spectrum:641 (MH+); 584 (MH-tBu+)

8) Synthesis of butyl ether 3-[6-(6-amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methylpyrimidin-4-ylamino]-2-benzyloxycarbonylamino acid 8:

Dissolve 100 mg (0.15 mmol) of 7 in 3 ml of ethanol and 0.3 ml of water. Enter 50 mg (0.75 mmol) of hydroxylaminopurine manufactured by ACROS, and heated to 90°C for 18 hours. Evaporated the solvent under reduced pressure (2 kPa) and the crude residue purified by chromatography on silica gel, elwira mixture of CH2Cl2/MeOH 90:10). Receive 30 mg (36%) of the desired product as a colourless resin.

SMS:Rf=0.5 (silica gel, eluent: CH2Cl2/MeOH 90:10).

1H-NMR (CCl 3):δ of 1.50 (s, S, tBu); of 1.97 (s, 3H, CH3); 2,02 is 2.10 (m, 4H, -CH2-CH2-N-CH2- N2-); to 2.18 (s, 6H, -CH3C=CH-CH=SSN3-); 3,20 and of 3.78 (m, 4H, -CH2-CH2-NN2-CH2-); 3,00 (m, 1H, CH-CH2-CH2-N-CH2-); from 3.85 to 4.00 (m, 2H, NH-CH2-CHCOOtBuNH); 4,47 (m, 1H, NH-CH2CH-COOtBuNH); 5,12 (2H, -O-CH2-phenyl); of 5.92 (s, 2H, -CH3C=CH-CH=CCH3-); 6,18, 6,57, 6,62 (3D, H3 and H5 +1H mobile); was 7.45 (m, 5H, aromatic); of 7.60 (t, 1H, H4); 8,32 (s, 1H, =N-CH=N).

Mass spectrum:562 (MH+); 372 (MH-tBu-CO-O-benzyl+).

9) Synthesis of 3-[6-(6-amino-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-yl)-5-methylpyrimidin-4-ylamino]-2-benzyloxycarbonylamino acid 9:

Dissolve 30 mg (0,053 mmol) of 8, obtained at the previous stage, in 2 ml of dichloromethane and 0.2 ml triperoxonane acid. Shaken for 9 hours at ambient temperature. Enter toluene and evaporated to dryness under reduced pressure (2 kPa). The product was then purified by chromatography on silica gel, elwira mixture of CH2Cl2/MeOH/acetic acid 90:10:1.

Receive 10 mg (yield=37%) of the desired product in the form of a solid beige color in a mixture of CH2Cl2/simple isopropyl ether.

SMS:Rf=0.2 (silica gel, eluent: CH2Cl2/MeOH/acetic acid 90:10:1).

1H-NMR (DSO):δ 1,90 (s, 3H, CH 3); 1,80-1,85 (m, 4H,-CH2-CH2-N-CH2-CH2-); partially obscured by water DSO :(4H, -CH2-CH2-N-CH2-CH2-) and (2H, NH-CH2-CHCOOtBuNH); 2,80 (m, 1H,N-CH2-CH2-N-CH2-); 4,15 (m, 1H, CH2-CH-COOtBuNH-); 5,02 (2H,-O-CH2-phenyl); 6,27 (d, 1H, H3 or H5); 6,40 (d, 1H, H3 or H5); of 6.52 (m, 1H, H4); 7.5 (m, 5H, aromatic); 8,10 (s, 1H, =N-CH=N).

Mass spectrum:506 (MH+); 372 (MN - CO-O-benzyl+)

Example 39

3-[5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptorelin)

Stage a)

Synthesis of (1,1-dimethylethyl)-(4-aminomethylpyridine)-1-carboxylate

In a solution of 10 g (of 87.5 mmol) of 4-aminomethylpyridine (company Aldrich) in 110 ml of toluene, under a flow of nitrogen, is injected 9 ml of benzaldehyde (87,5 mmol), then heated the mixture to 120°C (in the presence of a Dean Stark) for 8 hours. The reaction mixture was cooled to ambient temperature, then give 21 g (96,25 mmol) distritbution at 0°C for ¼ hour. Shaken in an atmosphere of nitrogen overnight. The next day the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) and the oil is treated with 115 ml aqueous KHSO41N and strongly shaken in an atmosphere of nitrogen for 7 hours. In the reaction mixture is injected acetate and water the ABC extracted twice with ethyl acetate. Then the mother solution is alkalinized by adding pellets of NaOH, after which the aqueous phase is extracted three times with chloroform, Visalia NaCl. The combined organic phases are dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). Obtain 17.3 g (Yield=92%) of the desired product as yellow oil.

SMS:Rf=0.5 (aluminium oxide, eluent: dichloromethane-methanol 90-10).

1H-NMR (CDCl3):δ 1,05 and 1.67 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); 1,17 (s, 2H,NH2); to 1.42 (s, 10H, tBu, CH2-CH-CH2); to 2.55 (d, 2H,CH2-NH2); 2.65 and 4,07 (2m, 4H, N-CH2-CH2-CH-CH2-CH2).

Mass spectrum:215 (MH+); 159 (MH-tBu+).

Stage b)

Synthesis of (1,1-dimethylethyl)-(4-(2-aminomethylpyridine)piperidine)-1-carboxylate

A mixture of 2.18 g (10,19 mmol) of (1,1-dimethylethyl)-(4-aminomethylpyridine)-1-carboxylate in 5 ml of 2-herperidin heated under reflux for 6 hours. After cooling to ambient temperature the solvent is evaporated under reduced pressure (2 kPa) and the solid yellow residue treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted, washed with a saturated solution of sodium chloride, then dried on magnesium sulfate and evaporated DOS is ha under reduced pressure of 1.3 kPa). The remainder chromatographic on silica gel, elwira with ethyl acetate-cyclohexane 70-30. Obtain 1.19 g (Yield=40%) of the target product.

SMS:Rf=0,4 (silica gel, eluent: ethyl acetate-cyclohexane 70-30).

1H-NMR (CDCl3):δ 1.20 and 1,80 (2m, 5H, N-CH2-CH2-CH-CH2-CH2); to 1.47 (s, 9H, tBu); 2,71 and 4,15 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); is 3.21 (m, 2H, CH-CH2-NH); 4,80 (m, 1H, CH-CH2-NH); 6,41 (d, 1H, CH=CH pyridine); 6,60 (m, 1H, CH=CH pyridine); 7,45 (m, 1H, CH=CH pyridine); 8,07 (m, 1H, N-CH=CH).

Mass spectrum:292 (MH+), 192(MH-tBu+).

Stage C)

Synthesis of 2-(4-methylpiperidino)aminopyridine

Shake 1,09 g (3,74 mmol) of (1,1-dimethylethyl)-(4-(2-aminomethylpyridine)piperidine)-1-carboxylate in 25 ml of dichloromethane, 6 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: ethyl acetate 100%). Add 20 ml of toluene and the mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is treated with a mixture of methylene chloride and an aqueous solution of 2N sodium hydroxide. The organic phase is decanted, washed with a saturated solution of sodium chloride, then dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). The oil obtained is treated with a small amount of simple diisopropyl ether and PE is Tana, then condense to dryness under reduced pressure (2 kPa). Obtain 590 mg (Yield=82%) of the desired product in the form of a solid yellow color.

SMS:Rf=0.2 (silica gel, eluent: dichloromethane-methanol-water-acetic Celta 70-30-6-3).

1H-NMR (CDCl3):δ 1.25 and 1.8 m (2m, 4H, NH-CH2-CH2-CH-CH2-CH2); 1,72 (m, 1H, CH2-CH-CH2); 2,62 and 3.15 (2m, 6H, NH-CH2-CH2-CH-CH2-CH2and CH-CH2-NH); to 4.62 (s, 1H,NHmobile); 6,37 (d, 1H, CH=CH pyridine); 6,56 (m, 1H, CH=CH pyridine); 7,41 (m, 1H, CH=CH pyridine); 8,07 (m, 1H, N-CH=SN).

Mass spectrum:192 (MH+).

Stage d)

Synthesis of 4-bromo-5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]pyrimidine

In a mixture of 657 mg (2,47 mmol) of 4,6-dibromo-5-ethylpyrimidine and 450 mg (2,35 mmol) of 2-(4-methylpiperidino)aminopyridine in 55 ml of N,N-dimethylacetamide injected 1.8 ml of diisopropylethylamine. Heat the mixture to 110°C for 4 hours. The solvent is removed under reduced pressure (0.2 kPa) and treat the residue with a mixture of water, ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is decanted, dried on magnesium sulfate and condensed under reduced pressure (2 kPa). The obtained brown-colored oil chromatographic aluminum oxide, elwira the following gradient: heptane-ethyl acetate from 80-20 to 70-30. Paul is anxious 747 mg (Yield=84%) of the desired product in the form of a solid beige color.

SMS:Rf=0.5 (aluminium oxide, eluent: heptane-ethyl acetate 50-50)

1H-NMR (CDCl3):δ of 1.29 (t, 3H, CH2-CH3); 1,42 and 1.9 (2m, 5H, N-CH2-CH2-CH-CH2-CH2); 2,70 (q, 2H,CH2-CH3); 2,95 and 3,88 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); with 3.27 (m, 2H, CH-CH2-NH); to 4.81 (m, 1H,NHmobile); 6.42 per (m, 1H, CH=CH pyridine); 6,60 (m, 1H, CH=CH pyridine); 7,46 (m, 1H, CH=CH pyridine); of 8.09 (m, 1H, N-CH=CH); 8,31 (s, 1H, N=CH-N).

Mass spectrum:378 (MH+).

Stage e)

Synthesis of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alaninate

A mixture of 300 mg (0,79 mmol) 4-bromo-5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]pyrimidine, of 282.5 mg (0.96 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 168,6 mg (1.11 mmol) of cesium fluoride, to 49.8 mg (0.08 mmol) of Tris(dibenzylideneacetone)diplegia(0) and 49.8 mg (0.08 mmol) of rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 8 ml of 1,4-dioxane is heated under reflux for 7 hours. The reaction mixture is then brought to ambient temperature for introduction of 49.8 mg (0.08 mmol) of Tris(dibenzylideneacetone)diplegia(0), then heated under reflux for 4 hours. After cooling, the mixture is concentrated under reduced pressure (2 kPa), and then receive the config residue is treated with a mixture of ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is decanted, dried on magnesium sulfate, then concentrated under reduced pressure (2 kPa).

The remainder chromatographic first time on aluminium oxide, elwira the following gradient: diisopropyl ether-ethyl acetate from 80-20 to 100% ethyl acetate. The second time chromatographic on silica gel, using as eluent ethyl acetate.

Get 272 mg of the target product (yield = 58%).

SMS:Rf=0,4 (silica gel, eluent: ethyl acetate).

1H-NMR (CDCl3):δ of 1.15 (t, 3H, CH2-CH3); 1,47 and 1,90 (2 m, 13H, tBu, N-CH2-CH2-CH-CH2-CH2); is 1.81 (m, 1H, N-CH2-CH2-CH-CH2-CH2); to 2.41 (q, 2H,CH2-CH3); 2,85 and 3,50 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); with 3.27 (m, 2H, CH-CH2-NH); 3,90 (m, 2H, NH-CH2-CH-NH); of 4.45 (m, 1H, NH-CH2-CH-NH); is 4.85 (m, 1H,NHmobile); of 5.05 (m, 1H,NHmobile); 5,12 (s, 2H, O-CH2-Ph); 6,16 (ush. d, 1H,NHmobile); 6.42 per (d, 1H, CH=CH pyridine); 6,60 (m, 1H, CH=CH pyridine); 7,35 (m, 5H, Ph); 7,45 (m, 1H, CH=CH pyridine); 8,07 (ush. d, 1H, N-CH=CH); of 8.28 (s, 1H, N=CH-N).

Mass spectrum:590 (MH+); 534 (MH-tBu+)].

D](CHCl3)=+2,9.

Stage f)

Synthesis of 3-[5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alanine, bis(triptorelin)

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Shake 229 mg (0,39 mmol) of (1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(aminomethyl-2-pyridinyl)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alaninate in 7.5 ml of dichloromethane with 0.9 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1). At the end of the reaction the mixture was added toluene and evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple ethyl ester. The precipitate is filtered. Get 97,4 mg (Yield=38%) of the desired product in the form of a solid amorphous substance.

SMS:Rf=0.1 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (CDCl3+ 2 drops eOD):δ of 1.12 (t, 3H, CH2-CH3); 1,43 and 1.95 (2m, 5H, N-CH2-CH2-CH-CH2-CH2); to 2.41 (q, 2H,CH2-CH3); 3,10 & 3.65 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); 3,26 (d, 2H, CH-CH2-MN); of 3.80 and £ 4.02 (2m, 2H, NH-CH2-CH-NH); to 4.41 (m, 1H, NH-CH2-CH-NH); 5,10 (s, 2H, O-CH2-Ph); 6,74 (t, 1H, CH=CH pyridine); 6.87 in (d, 1H, CH=CH pyridine); 7,32 (m, 5H, Ph); 7,81 (m, 2H, CH=CH pyridine and N-CH=CH); 8,23 (s, 1H, N=CH-N).

Mass spectrum:534 (MH+).

D (CHCl3)=+1,88.

Example 40

Stage a)

Synthesis of (1,1-dimethylethyl)-4-[3-(4-methoxy-2-nitrophenyl)theoretically]piperidine-1-carboxylate

A mixture of 1 g (4,67 mmol) of (1,1-dimethylethyl)-4-aminomethylpyridine)-1-carboxylate and 1.08 g (the 6.06 mmol) 4-methoxy-2-nitrophenylacetylene in 70 ml of tetrahydrofuran shaken for 5 hours at ambient temperature in a stream of nitrogen. The solvent is evaporated under reduced pressure (2 kPa) and the residue chromatographic on silica gel using the following eluent: ethyl acetate-heptane from 20-80 30-70. Obtain 1.66 g (Yield=84%) of the target product.

SMS:Rf=0,4 (silica gel, eluent: ethyl acetate-heptane 50-50).

1H-NMR (CDCl3):δ 1.25 and 1,76 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); to 1.47 (s, 9H, tBu); at 1.91 (m, 1H, N-CH2-CH2-CH-CH2-CH2); 2,73 and 4,15 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); 3,51 (m, 2H, CH-CH2-NH); 3,90 (s, 3H, O-CH3); 6,66 (m, 1H, CH=CH aromatic); 7,22 (m, 1H, CH=CH aromatic); to 7.59 (m, 1H, CH=CH aromatic).

Mass spectrum:425 (MH+), 325 (MN-tBu+).

Stage b)

Synthesis of (1,1-dimethylethyl)-4-[(6-methoxy-2-aminomethylpyrimidine)]piperidine-1-carboxylate

In a solution of 1.12 g (of 2.64 mmol) of (1,1-dimethylethyl)-4-[3-(4-methoxy-2-nitrophenyl)theoretically]piperid the n-1-carboxylate in 100 ml of acetic acid injected with 2 g of activated zinc in a small amount of acetic acid (zinc is activated by heating with a pistol-heater). Shake for 5 hours, then the solution is injected clarcel, the mixture is filtered through clarcel and the solvent is evaporated to dryness under reduced pressure (2 kPa). Obtain 1.8 g of the target product.

This crude product is then dissolved in 100 ml of dimethylformamide, and inject 10 ml of triethylamine and 500 mg of mercury dichloride. Shake the reaction mixture at ambient temperature for 15 hours. Then the solvent is evaporated under reduced pressure (0.2 kPa) and the residue is treated with a mixture of water, saturated sodium bicarbonate solution and ethyl acetate. The organic phase is decanted, dried on magnesium sulfate and the solvent is evaporated under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide, elwira the following gradient: ethyl acetate : dichloromethane/methanol from 50-50 (100% CH2Cl2) to 50-50 (95/5 CH2Cl2/Meon). Obtain 740 mg (Yield=77% in two stages) of the target product.

SMS:Rf=0.4 (of alumina, eluent: ethyl acetate-dichloromethane/methanol 50-50(95/5)).

1H-NMR (CDCl3):δ 1.07 and 1,64 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); of 1.46 (s, 9H, tBu); to 1.76 (m, 1H, N-CH2-CH2-CH-CH2-CH2); 2,61 and of 4.05 (2m, 4H, NH-CH2-CH2-CH-CH2-CH2); 3,29 (m, 2H, CH-CH2-NH); 3,81 (s, 3H, O-CH3); 6,66 and for 7.12 (2D, 2H, CH=CH benzimidazole); to 6.88 (s, 1H, NH-C=CH-C-OCH3).

Mass spectrum:361 (MH+), 305 (MH-tBu+), 261 (MN-tBu+).

Stage C)

Synthesis of 4-(6-methoxy-2-aminomethylpyrimidine)piperidine, Tris(triptorelin).

Shake 918 mg (2.55 mmol) of (1,1-dimethylethyl)-4-[(6-methoxy-2-aminomethylpyrimidine)]piperidine-1-carboxylate in 35 ml of dichloromethane, 6 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1). Then add toluene and the mixture is evaporated under reduced pressure (2 kPa). Get to 1.15 g of the desired product in the form of salts trifenatate.

SMS:Rf=0.15 in (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (eOD):δ 1.50 and was 2.05 (2m, 5H, NH-CH2-CH2-CH-CH2-CH2); 3.00 and 3,43 (2m, 4H, NH-CH2-CH2-CH-CH2-CH2); the 3.35 (d, 2H, CH-CH2-NH); 3,81 (s, 3H, O-CH3); 6,85 and 7,25 (2m, 2H, CH=CH benzimidazole); 6,91 (s, 1H, NH-C=CH-C-OCH3).

Mass spectrum:261 (MH+).

Stage d)

Synthesis of 4-bromo-5-ethyl-6-[4-(6-methoxy-2-aminomethylpyrimidine)-1-piperidinyl]pyrimidine

In odnogolosy flask containing 356 mg (1.37 mmol) of 4-(6-methoxy-2-aminomethylpyrimidine)piperidine obtained from its salts, enter 35 ml of N,N-dimethylacetamide, 381,84 mg (1,43 mmol) of 4,6-dibromo-5-ethylpyrimidine in the solution is, then inject 1.2 ml of diisopropylethylamine. This mixture is heated to 110°C for 3 hours, then concentrated under reduced pressure (2 kPa). The resulting residue is treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered, then the solvent is evaporated to dryness under reduced pressure (kPa). The resulting product chromatographic on silica gel, elwira gradient of dichloromethane-methanol 95-5, then dichloromethane-methanol 90-10.

Receive 383 mg of the target product (yield = 63%).

Getting 4-(6-methoxy-2-aminomethylpyrimidine)piperidine in the form of a free amine.

700 mg of 4-(6-methoxy-2-aminomethylpyrimidine)piperidine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent. This operation was repeated 3 times to complete exclusion of salt. After filtration of the resin and evaporation of the solvents are 356 mg (1.37 mmol) of the free 4-(6-methoxy-2-aminomethylpyrimidine)piperidine.

SMS:Rf=0,23 (silica gel, eluent: dichloromethane-methanol 90-10).

1H-NMR (CDCl 3):δ of 1.27 (t, 3H, CH2-CH3); 1.32; and 1,80 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); 1,89 (m, 1H, N-CH2-CH2-CH-CH2-CH2); 2,63 (q, 2H,CH2-CH3); 2,85 and 3,82 (2m, 7H, N-CH2-CH2-CH-CH2-CH2,- CH3); 3,37 (m, 2H, CH-CH2-NH); 6,67 and to 7.15 (2D, 2H, CH=CH is the benzimidazole); make 6.90 (s, 1H, NH-C=CHWith co3); of 8.27 (s, 1H, N=CH-N).

Mass spectrum:446 (MH+).

Stage e)

Synthesis of 4-bromo-5-ethyl-6-[4-((1,1-dimethylethyl)benzimidazole - 6-methoxy-2-aminomethyl-1-carboxylate)-1-piperidinyl]pyrimidine

The mixture 159,7 mg (0.36 mmol) of 4-bromo-5-ethyl-6-[4-(6-methoxy-2-aminomethylpyrimidine)-1-piperidinyl]pyrimidine in 15 ml of dichloromethane injected 1.5 ml of pyridine, then 471 mg (2,16 mmol) distritbution. Shaken at ambient temperature overnight. Injected into the reaction mixture a small amount of toluene, then Restoral is evaporated under reduced pressure (2 kPa). Treat the residue with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted, dried on magnesium sulfate and condensed under reduced pressure (2 kPa). The resulting crude product chromatographic on silica gel, elwira the following gradient: heptane-ethyl acetate from 60-40 to 50-50. Obtain 136 mg (Yield=69%) t the left of the product (in the form of two regioisomers, determined by NMR in a ratio of 50-50).

SMS:Rf=0.5 (silica gel, eluent: dichloromethane-methanol 90-10).

1H-NMR (CDCl3):δ of 1.30 (t, 6H, CH2-CH3); 1,47 and 1.96 (2m, 8H, N-CH2-CH2-CH-CH2-CH2); 1,72 (2 ush. s, 20H, tBu, N-CH2-CH2-CH-CH2-CH2); 2,70 (kV 4H,CH2-CH3); 2,97 and the 3.89 (2m, 8H, N-CH2-CH2-CH-CH2-CH2); to 3.52 (m, 4H, CH-CH2-NH); is 3.82 (s, 6H, OCH3); 6,62 and 6.82 and 7,31 and 7,46 (4D, 4H, CH=CH benzimidazole); 7.00 and 7,26 (2s, 2H, NH-C=CH-C-OCH3); 8,31 (s, 2H, N=CH-N).

Mass spectrum:545/547 (MH+).

Stage f)

Synthesis of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-((1,1-dimethylethyl)-6-methoxy-2-aminomethylpyrimidine-1-carboxylate)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alaninate

A mixture of 136 mg (0.25 mmol) 4-bromo-5-ethyl-6-[4-((1,1-dimethylethyl)benzimidazole-6-methoxy-2-aminomethyl-1-carboxylate)-1-piperidinyl]pyrimidine, and 88.5 mg (0.30 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, a 53.2 mg (0.35 mmol) of cesium fluoride, 11.4 mg (0.012 mmol) of Tris(dibenzylideneacetone)diplegia(0) and 15.6 mg (of 0.025 mmol) of rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 6 ml of 1,2-dimethoxyethane heated under reflux for 24 hours. During the reaction injected 11.4 mg of Tris(dibenzylideneacetone)diplegia(0). After cooling, the mixture conc the shape under reduced pressure (2 kPa), then the obtained residue is treated with a mixture of ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is decanted, dried on magnesium sulfate, then concentrated under reduced pressure (2 kPa). The remainder chromatographic first time on silica gel, elwira the following gradient: ethyl acetate-heptane from 40-60% to 100% ethyl acetate. The second time chromatographic aluminum oxide, elwira the following gradient: ethyl acetate-dichloromethane-methanol from 50-50-0 to 50-50-2.

Obtain 58 mg (yield = 30%) of the desired product (2 regioisomers determined using NMR 50/50).

SMS:Rf=0,4 (silica gel, eluent: ethyl acetate).

1H-NMR (CDCl3):δ of 1.15 (t, 6H, CH2-CH3); 1.46 and 1,91 (2m, 26H, tBu, N-CH2-CH2-CH-CH2-CH2); 1,72 (m, 20H, tBu, N-CH2-CH2-CH-CH2-CH2); 2,41 (kV 4H,CH2-CH3); 2,87 and 3,51 (2m, 12H, N-CH2-CH2-CH-CH2-CH2CH-CH2-NH); is 3.82 (s, 6H, OCH3); 3,90 (m, 4H, NH-CH2-CH-NH); 4,43 (m, 2H, NH-CH2-CH-NH); 5,12 (s, 4H, O-CH2-Ph); 6,12 (ush. d, 2H,NHmobile); is 6.61 (d, 1H, CH=CH benzimidazole); PC 6.82 (m, 1H, CH=CH benzimidazole); 7,00 (ush. s, 1H, NH-C=CH-C-OCH3); 7,35 (m, 12H, Ph-CH=CH benzimidazole); was 7.45 (d, 1H, CH=CH benzimidazole); 8,29 (s, 2H, N=CH-N).

HPLC/mass spectrum:759 (MH+); 659 (MH-tBu+); 603(MH-tBu-tBu+).

Stage g)

Synthesis of 3-[etil-6-[4-(6-methoxy-2-aminomethylpyrimidine)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alanine, bis-trifenatate

Shaken 58 mg (0.08 mmol) of (1,1-dimethylethyl)-3-[5-ethyl-6-[4-((1,1-dimethylethyl)-6-methoxy-2-aminomethylpyrimidine-1-carboxylate)-1-piperidinyl]-4-pyrimidinamine]-N-[(phenylmethoxy)carbonyl]alaninate in 2 ml of dichloromethane with 0.2 ml triperoxonane acid at ambient temperature until the disappearance of the original product in the SMS (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1). At the end of the reaction the mixture was added toluene and evaporated to dryness under reduced pressure (2 kPa). The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Receive 16 mg (Yield=35%) of the desired product in the form of a solid amorphous substance.

SMS:Rf=0,3 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (eOD):δ of 1.12 (t, 3H, CH2-CH3); 1.49 and 1,95 (2m, 5H, N-CH2-CH2-CH-CH2-CH2); of 2.51 (q, 2H,CH2-CH3); 3.00 and 3,52 (2m, 4H, N-CH2-CH2-CH-CH2-CH2); 3,39 (d, 2H, CH-CH2-NH); of 3.77 and 4,01 (2m, 2H, NH-CH2-CH-NH); 3,86 (s, 3H, OCH3); 4,56 (m, 1H, NH-CH2-CH-NH); 5,07 (m, 2H, O-CH2-Ph); 6,91 (d, 1H, CH=CH benzimidazole); of 6.96 (s, 1H, NH-C=CH-C-OCH3); 7,32 (m, 6H, Ph, CH=CH, benzimidazo is); to 8.20 (s, 1H, N=CH-N).

HPLC/mass spectrum:603 (MH+).

Example 41

Synthesis of 2,5-dimethyl-4,6-dihydroxypyrimidine:

Odnogolosy flask containing 40 ml of methanol, under nitrogen atmosphere, cooled to 0°C in an ice bath, the reaction mixture is injected 9,72 g of sodium methylate (solution having a concentration of C=3 mol. l-1), then at 0°C is injected in small portions 5 g (53 mmol) of acetamidomalonate. Shaken at ambient temperature for 20 minutes, then injected dropwise to 8.3 ml diethylmalonate. Continue to shake for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The resulting crude product is treated with a minimum amount of water, cooled to 0°C., then acidified with pure acetic acid to obtain a pH of from 4 to 5. The resulting white precipitate was filtered, washed with water, ethyl ether and pentane. Then the white product is dried at P2About5under reduced pressure (0.2 kPa). Gain of 3.3 g (yield=49%) of the target product.

SMS:Rf=0.2 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).

1H-NMR (DMSOd6):δ by 1.68 (s, 3H, HE-CH-=C-CH3); to 2.18 (s, 3H, N=C-CH3).

Synthesis of 2,5-dimethyl-4,6-dichloropyrimidine

A mixture of 3.3 g (23.5 mmol) of 2,5-dimethyl-4,6-dihydroxyphenyl the Dean and 15 ml of phosphorus oxychloride is heated under reflux for 8 hours. After cooling to ambient temperature the reaction medium slowly poured into a mixture of ice water. This aqueous phase is further extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, then dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). Get 3,39 g (Yield=81%) of the target product.

SMS:Rf=0,9 (silica gel, eluent: ethyl acetate 100%).

1H-NMR (CDCl3):δ of 2.46 (s, 3H, Cl-CH=C-CH3); in 2.68 (s, 3H, N=C-CH3).

Mass spectrum:177/179(MH+).

Synthesis of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-2,5-dimethyl-4-chloropyrimidine:

In odnogolosy flask containing 2,95 g (13.5 mmol) of 4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidine, obtained from its salts, administered 2 g (11.3 mmol) of 4,6-dichloro-2,5-dimethylpyrimidine in solution in 25 ml of dimethylacetamide and 5 ml of diisopropylethylamine. This mixture is heated to 130°C for 4 hours, then concentrated to dryness in vacuo. The resulting residue is treated with a mixture of ethyl acetate, water and saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate, then the solvent is evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic on silica gel, elwer the I gradient of ethyl acetate (100%), then ethyl acetate-methanol (95-5). Obtain 2.2 g of the target product (yield = 55%).

Getting naphthiridine in the form of free amine:

8,3 g naphthiridine displace from its salts 6-mass equivalents of alkaline resin amberlyst A21 (type resin R-Ne2) in a mixture of CH2Cl2/MeOH/AcOEt 1/1/1, shaking for 30 minutes. The resin is pre-washed and leave for 20 minutes for swelling in the mixture solvent. This operation was repeated 3 times to complete exclusion of salt.

After filtration of the resin and evaporation of the solvents get 2,95 g (13.5 mmol) of the free naphthiridine.

SMS:Rf=0.15 in (silica gel, eluent: dichloromethane-methanol 95-5).

1H-NMR (CDCl3):δ 1,90 and 2,01 (2m, 6H, NH-CH2-CH2-CH2N-CH2-CH2CH-CH2-CH2); and 2.26 (s, 3H, CH3); of 2.51 (s, 3H, N=C-CH3); 2,72 (m, 3H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2-CH2); 2,97 and 3.97 (2m, 4H, CH2-CH2-NCH2-CH2); of 3.42 (m, 2H, NH-CH2-CH2-CH2); 6,41 and 7,16 (2D, 2H,CH=CHthe naphthiridine).

Mass spectrum:358 (MH+).

Synthesis of (1,1-dimethylethyl)-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate

A mixture of 2.2 g (x 6.15 mmol) 6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-is l)-1-piperidinyl]-2,5-dimethyl-4-chloropyrimidine and 2.17 g (7,38 mmol) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate (obtained in accordance with J.Med.Chem. (2001), 44(8), 1158-1176) in the presence of 1.31 g (8,61 mmol) of cesium fluoride, 383 mg (of 0.615 mmol) of (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 281 mg (0,307 mmol) of Tris(dibenzylideneacetone)diplegia(0) in 55 ml of 1,2-dimethoxyethane heated to boiling under reflux for 24 hours. Then the reaction mixture was cooled to ambient temperature and injected 281 mg (0,307 mmol) of Tris(dibenzylideneacetone)diplegia(0), then the reaction mixture is heated at the boil under reflux for a further 24 hours. After cooling, the solution is concentrated to dryness under reduced pressure (2 kPa), then treated with a mixture of water, ethyl acetate and saturated sodium bicarbonate solution. The organic phase is decanted and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried on magnesium sulfate and evaporated to dryness under reduced pressure (2 kPa). The remainder chromatographic aluminum oxide gradient simple isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50). The fractions containing the desired product are pooled for re-purification on silica gel with gradient ethyl acetate-heptane-methanol from 50-50-0 to 90-0-10. Get 550 mg (yield = 15%) of the target product.

SMS:Rf=0,3 (silica gel, eluent: dichloromethane-methanol 90-10)).

1H-NMR (CDCl3):δ of 1.46 (s, 9H, tBu); of 1.92 (m, 9H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH 2-CH2C=C-CH3); to 2.41 (s, 3H, N=C-CH3); 2,70 (m, 3H, NH-CH2-CH2-CH2N-CH2-CH2-CH-CH2-CH2); 2.91 in and 3,66 (2m, 4H, CH2-CH2-NCH2-CH2); 3,44 (m, 2H, NH-CH2-CH2-CH2); 3,90 (m, 2H, NH-CH2-CH-NH); to 4.38 (m, 1H, NH-CH2-CH-NH); to 5.13 (s, 2H, O-CH2-Ph); 6.42 per 7,16 and (2D, 2H,CH=CHthe naphthiridine); 7,35 (m, 5H, Ph).

Mass spectrum:616 (MH+).

The synthesis of the appropriate acid:

Shaken when the ambient temperature is 500 mg (0.81 mmol) of (1,1-dimethylethyl)-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate and 5 ml triperoxonane acid in 30 ml of dichloromethane for 24 hours. Then add toluene and the mixture is evaporated to dryness. The residue is dissolved in a minimum amount of dichloromethane with a small amount of methanol, then pour out on a simple diisopropyl ether. The precipitate is filtered. Obtain 485 mg (Yield=76%, expressed in DATEFORMAT) of the target product.

SMS:Rf=0,3 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1).

1H-NMR (CDCl3):δ of 1.97 (m, 9H, NH-CH2-CH2-CH2N-CH2-CH2CH-CH2-CH2, C=C-CH3); to 2.54 (s, 3H, N=C-CH3); 2,78 (m, 2H, NH-CH2 -CH2-CH2); 2,98 (m, 1H, N-CH2-CH2-CH-CH2-CH2); 3,22 and 3,80-4,07 (2m, 6H, N-CH2-CH2-CH-CH2-CH2, NH-CH2-CH-NH); 3,51 (m, 2H, NH-CH2-CH2-CH2), of 4.45 (m, 1H, NH-CH2-CH-NH); 5,10 (s, 2H, O-CH2-Ph); 6.42 per and 7,37 (2m, 3H),CH=CHthe naphthiridine, NH mobile); 7,32 (m, 5H, Ph).

Mass spectrum:560 (MH+); 426 [MH+ -(SOON2PH)]+.

Pharmacological test:Test ELISA kistryn/vitronectin receptor (alphavβ3)

Protocol:

96-well tablets MaxiSorp cover over night at 40°C, 100 µl kistrina at a concentration of 1 µg/ml (dilution buffer coating: 0.05 M carbonate/NaOH pH 9,6). The next day, the wells are empty and the ligands (citrin) bind (binding buffer: PBS containing 0.5% BS (pH 7.4)) for 1 hour at ambient temperature under conditions of weak mixing 125 rpm. The wells are washed six times (the buffer for washing: PBS containing 0.5% Tween 20 (pH of 7.7), then each well is administered in the following order:

- 40 ál of incubation buffer

to 10 μl of the diluted test product (dissolved in a mixture of 50:50 DMSO/water)

50 ál receptor αvβ3man (cf. Pytella et al. Methods Enzymol. (1987) 144 (dilution in incubation buffer solution, adapt depending on the number of receptor and depending on the ligand). The ligand, receptor αv/sub> β3and investigational products are incubated together for 3 hours at ambient temperature under weak stirring 125 rpm.

The wells are again washed six times, and then incubated for 2 hours at ambient temperature under weak stirring 125 rpm in the presence of 100 μl antireceptor antibodies coupled to peroxidase (antibody V-HRP diluted in incubation buffer (50 mm TRIS pH 7,4; 05% BSA; 0.05% of Tween 20; 1 mm MnCl2; 50 mm CaCl2; 50 μm MgCl2; 100 mM NaCl). Breeding adapt to the number of receptor.

Then the wells are washed six times, before measuring the binding of the ligand-receptor through recruitment to detect peroxidase (TBM Microwell Substrate Buffer System Kirkgaard; Ref cat 50-76-00).

This set contains a bottle And substrate (3,3',5,5'-tetramethylbenzidine in a concentration of 0.4 g/l) and bottle (0.02% Of N2About2in the buffer solution, a citrate/citric acid). Immediately prior to use volume And mixed with a volume, then the reaction mixture was distributed at the rate of 100 μl per well.

The enzymatic reaction develops within 6-10 minutes in relation Kistrine/αvβ3then , it is stopped by injection of 100 μl of 1M phosphoric acid. The optical density is determined at 450 nm.

The obtained results

Build the following curve: percentage of binding as fu the Ktsia logarithm of each concentration of the test product.

For each product determine IC50 according to the following formula: IC50=(B0+Bmin)/2,

B0 = maximum binding in the complete absence of the product;

Inmin= minimum binding at the highest concentration of product.

ExampleK/VnR IC50(nm)
13
2160
33,1
45,1

Activity in vivo

Hypercalcemia caused by parathyroid hormone (PTH) on the model thyroparathyroidectomy (TRT) rats.

Stimulation of bone resorption in TRT rats caused by perfusion PTH and changes of bone resorption cause concentration of calcium in serum.

Rats male Sprague Dawleyecom weighing 150-200 g thyroparathyroidectomy. Rats receiving a standard diet containing 7 g CA/kg (UAR) and Volvic water. The effectiveness of thyroparathyroidectomy tested 8 days after surgery by measuring the concentrations of CA in serum of animals carried out on an empty stomach. Rats are considered thyroparathyroidectomy, if the content of CA in serum is less than 80 mg/is. PTH (1-34) in rats (Bachem) was dissolved in 0,15M NaCl Cys.HCl 2% and serves osmotic minimalisme (ALZET 2001D) doses, components 200 pmol/kg/h. Minnesota injected under anesthesia (ketamine 75 mg/kg and acepromazine-2.5 mg/kg) in the intra-abdominal cavity TRGT rats on an empty stomach. Control TRT rats injected pumps containing vector PTH.

Or test the product, or vector (control or rats treated with PTH) was injected subcutaneously twice (2 ml/kg body weight) during the 0 to 3 hours after start of infusion RNT. The test continued for further 6 hours. At the end of processing whole blood is collected after decapitate. The blood samples are centrifuged with a speed of 3000 tpm for 15 min (Jouan CR422) to obtain serum.

Common indicators of concentration of CA in serum was measured using colorimetry (Ciba-Corning)using the reader system of microplasmin Labsystems IEMS at 540 nm.

The difference between the average performance of calcaemia in rats after the treatment and control groups analyzed by ANOVA and Dunnett test.

The activity of the product is calculated by the following formula:

The products of examples 6, 9, 13, and 15-19, tested using the above method, showed activity in rats after subcutaneous administration of 1 mg/kg twice to 10 mg/kg twice.

1. The compounds of formula (I):

fo the IU (R) or (S)-isomers, individually or in mixtures, as well as their physiologically acceptable additive salts and their hydrates, in which: G means:
Het-NH-CO-;
Het-NH-CH2-;
Het-;
Het thus denotes monocyclic or bicyclic system, each cycle represents a 5 - or 6-membered aromatic or nonaromatic ring, and the ring or at least one of the rings contains 1 to 2 nitrogen atoms as heteroatoms, when Het is substituted or unsubstituted by one or more groups R9;
R1denotes a hydrogen atom; and (C6-C14)aryl group; (C6-C14)aryl(C1-C4)alkyl; an amino radical, unsubstituted, monosubstituted or disubstituted by alkyl and/or acyl containing from 1 to 4 carbon atoms;
R2denotes a hydrogen atom; a halogen atom; a nitro-group; alkyl containing from 1 to 4 carbon atoms; a radical of amino, unsubstituted, monosubstituted or disubstituted by alkyl and/or acyl containing from 1 to 4 carbon atoms; a group -(CH2)0-2-OR5;
R3means:
a hydrogen atom;
the radical-CO2R5;
radical-SO2R5or
monocyclic or bicyclic system, each cycle represents a 5 - or 6-membered aromatic or nonaromatic ring, and the ring or at least one of the rings will gain from 1 to 4 heteroatoms, selected from N, O or S, unsubstituted or substituted by one or more radicals R9;
R4IT refers; and (C1-C8)alkoxy; an amino radical, unsubstituted, monosubstituted or disubstituted by (C1-C4)alkyl; or an amino acid residue (D or L;
R5means (C1-C8)alkyl, (C6-C14)aryl; and (C6-C14)aryl(C1-C4)alkyl, (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bicycloalkyl(C1-C4)alkyl; tricyclohexyl(C1-C4)alkyl; moreover, these radicals: arily, alkali, cycloalkyl, bicycloalkyl and critically not substituted or substituted by one or more selected groups of R9;
R9denotes halogen; amino; nitro; hydroxyl; (C1-C4)alkyloxy-; carboxy; (C1-C4)allyloxycarbonyl-; and (C1-C8)alkyl, unsubstituted or substituted by one or more halogen atoms; phenyl,
provided that the phenyl radicals can be unsubstituted or substituted by one or more identical or different radicals selected from (C1-C8)alkyl, in particular (C1-C4)alkyl, hydroxyl, (C1-C8)alkyloxy, halogen selected from fluorine, chlorine and bromine, nitro, amino, (C1-C4)alnilam is but di(C1-C4)alkylamino, trifloromethyl, cyano, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, carboxy, (C1-C4)alkoxycarbonyl,
or
G denotes 1,2,3,4-tetrahydro-1,8-naphthiridine-7-Il,
R1denotes methyl,
R2denotes methyl,
R3denotes benzyloxycarbonyl, and
R4indicates HE or tert-butoxy.

2. The compounds of formula (I) according to claim 1, in which G denotes the group Het, Het-NHCO-, or Het-NH-CH2-in which Het denotes the following heterocycles:






where n=1 or 2.

3. The compounds of formula (I) according to any one of claims 1 and 2, in which R3means a heterocycle selected from


and their pharmaceutically acceptable additive salt.

4. The compounds of formula (I) according to any one of claims 1 and 2, in which R3means benzyloxycarbonyloxy group, and their pharmaceutically acceptable additive salt.

5. The compounds of formula (I) according to claim 2, in which R2denotes hydrogen, an alkyl radical containing from 1 to 4 carbon atoms or a fluorine atom, and their pharmaceutically acceptable additive salt.

6. The compounds of formula (I) according to claim 5, in which R2denotes methyl or ethyl.

7. The compounds of formula (I) according to claim 1, in which
G means:

and their pharmaceutically acceptable additive salt.

8. The compounds of formula (I) according to claim 1, in which G denotes:

R1denotes a hydrogen atom,
R2denotes a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical,
R3denotes benzyloxycarbonyloxy,
R4denotes a hydroxyl group,
and their pharmaceutically acceptable additive salt.

9. The compounds of formula (I) according to claim 1, having the following names:
3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidine is]amino]-N-[(phenylmethoxy)carbonyl]alanine,
3-[[5-ethyl-6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl)aminocarbonyl]-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
3-[[6-[4-[(1,2,3,4,5,6-hexahydro-2-pyrimidinyl)aminocarbonyl]-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine,
ethyl-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate,
isopropyl-3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate,
(1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate,
(1,1-dimethylethyl)-3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate,
(1,1-dimethylethyl)-3-[[6-[4-[(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-2,5-dimethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate,
(1,1-dimethylethyl)-3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthiridine-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(1-naphthalenesulfonyl)alaninate,
with the configuration (R) or configuration (S) or mixtures thereof, as well as their additive salt.

10. The method of obtaining compounds of formula (I), in which
a) PR the lead in the interaction of the compound of formula (II)

in which R1, R2, R3and R4such as described in claim 1, with a compound of formula (III)

in which G is as described in claim 1, in the presence of a base,
b) and, if necessary, in the thus obtained compound of formula (I) make one group R3in another group, R3by removing one of the groups R3to obtain the free amine with subsequent condensation with a compound containing another group R3selected from-CO2-R5or-SO2-R5and/or, if necessary, the compound of formula (I) is subjected to hydrolysis to obtain the corresponding acid or perhaps the esterification to obtain the corresponding ester or amidation to obtain the corresponding amide and/or a compound of formula (I) is transferred in pharmaceutically acceptable salt.

11. The method of obtaining compounds of formula (I), in which
a) result in the interaction of the compound of formula (II), such as described in paragraph 10, with the compound of formula (IIIa)

to obtain the intermediate compounds of formula (IV):

b) result in the interaction of the compound of formula (IV) with the compound Het-NH2to obtain the compounds of formula (I), where G denotes the group Het-NHCO-,
c) and, if necessary, to receive nom thus the compound of formula (I) make one group R 3in another group, R3by removing one of the groups R3to obtain the free amine with subsequent condensation with a compound containing another group R3selected from-CO2-R5or-SO2-R5and/or, if necessary, the compound of formula (I) is subjected to esterification to obtain the corresponding ester or amidation to obtain the corresponding amide and/or a compound of formula (I) is transferred in pharmaceutically acceptable salt.

12. The method of obtaining compounds of formula (I) according to any one of claims 1 to 9, characterized in that
a) result in the interaction of the compound of General formula (IIa)

in which R1, R2, G, and X, as described above,
with the compound of the formula (VI)

in which R3and R4such as described above, or in the presence of a strong base, or by catalysis with palladium
b) and, if necessary, in the thus obtained compound of formula (I) make one group R3in another group, R3by removing one of the groups R3to obtain the free amine with subsequent condensation with a compound containing another group R3selected from-CO2-R5or-SO2-R5and/or, if necessary, the compound of formula (I) is subjected to hydrolysis with receiving the receiving the appropriate acid or perhaps the esterification to obtain the corresponding ester or amidation to obtain the corresponding amide and/or a compound of formula (I) is transferred in pharmaceutically acceptable salt.

13. Medicinal product which has the properties of the vitronectin receptor antagonist, which are compounds of formula (I) and/or their physiologically acceptable salts, such as described above according to any one of claims 1 to 9.

14. The drug is indicated in paragraph 13, inhibiting bone resorption in the treatment or prevention of osteoporosis.

15. The drug is indicated in paragraph 13, inhibiting tumor growth or bone metastasis.

16. The drug is indicated in paragraph 13, which has anti-inflammatory activity in the treatment or prevention of cardiovascular disease, restenosis, arteriosclerosis, or retinopathy.

17. Pharmaceutical composition having activity of vitronectin receptor antagonist containing a compound of the formula (I) according to claims 1 to 9, in an effective amount, and one or more excipients.

18. The use of compounds of formula (I) and/or their physiologically acceptable salts, such as described according to any one of claims 1 to 9 to obtain drugs having activity of vitronectin receptor antagonist.

19. Use p in which the drug is intended for the prevention or treatment of osteoporosis.

20. Use p in which the drug is intended to inhibit the growth of tumors or bone metastasis.

21. Use p, in the cat the rum drug is intended for the prevention or treatment of cardiovascular diseases, restenosis, arteriosclerosis, or retinopathy.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

Organic compounds // 2411239

FIELD: chemistry.

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

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

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of pyrrolo[3,2-c]pyridine-4-one 2-indolinone of formula (I). Compound of formula (I): , where: represents single or binary bond; X and Y independently on each other are selected from C or N; X and Y represent N, then R5 and R7 are absent; R1 and R2 represent H; R3 is selected from alkyl, trifluormethyl, aryl and aralkyl, where said alkyl, aryl or aralkyl iis substituted by one or more halogens or hydroxyls; R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, -[CH2CH(OH)]rCH2NR9R10 and -(CH2)nNR9R10, where said alkyl or heterocycloalkyl is probably substituted by one or more groups, selected from group, consisting of hydroxyl, amino, aminoalkyl, hydroxyalkyl and -NR9R10; X and Y represent C, then R5, R6, R7, R8 are independently on each other selected from hydrogen, halo, alkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, -OR9, -NR9R10, -NSO2R9, -NR9COR10, -NHCO2R10, where said aryl, heteroaryl, heterocycloalkyl are substituted by one or more groups, consisting of alkyl, alkoxyl and halogen; R9 and R10 independently on each other are selected from hydrogen, alkyl, cycloalkyl, where said alkyl, aryl, independently on each other are substituted by one or more groups, consisting of alkyl, aryl, hydroxyl, alkoxyl; R9 and R10 together with atom, to which they are bound, form 4-6-member rings, where 4-6-member rings can, in addition, contain one-two heteroatoms, selected from group, consisting of N and O, and each 4-6-member ring, formed in said way, is probably substituted by one or more groups, consisting of alkyl; n represents 2-6 and their pharmaceutically acceptable salts, where R1, R2, R3, R4, R5, R6, R7, R8, X, Y and -have values given in description. Also described is pharmaceutical composition, containing said compounds and possessing activity of proteinkinase inhibitor, methods of obtaining and pharmaceutical applications.

EFFECT: obtained and described are novel compounds, which can be useful as proteinkinase inhibitors.

20 cl, 131 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention describes dibenzo[b,f]pyrido[1,2-d][1,4]diazepinyl derivatives of general formula I: or pharmaceutically acceptable salts thereof (values of radicals are listed in the claim), which are glucocorticoid receptor modulators.

EFFECT: derivatives can be used in treating immunological and inflammatory diseases.

11 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to systems containing an imidazole ring, which correspond to a substance of formula (I-1): , in which: X denotes alkylene which is facultatively interrupted with one or more -O- groups; Z denotes -C(O)-; R1-1 is selected from a group comprising: hydrogen, alkyl, phenyl, -N(CH3)(OCH3), and phenyl which is substituted with one or more halogens; R2 denotes hydrogen; alkyl; hydroxyalkyl; or alkoxyalkyl; RA and RB taken together form an open phenyl ring, or to pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions for inducing biosynthesis of cytokine, which contains such substances.

EFFECT: substances can be used in medicine as immunomodulators for inducing or inhibiting biosynthesis of cytokines in animals and when treating diseases, including viral and malignant diseases.

18 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to imidazo[1,2-a]pyridine derivatives of formula in which radicals R1, R2, R3 and R4 independently denote a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a (C1-C12)alkyl radical which can be substituted with one or more halogen atoms or OH, and a O-(C1-C12)alkyl radicalwhich is substituted with phenyl, or two of radicals R1, R2, R3 and R4 can denote part of a phenyl ring; R5 denotes a (C1-C12)alkyl radical which can be substituted with one or more OH, methanesulphanyl, COOH or a halogen atom, (C2-C12)alkenyl radical, (C2-C12)alkynyl radical, (C6-C10)aryl radical, heteroaryl radical, which is an aromatic groupcontaining 5-10 ring members and 1-2 nitrogen or oxygen ring atoms, (C3-C10)cycloalkyl radical, (C1-C12)alkyl(C3-C10)cycloalkyl radical, (C6-C10)aryl(C1-C12)alkyl radical; radicals R6 and R7 independently denote a hydrogen atom or a (C1-C12)alkyl radical, which can be substituted with COOH, (C6-C10)aryl radical; and X denotes a group of formula - CO-NHOH or formula where U denotes a bond, CH2, V denotes O, S, W denotes NH, and Y denotes OH, or pharmaceutically acceptable salts thereof, solvates, hydrates. The invention also relates to the pharmaceutical composition based on the formula I compound and use of the formula I compound.

EFFECT: novel derivatives have peptide deformylase inhibiting activity.

16 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel ligands, including novel compounds of general formula 1, a wide range of biological activity which simultaneously includes alpha-adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors and serotonin receptors, including serotonin 5-HT7 receptors, in form of free bases, geometric isomers, racemic mixtures or separate optical isomers, as well as in form of pharmaceutically acceptable salts and/or hydrates. In formula 1

R1 denotes hydrogen; C1-C4alkyl optionally substituted with C1-C4alkoxycarbonyl, aromatic or saturated optionally annelated or optionally substituted with a five- or six-member heterocycle containing 1-2 N heteroatoms; C1-C3acyl; saturated optionally substituted six-member N-heterocycle; C1-C4alkoxycarbonyl; optionally substituted arylsulphonyl, R2 denotes a substitute of a cyclic system, including hydrogen; halogen; optionally substituted C1-C4alkyl;CF3, CN, C1-C4alkoxy; C1-C4alkoxycarbonyl; carboxyl; unsaturated six-member N-containing heterocyclyl or optionally substituted arylsulphonyl, Ar denotes phenyl, optionally substituted with C1-C4alkyl, dimethylamino group, one or more C1-C4alkoxy groups, one or more halides, CF3 group, nitro group, carboxyl, C1-C4alkoxycarbonyl, C1-C4acylamino group, CN, optionally annelated with a saturated heterocycle; optionally annelated and optionally substituted unsaturated five- or six-member heterocycle containing one or two heteroatoms selected from nitrogen, oxygen or sulphur; W denotes an optionally substituted (CH2)m group, optionally substituted CH=CH group, optionally substituted CH2-CH=CH group, C≡C group, SO2 group; n = 1 or 2; m=1, 2 or 3, the solid line accompanied by a dotted line (---) denotes a single or double bond.

EFFECT: compounds can be used to treat and/or prevent diseases or pathological conditions of the central nervous system, whose pathogenesis is associated with hyper- or hypo-activation of said receptors, for example anxiety or cognitive disorders, neurodegenerative and psychotic diseases.

42 cl, 26 dwg, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds described by a structural formula wherein: R1 is chosen from a group including R9-phenyl, and R2 is chosen from a group including H and (C1-C6)-alkyl; R3 is chosen from a group including (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl- and R9-(C6-C10)-aryl; R4, R5, R6 and R7 are independently chosen from a group including H and (C1-C6)-alkyl; R8 is chosen from a group including и ; R9 means 1, 2 or 3 substitutes independently chosen from a group, including H, halogen and -CF3; R10 is chosen from a group including H and (C1-C6)-alkyl; R11 is (C3-C10)-cycloalkyl-S (O2)-; R15 and R16 are independently (C1-C6)-alkyl; R17 is R20O-; R20 is chosen from a group including H, and (C1-C6)-alkyl-(C6-C10)-aryl; Q is N; Z is CH; n is equal to 0; s is equal to 2; and t is equal to 2. Also, the invention concerns a pharmaceutical composition exhibiting properties of a chemokine receptor inhibitor, based on these compounds.

EFFECT: produced are the new compounds and based pharmaceutical composition can find application in medicine for treating human immunodeficiency virus (HIV) infection.

8 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

Organic compounds // 2411239

FIELD: chemistry.

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

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

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), where R1 denotes a 5- or 6-member ring of formulae

(II) or (III), respectively: R2 denotes H, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m,-Ra; R3 denotes aryl or heteroaryl, which can be substituted with CN, Cl, F, Br, CF3, CHF2, C3-C6-cycloalkyl or denotes heteroaryl which can be possibly substituted with C1-C7-alkyl; R4 denotes H, -OH, Cl, F, Br, CN, -CHF2, CF3, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m-Re; R5 denotes C1-C7-alkyl, -(CH2)n-O-Rf, or -(CH2)n-Re; Ra denotes -OH; Re denotes -OH; Rf denotes C1-C7-alkyl; m equals 1-4; n equals 2-6; and pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent containing said derivatives, use thereof in preparing medicinal agents suitable for treating diseases of the central nervous system.

EFFECT: novel compounds suitable for treating diseases of the central nervous system are obtained and described.

29 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1,3-dihydrobenzimidazol-3-ylidenamine of formula (I) and its additive salts, where each Alk independently represents C1-6alkandiyl; Q represents hydrogen atom; C1-6alkyl, substituted by one or two radicals Ar2; C1-6alkyl, substituted by quinilinyl, morpholinyl or pyrrolidinonyl; -CO-Ar2; or Q represents radical, which has formula (a), where t can take value 2; R4 represents amino; R1 represents morpholinyl, pyridyl or quinolinyl, where each of said monocyclic or bicyclic heterocycles can optionally have 2 substituents, selected from hydroxyl and C1-6alkyl; R2 represents Ar2 or -CO-Ar2 ; where Q is not hydrogen, R3 represents hydrogen atom; or where Q is hydrogen atom, R1 represents hydrogen or morpholinyl and R3 represents radical which has formula (b), where R6 represents hydrogen atom; R7, R8 and R9 each independently, selected from C1-6alkyl, R10a-O-C1-6alkyl; and R8 or R9 can also represent hydrogen atoms; R10a represents hydrogen atom; Ar1 represents phenyl; Ar2 represents phenyl or phenyl substituted by 1,2 or 3 substituents, independently selected from halogen, hydroxy, C1-6alkyl, cyano, nitro, hydroxy-C1-6alkyl; polyhalogeno-C1-6alkyl, C1-6alkyloxyl, hydroxy-C1-6alkyloxyl, C1-6alkyloxycarbonyl, Ar1 and Ar1O. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compounds.

EFFECT: obtained are novel derivatives of 1,3-dihydrobenzimidazole-2-yledenamine, which are RSV inhibitors.

10 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-alkylamides of formula I

, where A is selected from such groups as -CH2-CH2-, -CH2-CH2-CH2- and -Y-CH2-CH2-, where Y is selected from O, S and NR11 and Y is bonded to a Het group; Het denotes a 5-member or 6-member monocyclic aromatic group which contains one or two identical or different heterocyclic ring elements selected from N, NR13 and S, and which can be substituted with one or more identical or different substitutes R5; X denotes a single bond; R1 and R2 together with a N-CO group which contains them, form a 4-10-member monocyclic or bicyclic saturated or unsaturated ring which, besides a nitrogen ring atom which is part of the N-CO group, can contain one or two additional heterocyclic ring elements selected from N, NR12, O and S, which can be identical or different, provided that two ring elements from O and S cannot be in neighbouring positions in the ring, where the ring, formed by R1 and R2 and the N-CO group containing them, can be substituted with one or more identical or different substitutes R8; R3 is selected from phenyl, naphthalinyl and heteroaryl, which all can be substituted with one or more identical or different substitutes selected from a halogen atom, (C1-C4)alkyl, (C1-C4)alkyloxy group, which can be substituted with one or more fluorine atoms, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, ((C1-C4)alkyl)-CONH-, CONH2, CN, CF3, H2NSO2- and (C1-C4)alkyl-SO2-; R5 is selected from a halogen atom and (C1-C4)alkyl; R8 is selected from a halogen atom, (C1-C4)alkyl and an oxo-group; R11 denotes a hydrogen atom; R12 is selected from a hydrogen atom and (C1-C4)alkyl; R13 is selected from a hydrogen atom and (C1-C4)alkyl; heteraryl is a 5-member or 6-member monocyclic aromatic group which contains one, two or three identical or different heterocyclic ring elements selected from N, NR13, O and S; in any of its stereoisomeric forms or mixture of stereoisomeric forms in any ratio, or its physiologically acceptable salt; provided that the -N(R2)-CO-R1 group cannot be an unsubstituted 2-oxopyrrolidin-1-yl group or unsubstituted 2-oxoimidazolin-1-yl group if the -N(R2)-CO-R1 group simultaneously denotes a group of formula

,

in which the bond through which the group is bonded to group A, is denoted by a line starting from position 2 of the pyridine ring, and in which R90 is selected from imidazol-1-yl, isoxazol-5-yl, isothiazol-5-yl, 1,2,4-thiazol-1-yl, pyrazin-2-yl and pyrazol-3-yl, which can all be substituted with (C1-C4)alkyl and which can be substituted in the pyridine ring with at most four substitutes selected from (C1-C4)alkyl and a halogen atom; and provided that the -N(R2)-CO-R1 cannot be a 1,3-dioxoisoindol-2-yl group of formula

in which the bond through which the group is bonded to group A is denoted by a line beginning from the nitrogen atom. The invention also relates to a method of producing said compounds, a pharmaceutical composition for stimulating endothelia NO synthase, as well as to use thereof in preparing a medicinal agent.

EFFECT: novel compounds which can be used in conditions where high expression of the said enzyme, high content of NO or normalisation of low content of NO is desired are obtained and described.

18 cl, 87 ex, 1 tbl

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