The isoxazolines and isoxazoles, the method of suppressing platelet aggregation, pharmaceutical composition that inhibits platelet aggregation

 

(57) Abstract:

The invention relates to new isoxazolines and isoxazoles of formula I, where R1, R14, R15, U, V, W, X, Y, b have the meanings indicated in the claims, which are useful as antagonists of glycoprotein fibrinogen receptor IIb/IIIa platelet, pharmaceutical compositions containing such compounds, a method of suppressing platelet aggregation on the basis of these compounds as thrombolytics. 6 C. and 18 h.p. f-crystals, 16 PL.

The scope of the invention

The invention relates to new isoxazolines and isoxazoles, which are useful as antagonists of glycoprotein receptor complex IIb/IIIa fibrinogen platelets, pharmaceutical compositions containing such compounds, the process of obtaining such compounds and methods of using these compounds, alone or in combination with other drugs to suppress platelet aggregation, as thrombolytics, and/or treatment of thromboembolic complications.

Background of the invention

Hemostasis is a normal physiological process that stops bleeding from damaged crowton city become active and the contact surface of the damaged vessel by phenomenon called adhesion (adhesion) of platelets. Activated platelets also are associated with each other in a process called platelet aggregation with the formation of platelet plugs. Platelet plug can quickly stop the bleeding, but it must be reinforced by fibrin in order to provide stop bleeding until complete healing of the vessel.

Thrombosis can be regarded as a pathological condition in which the violation hemostasis leads to the formation of blood clots within the vessel. Activation of platelets, and their subsequent aggregation and secretion of platelet-derived factors are associated with various pathophysiological conditions, including cardiovascular and related cerebral vascular thromboembolic complications, such as trombolicheskih complication associated with unstable angina, myocardial infarction undergoing heart attack, stroke, atherosclerosis, and diabetes. The contribution of platelets in these pathological processes stems from their ability to form aggregates, or platelet thrombi, especially on the arterial wall as a result of damage.

Platelets are activated by a number of agonists, causing ISM is Agam subsequent formation of a clot due to the concentration of activated coagulation factors at the injury site. Identified some endogenous agonists, including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin and collagen. Due to the participation of several endogenous agonists of platelet activation and aggregation inhibitor, which acted against all agonists, would be more effective antiplatelet agent than available at present medications, which is agonist-specific.

Modern antiplatelet drugs are only effective against one type of agonist: these include aspirin, which acts against arachidonic acid, ticlopidine, which acts against ADP, inhibitors of the thromboxane A2synthetase or antagonists of the receptors, which act against thromboxane A2and hirudin which is effective against thrombin.

Recently identified common path of all known agonists, namely platelet glycoprotein complex IIb/IIIa, which is a membrane protein mediating platelet aggregation. The last review about IIb/IIIa made Phillips et al. , Cell (1991) 65^ 359-362. Detection of antagonists IIb/IIIa represents a new promising approach antiplatelet therapy.

The IIb/IIIa is associated with four instant adhesion proteins, namely fibrinogen, factor a background of Villebranda, fibronectin and vitronectin. The binding of fibrinogen and factor a background of Villebranda IIb/IIIa causes platelet aggregation. The binding of fibrinogen mediated partly by sequence recognition Arg-Gly-Asp (RGD), which is common for adhesion proteins that are associated with IIb/IIIa.

In addition IIb/IIIa identify an increasing number of other cell surface receptors that bind to ligands of the extracellular matrix or ligands adhesion of other cells, Poreba thus the processes of adhesion cell-cell and cell-matrix. These receptors belong to the subfamily of genes, called integrins, and consist of heterodimeric transmembrane glycoproteins containing alpha - and beta-subunit. Subfamilies of integrins contain a common beta-subunit in combination with different alpha subunits, forming the adhesion receptors with unique specificity. To date, the cloned genes in eight different beta-subunits and determined their sequence.

Two members of the subfamily1,4/1and5/1involved in various inflammatory processes. Antibodies to4prevent pickup in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147: 4207). Other studies with monoclonal antibodies to4provide proof that4/1may also play a role in Allergy, asthma and autoimmune diseases (Walsh et al., J. Immunol., 1991. 146:3419; Bocher et al., J. Exp. Med., 1991, 173:1553; Yednock et al., Nature 1992, 356: 63). Antibodies to4also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).

Heterodimerv/3usually referred to as the vitronectin receptor, another member of the subfamily3integrins, characterized in platelets, endothelial cells, melanoma cells, smooth muscle and on the surface of osteoblasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109: 1817-1826: Horton, Int. J. Exp. Pathol., 1990, 71: 741-759). Like IIb/IIIa receptor vitronectin is associated with a number of RGD-containing adhesion proteins, such as vitronectin, fibronectin, FVF, fibrinogen, osteopontin, bone selobloc II and thrombospondin, with the participation of the RGD sequence. Suggested possible rolesv/3in angiogenesis, tumor growth and revascularization (Brooks et al., Science, 1994, 264: 569-571). The adhesion of osteoclasts to the bone matrix is a key event of bone resorption. Studies using mo the AUX v/3the antagonist would be useful for blocking the process of bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).

There was a post about some of RGD-coworkers peptide compounds that block the binding of fibrinogen and prevent the formation of blood clots.

European Patent N 478363 relates to compounds of General formula

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European patent N 478328 relates to compounds of General formula

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European patent N 525626 (corresponding to patent Canada N 2074685) opens compounds of General formula

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PCT patent 9307867 relates to compounds of General formula

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European patent N 4512831 relates to compounds of General formula

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None of the above links does not or does not have in mind the compounds of the present invention, which are described in detail below.

Brief description of the invention

The present invention provides new compounds of ones nature, which are associated with integrins, thereby changing the processes of adhesion cell-cell and cell-matrix. Compounds of the present invention is suitable for treatment of inflammatory processes of bone resorption, tumor, metastasis, thrombosis, States, svyazannaya formula I (described below), which are useful as antagonists of the receptor glycoprotein complex IIb/IIIa platelet. Compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein complex IIb/IIIa and inhibit platelet aggregation. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds as thrombolytics to suppress platelet aggregation and/or treatment of thromboembolic complications.

The present invention also includes methods of treatment of cardiovascular diseases, thrombosis or harmful platelet aggregation, re-blockage after thrombosis, reperfusion injury and restenosis introduction of the compounds of formula I alone or in combination with one or more drugs selected from: anticoagulation means, such as heparin and warfarin; protivodiabeticakih means, such as aspirin, piroxicam or ticlopidine; thrombin inhibitors, such as derivatives of moreargentina, hirudin or argatroban; or thrombolytics such as tissue activator of plasminogen, anistreplase, urokinase elematics compositions and methods which can be used in the treatment or prevention of diseases in which occur the processes of cell adhesion, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress, the reaction of "graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.

Also included in the present invention are pharmaceutical kits comprising one or more packages containing pharmaceutical unit dose comprising the compounds of formula I for the treatment of disorders associated with aggregation of cells, including, but not limited to, thromboembolic complications.

Detailed description of the invention

The present invention provides new compounds of ones nature, which are associated with integrins, thereby changing the processes of adhesion cell-cell and cell-matrix. Compounds of the present invention is suitable for treatment of inflammatory processes of bone resorption, tumor, metastasis, thrombosis, supports the new compounds of formula I (described below), which are useful as antagonists of the receptor glycoprotein complex IIb/IIIa platelet. Compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein complex IIb/IIIa and inhibit platelet aggregation. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds as thrombolytics to suppress platelet aggregation and/or for the treatment of thromboembolic complications.

This invention relates to new compounds of the formula I

< / BR>
or pharmaceutically acceptable salts or prodrugs of them.

[1] the First embodiment of this invention provides the compounds of formula I

< / BR>
or pharmaceutically acceptable salts and prodrugs of them,

where b is a single or double bond;

R1is selected from R2(R3)N(CH2)qZ-, R2(R3)N(R2N=)CN(R2)(CH2)qZ-,

piperazinil-(CH2)qZ - or

< / BR>
Z is selected from O, S, S(=O) or S(=O)2;

R2and R3independently selected from: H, C1-C10-alkyl, C2-C6alkenyl, C3-C11-the CEC is>C7-alkylsulphonyl, C6-C10-arylcarbamoyl, C2-C10-alkoxycarbonyl, C4-C11-cycloalkylcarbonyl, C7-C11-bicycloalkanes, C6-C10-aryloxyalkyl, aryl(C1-C10-alkoxy)carbonyl, C1-C6-alkylcarboxylic(C1-C4-alkoxy)carbonyl, C6-C10-arylcarbamoyl(C1-C4-alkoxy)carbonyl, C4-C11-cycloalkylcarbonyl(C1-C4- alkoxy)carbonyl;

U is selected from: a single bond (i.e., U is not present), -(C1-C7-alkyl)-, -(C2-C7alkenyl)-, -(C2-C7-quinil)-, -(aryl)-substituted 0-3 R6aor -(pyridyl) substituted 0-3 R6a;

V is selected from: a single bond (i.e., V is not present); -(C1-C7-alkyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7alkenyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7-quinil)-, substituted 0-2 groups independently selected from R6or R7; -(aryl)-, substituted 0-2 groups independently selected from R6or R7; -(pyridyl)-, substituted 0-2 groups independently selected from R6or R7; the C: single bond (so that is, W is not present), -(C1-C7-alkyl)-, -(C2-C7alkenyl)-, -(C2-C7-quinil)-, or -(C(R5)2)nC(=O)N(R5a)-;

X is selected from: a single bond (i.e., X is not present), -(C1-C7-alkyl)-, substituted 0-3 groups independently selected from R4, R8or R14; -(C2-C7alkenyl)-, substituted 0-3 groups independently selected from R4, R8or R14; -(C2-C7-quinil)-, substituted 0-3 groups independently selected from R4, R8or R14; or

< / BR>
Y is selected from hydroxy, C1-C10-alkoxy, C3-C11-cycloalkane, C6-C10-aryloxy, C7-C11-aralkylated, C3-C10-alkylcarboxylic, C3-C10-alkoxycarbonylmethyl, C2-C10-alkoxycarbonylmethyl, C5-C10-cycloalkylcarbonyl, C5-C10-cycloalkylcarbonyl, C5-C10-cycloalkylcarbonyl, C7-C11-aryloxypropanolamine, C8-C12-aryloxypropanolamine, C8-C12-arylcarboxylic, C5-C10-alkoxycarbonylmethyl, C52)(R3)N-(C1-C10-alkoxy)-:

R4and Rbindependently selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylcarboxylic or-N(R12R13;

R5is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C6-C10-aryl, C7-C11-arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

R5ais selected from hydrogen, hydroxy, C1-C8-alkyl, C2to C6alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C1-C6-alkoxy, benzyloxy, C6to C10aryl, heteroaryl, heteroaromatic, C7to C11arylalkyl, adamantylamine or C1-C10of alkyl, substituted 0-2 R4b;

or R5and R5acan be connected together, as 3-azabicycloalkanes, 1-piperidinyl, 1-morpholinyl or 1-piperazinil, each optional substituted C1-C6-alkyl, C6-C10-aryl, heteroaryl, C7-C11-arylalkyl, C1-C6-alkylcarboxylic, C3-C7-cycloalkyl
-alkylsulfonyl or C6-C10-arylsulfonyl;

R5bis selected from C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C6-C10-aryl, C7-C11-arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

R6is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, -N(R12R13, cyano, halo, CF3CHO, CO2R5C(=O)R5a, CONR5R5a, OC(=O)R5a, OC(=O)OR5b, OR5a, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(=O)R5a, NR5aC(=O)OR5b, NR5aC(=O)NR5R5a, NR5aSO2NR5R5a, NR5aSO2R5, S(O)pR5a, SO2NR5R5afrom C2to C6alkenyl, C3to C11cycloalkyl, C4to C11cycloalkenyl; C6to C10aryl, optionally substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; C7to C11arylalkyl, the above is>of alkyl, CF3, S(O)mMe, or-NMe2; methylendioxy, when R6is the Deputy aryl; or a 5-10 membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R7;

R6ais selected from C1-C4-alkyl, C1-C4-alkoxy, halo, CF3, NO2or NR12R13;

R7is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, -N(R12R13, cyano, halo, CF3CHO, CO2R5C(=O)R5a, CONR5R5a, OC(=O)R5a, OC(=O)OR5b, OR5a, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(=O)R5a, NR5aC(=O)OR5b, NR5aC(=O)NR5R5a, NR5aSO2NR5R5a, NR5aSO2R5,

S(O)pR5a, SO2NR5R5afrom C2to C6alkenyl, C3to C11cycloalkyl, C4to C11cycloalkenyl, C6to C10aryl or C7to C11-C10-alkenyl, substituted 0-3 R6; C2-C10-quinil, substituted 0-3 R6; C3-C8-cycloalkyl, substituted 0-3 R6; C5-C6-cycloalkenyl, substituted 0-2 R6; aryl, substituted 0-2 R6; 5-10-membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R6;

R12and R13independently are H, C1-C10-alkyl, C1-C10-alkoxycarbonyl, C1-C10-alkylcarboxylic, C1-C10-alkylsulfonyl,

aryl(C1-C10-alkyl)sulfonium, arylsulfonyl, aryl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylation, C7-C11-arylalkyl, C2-C7-alkylcarboxylic, C7-C11-arylcarbamoyl, C2-C10-alkoxycarbonyl, C4-C11-cycloalkylcarbonyl, C7-C11-bicycloalkanes, C7-C11-arylcarbamoyl, heteroarylboronic, heteroarylboronic or aryl(C1-C10-alkoxy) carbonyl;

UB>1
-C10-alkoxy, aryl, heteroaryl or C1-C10-alkoxycarbonyl, CO2R5or-C(=O)N(R5R5a;

R15is selected from: H; R6; C1-C10of alkyl, substituted 0-8 R6; C2-C10-alkenyl, substituted 0-6 R6; C1-C10-alkoxy, substituted 0-6 R6; aryl, substituted 0-5 R6; 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted by 0-5 R6; C1-C10-alkoxycarbonyl, substituted 0-8 R6; CO2R5or-C(=O)N(R5R5a;

n = 0-4;

q = 2-7;

r = 0-3;

provided that when b is a double bond, there is only one of R14or R15;

provided that n, q and r are chosen so that the number of atoms in the chain between R1and

Y is in the range of 8-18.

[2] the Preferred compounds of this first embodiment are those compounds of formula II (where W is single bond (i.e. is absent), and U is a single bond (i.e. is absent))

< / BR>
where R1vybiral

< / BR>
and/or

R2is selected from H, aryl(C1-C10-alkoxy)carbonyl, C1-C10-alkoxycarbonyl; and/or

R8is selected from H, C1-C10-alkyl, C2-C10alkenyl, C5-C6-cycloalkenyl, C3-C8-cycloalkyl, aryl, 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated; and/or

R6and R7selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, -N(R12R13, cyano or halo.

[3] More preferred compounds of this first embodiment are those compounds of formula II (where W is the concatenation of/absent and U is the connection/no)

< / BR>
where X is selected from: a single bond (i.e., X is not present); -(C1-C7the alkyl)-, substituted 0-2 groups independently selected from R4, R8or R14; -(C2-C7-alkenyl)-, substituted 0-2 groups independently selected from R4, R8or R14; -(C2-C7-quinil)-, substituted 0-2 groups independently selected 6alkenyl, C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aryl, 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated; and/or

[4] the most preferred compounds of this first embodiment are the compounds of formula I, where R1is

< / BR>
V is phenylene or peredilenim;

n = 1 or 2;

X is-C1-C2the alkyl-substituted 0-2 R4;

Y is selected from: hydroxy; C1to C10alkoxy; methylcarbonate-; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1-(methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy-; 1-(t-butylboronic)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; i-propylenecarbonate-; t-butyloxycarbonyl-; 1-(i-propylenecarbonate)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2-IU the SUB>-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulfonyl, arylalkylamines, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylamines, pyridylcarbonyl or pyridinedicarboxylate;

R13is H.

[5] Particularly preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug of them, chosen from:

5(R, S)-3-[[4-(2-piperidine-4-yl)ethoxyphenyl] isoxazolin-5-yl] acetic acid;

5(R, S)-N-(butanesulfonyl)-L-{ 3-[4-(2-piperidine-4 - yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R, S)-N-(a-toluensulfonyl)-L-{ 3-[4-(2-piperidine-4 - yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R, S)-N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidine-4 - yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R, S)-N-(pentanoyl)-L-{ 3-[4-(2-piperidine-4-yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R,S)-3-[4-(piperidine-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(butanesulfonyl)amino-{3-[4-(piperidine-4 - yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(a-toluensulfonyl)amino-{3-[4-(piperidine-4 - yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

>/BR>2(R, S)-5(R, S)-N-(pentanoyl)amino-{ 3-[4-(piperidine-4 - yl)methoxyphenyl] isoxazolin-5-yl}propanoic acid.

[6] the Second embodiment of this invention provides the compounds of formula I:

< / BR>
or a pharmaceutically acceptable salt or prodrug of him,

where b is a single or double bond;

R1is selected from R2aR3N-, R2(R3)N(R2N=)C-, R2a(R3)N(CH2)qZ-, R2(R3)N(R2N=)C(CH2)qZ-, R2(R3)N(R2N=)CN(R2)-,

< / BR>
or

< / BR>
Z is selected from the connection (i.e. is absent), O, S, S(=O) or S(=O)2;

R2and R3independently selected from: H, C1-C10-alkyl, C3-C6alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkyl, C6-C10-aryl, C7-C11-arylalkyl,

C2-C7-alkylsulphonyl, C7-C11-arylcarbamoyl, C2-C10-alkoxycarbonyl, C4-C11-cycloalkylcarbonyl, C7-C11-bicycloalkanes, C7-C11-aryloxyalkyl, aryl(C1-C10-alkoxy) carbonyl, C1-C6-arylcarboxylic (C1-C4-alkoxy)carbonyl, C4-C11-BR>
U is selected from: a single bond (i.e., U is not present), -(C1-C7-alkyl)-, -(C2-C7alkenyl)-, -(C2-C7-quinil)-, -(aryl)-, substituted 0-3 R6aor -(pyridyl)-, substituted 0-3 R6a;

V is selected from: a single bond (i.e., V is not present); -(C1-C7-alkyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7alkenyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7-quinil)-, substituted 0-3 groups independently selected from R6or R7; -(phenyl)-Q-specified phenyl, substituted by 0-2 groups independently selected from R6or R7; -(pyridyl)-Q-specified pyridyl, substituted by 0-2 groups independently selected from R6or R7: or(pyridazinyl)-Q-, specified pyridazinyl, substituted 0-2 groups independently selected from R6or R7;

Q is selected from: a single bond (i.e., Q is not present); -O-, -S(O)m-, -N(R12)-, -(CH2)m-, -C(= O)- N(R5a)C(=O)-, -C(=O)N(R5a)-, -CH2O-, -OCH2-, -CH2N(R12)-, -N(R12)CH2-, -CH2C(=O)-, -C(=O)CH2-, -CH2S(O)m- or-S(O)mCH2-, provided that when b is Odio-, -S(O)m-, -N(R12)-, -C(=O)N(R5a)-, -CH2O-, -CH2N(R12)- or - CH2S(O)m-.

W is selected from: -(C(R4)2)nC(=O)N(R5a)- or-C(=O)-N(R5a)-(C(R4)2)n-;

X is selected from: a single bond (i.e., X is not present), -(C(R4)2)n-C(R4)(R8)- C(R4)(R4a), provided that, when n equals 0 or 1, at least one of R4aor R8is not H or stands;

Y is selected from hydroxy, C1-C10-alkyloxy, C3-C11-cycloalkane, C6-C10-aryloxy, C7-C11-aralkylated, C3-C10-alkylcarboxylic, C3-C10-alkoxycarbonylmethyl, C2-C10-alkoxycarbonylmethyl, C5-C10-cycloalkylcarbonyl, C5-C10-cycloalkylcarbonyl, C5-C10-cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8-C12- aryloxypropanolamine, C8-C12- arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10(5-alkyl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi, C10-C14(5-Ari is biretta from H, C1-C10-alkyl, C1-C10-alkylsulphonyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl; or two R4groups on adjacent carbon atoms can be connected with the formation of the connection (i.e., double or triple carbon-carbon);

R4ais selected from H, hydroxy, nitro, C1-C10-alkoxy, -N(R5R5a; -N(R12R13; -N(R16R17; C1-C10-alkyl, substituted 0-3 R6; aryl, substituted 0-3 R6heteroaryl, substituted 0-3 R6or C1-C10- alkylsulphonyl;

R4bis selected from H, C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, C3-C7-cycloalkyl, C7-C14-bicycloalkyl, hydroxy, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, nitro, C1-C6-alkylsulphonyl, C6-C10-aryl, -N(R12R13, halo, CF3CN, C1-C6-alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R5is selected from H, C1-C8-alkyl, C3-C6alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C6-C10-aryl, C7-Cdroxi, C1-C8-alkyl, C3to C6alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C1-C6-alkoxy, benzyloxy, C6-C10-aryl, heteroaryl, heteroaromatic, C7-C11-arylalkyl of adamantylamine or C1-C10of alkyl, substituted 0-2 R4b;

or R5and R5aboth as substituents on the same nitrogen atom (as in-NR5R5a), can be combined with the nitrogen atom to which they are attached, form a 3-azabicycloalkanes, 1,2,3,4-tetrahydro-1-chinoline, 1,2,3,4-tetrahydro-2-izochinolina, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiomorpholine, thiazolidine or 1-piperazinil, each optional substituted C1-C6-alkyl, C6-C10-aryl, heteroaryl, C7-C11-arylalkyl, C1-C6-alkylcarboxylic, C3-C7- cycloalkylcarbonyl, C1-C6- alkoxycarbonyl, C7-C11- arylethoxysilanes, C1-C6- alkylsulfonyl or C6-C10- arylsulfonyl;

R5bis selected from C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C66is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, -N(R12R13, cyano, halo, CF3CHO, CO2R5C(=O)R5a, CONR5R5a, OC(=O)R5a, OC(=O)OR5b, OR5a, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(=O)R5a, NR5aC(=O)OR5b, NR5aC(=O)NR5R5a, NR5aSO2NR5R5a, NR5aSO2R5,

S(O)mR5a, SO2NR5R5afrom C2to C6alkenyl, C3to C11cycloalkyl, C4to C11cycloalkenyl; C6to C10the optional aryl substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; C7to C11arylalkyl, the above optional aryl substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; methylendioxy, when R6is the Deputy aryl; or a 5-10 membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic to LCO substituted 0-2 R7;

R6ais selected from C1-C4-alkyl, C1-C4-alkoxy, halo, CF3, NO2or NR12R13;

R7is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, N(R12R13, cyano, halo, CF3CHO, CO2R5C(=O)R5a, CONR5R5a, OC(=O)R5a, OC(=O)OR5b, OR5a, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(= O)R5a, NR5aC(= O)NR5R5a, NR5aSO2NR5R5a, NR5aSO2R5, S(O)mR5a, SO2NR5R5aC2-C6alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkenyl, C6-C10-aryl or C7-C11-arylalkyl;

R8is selected from: R6; C1-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C2-C10-quinil, substituted 0-3 R6; C3-C8-cycloalkyl, substituted 0-3 R6; C5-C6-cycloalkenyl, substituted 0-3 R6; aryl, substituted 0-3 R6; 5-10-membered heterocyclic ring containing 1-3 heterogeneneity, specified heterocyclic ring substituted 0-2 R6;

R12and R13independently are H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylcarboxylic, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonium, arylsulfonyl, aryl(C2-C10alkenyl)sulfonium, heteroarylboronic, aryl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11- cycloalkylation, C7-C11-arylalkyl, C7-C11- arylcarbamoyl, C4-C11- cycloalkylcarbonyl, C7-C11- bicycloalkanes, C7-C11- aryloxyalkyl, heteroarylboronic, heteroarylboronic or aryl(C1-C10- alkoxy)carbonyl where the specified arily selectively substituted by 0-3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halo, CF3and NO2;

R14is selected from H, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or-C(=O)N(R5R5a;

R15the choice is th 0-2 R6; C1-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C1-C10-alkoxy, substituted 0-3 R6; aryl, substituted 0-3 R6; 5-10-membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R6;

if b is a double bond, there is only one of R14or R15;

R16is selected from: -C(= O)-O-R18a; -C(=O)-R18b; -C(=O)N(R18b)2; -C(= O)NHSO2R18a; -C(=O)NHC(=O)R18b; -C(=O)NHC(=O)OR18a; -C(=O)NHSO2OTHER18b; -C(= S)-NH-R18b; -NH-C(= O)-O-R18a; -NH-C(=O)-R18b; -NH-C(=O)-NH-R18b; -SO2-O-R18a; -SO2-R18a; -SO2-N(R18b)2; -SO2-NHC(= O)OR18b; -P(=S)(OR18a)2; -P(= O)(OR18a)2; -P(=S)(R18a)2; -P(=O)(R18a)2or

< / BR>
TO17is selected from: H, C1-C10-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C15- cycloalkenyl, aryl, aryl(C1-C10- alkyl)-;

R18ais selected from C1-C8-alkylamino 0-2 R19; C3-C8-cycloalkyl, substituted 0-2 R19; aryl, substituted 0-4 R19; aryl(C1-C6- alkyl), substituted 0-4 R19; 5-6-membered heterocyclic system having 1-3 heteroatoms, selected independently from O, S or N, specified heterocyclic ring, substituted 0-4 R19; C1-C6of alkyl, substituted 5-10-membered heterocyclic system having 1-3 heteroatoms, selected independently from O, S or N, specified heterocyclic ring, substituted 0-4 R19;

R18bis selected from R18aor H;

R19is selected from H, halogen, CF3, CN, NO2, NR12R13C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, C3-C11-cycloalkyl, C4-C11- cycloalkenyl, aryl, aryl(C1-C6- alkyl)-, C1-C6-alkoxy or C1-C4- alkoxycarbonyl:

m = 0-2;

n = 0-4;

q = 1-7;

r = 0-3;

provided that n, q and r are chosen so that the number of atoms linking R1and

Y is in the range of 8-18.

[7] the Preferred compounds of this second embodiment are those compounds of formula Ia

< / BR>
where Z is selected from the connection (i.e10- alkoxycarbonyl; and/or

W is -(CH2)nC(=O)N(R5a)-; and/or

X is -(C(R4)2)n-C(R4)(R8)- CH(R4)-, provided that when n equals 0 or 1, at least one of R4aor R8is not H or stands; and/or

R5is selected from H or C1-C10of alkyl, substituted 0-6 R4b; and/or

R6is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylsulphonyl, -N(R12R13, CO2R5, -NR5R5a, OR5, S(O)mR5acyano, halo; C6to C10aryl, optionally substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; C7to C11arylalkyl, the above optional aryl substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; methylendioxy, when R6is the Deputy aryl; or a 5-10 membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated Iraida from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, N(R12R13, cyano or halo;

R8is selected from: -CONR5NR5a; -CO2R5; C1-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C2-C10-quinil, substituted 0-3 R6; C3-C8-cycloalkyl, substituted 0-3 R6; C5-C6- cycloalkenyl, substituted 0-3 R6; aryl, substituted 0-3 R6; 5-10-membered heterocyclic ring containing 1-3 heteroatoms N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R6; and/or

R12and R13each independently selected from H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylsulphonyl, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylboronic or heteroarylboronic where these arily selectively substituted by 0-3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-Ala the deposits are those compounds of formula Ia

< / BR>
where Z is selected from the connection (i.e. is absent), O; and/or

W is -(CH2)nC(=O)N(R12)-; and/or

X is-C(R4)(R8)-C(R4)2-.

[9] the Most preferred compounds of this second embodiment are the compounds of formula Ia, where R1is R2NHC(=NR2)- or R2NHC(=NR2)NH - and V is phenylene or peridinin, or R1< / BR>
< / BR>
V is a single bond (i.e., V is absent);

n = 1 or 2;

X is-CHR8CH2-;

Y is selected from: hydroxy; C1-C10-alkoxy; methylcarbonate-; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1-(methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy-; 1-(t-BUTYLCARBAMATE)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; i-propylenecarbonate-; t-butyloxycarbonyl-; 1-(i - propylenecarbonate)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t - butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3 - doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2-methoxypropyl) carbonyloxy)ethoxy-;

R6 is ylcarbonyl, -N(R12R13, CO2R5, -NR5R5a, OR5, S(O)mR5a, cyano, halo; C6to C10aryl, optionally substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; methylendioxy, when R6is the Deputy aryl; or a system of heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazoline or morpholinyl;

R8is selected from: -CONR5NR5a; -CO2R5; C1-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C2-C10-quinil, substituted 0-3 R6; C3-C8-cycloalkyl, substituted 0-3 R6; aryl, substituted 0-2 R6systems ; heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, Iginla, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-2 R6;

R12is selected from H, C1-C6-alkyl, C1-C4-alkoxycarbonyl, C1-C6- alkylsulphonyl, C1-C6- alkylsulfonyl, aryl(C1-C4- alkyl)sulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylamine where these arily selectively substituted by 0-3 substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halo, CF3and NO2;

R13is H.

[10] Particularly preferred compounds of this second embodiment are compounds or pharmaceutically acceptable salts or prodrugs of them, chosen from:

3(R,S)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}- 3-phenylpropane acid;

3(R,S)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3 - pentane acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3 - heptane acid;

3(R, S)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino}-4- (phenylthio)butane acid;

3(R, S)-{ 5(R, S)-N-(3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino}-4-sulfamido)butane acid;

3(S)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3- (adamantanecarbonyl)propanoic acid;

3(S)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3- (1-azabicyclo[3.2.2]noninterbank)propanoic acid;

3(S)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3- (penicillinaseand)propanoic acid;

3(R)-{ 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3- (3-pyridylethyl)propanoic acid;

3(R)-{ 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3- (2-pyridylethyl)propanoic acid;

3(R)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3- (phenylpropyl)propanoic acid.

[11] Also preferred compounds of the second embodiment are the compounds of formula IC

< / BR>
where b is a single or a double bond;

R1is selected from R2a(R3)N-, R2(R3)N(R2N=)C-, R2a(R3)N(CH2)qZ-, R2(R3)N(R2N=)C(CH2)qZ-, R2(R3)N(R2N=)CN(R2)-,

< / BR>
or

< / BR>
Z is selected from the connection (i.e. is absent), O, or S;

R2and R3independently selected from H, aryl(C1-C10-alkoxy) carbonyl or C1-C10- alkoxycarbonyl);

V is selected from: a single bond (i.e., V is not present); -(C1-C7-alkyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7alkenyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7-alkyl)-, substituted 0-3 groups independently selected from R6or R7; -(phenyl)-Q-specified phenyl, substituted by 0-2 groups independently selected from R6or R7; -(pyridyl)-Q-specified pyridyl, substituted by 0-2 groups independently selected from R6or R7or -(pyridazinyl)-Q-, specified pyridazinyl, substituted 0-2 groups independently selected from R6or R7;

Q is selected from: a single bond (i.e., Q is not present); -O-, -S(O)m-, -N(R12)-, -(CH2)m-, -C(= O)- N(R5a)C(=O)-, -C(=O)N(R5a)-, -CH2O-, -OCH2-, -CH2N(R12)-, -N(R12)CH2-, -CH2C(=O)-, -C(=O)CH2-, -CH2S(O)m- or-S(O)mCH2-, provided that when b is a single bond and R1-U-V- - the Deputy on C5 of the Central 5-membered ring of formula I, Q is-O-, -S(O)m-, -N(R12)-, -C(=O)N(R5a)-, -CH2O-CH2N(R12)- or-CH2S(O)m-;

W wybir the UB>-CHR4a-;

R4is selected from H, C1-C10-alkyl, C1-C10-carbonyl, aryl, arylalkyl, cycloalkyl or cycloalkenyl;

R4aselected from hydroxy, C1-C10-alkoxy, nitro, -N(R5R5a, -N(R12R13or-N(R16R17C1-C10of alkyl, substituted 0-3 R6, aryl, substituted 0-3 R6, heteroaryl, substituted 0-3 R6or C1-C10- alkylcarboxylic;

R4bis selected from H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-quinil, hydroxy, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6- alkylsulfonyl, C1-C6- alkylsulfonyl, nitro, C1-C6- alkylsulphonyl, C6-C10-aryl, -N(R17R13, halogen, CF3CN, C1-C6-alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridyl;

R5is selected from H or C1-C10of alkyl, substituted 0-6 R4b;

R5ais selected from hydrogen, hydroxy, C1-C8-alkyl, C2-C6-alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkenyl, C1-C6-alkoxy, benzyloxy, C6-C10-aryl, heteroaryl 0-2 R4b;

or, R5and R5acan be connected together, forming a 3-azabicycloalkanes, 1,2,3,4-tetrahydro-1-chinoline, 1,2,3,4-tetrahydro-2-ethenolysis, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiomorpholine, thiazolidine or 1-piperazinil, each selectively substituted C1-C6-alkyl, C6-C10-aryl, heteroaryl, C7-C11- arylalkyl, C1-C6- alkylcarboxylic, C3-C7- cycloalkylcarbonyl, C1-C6- alkoxycarbonyl or C7-C11- arylethoxysilanes;

R5bis selected from C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11- cycloalkenyl, C6-C10-aryl, C7-C11-arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

Y is selected from hydroxy, C1-C10-alkoxy, C3-C11- cycloalkane, C6-C10-aryloxy, C7-C11- aralkylated, C3-C10- alkylcarboxylic, C3-C10- alkoxycarbonylmethyl, C2-C10- alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C5-Cxcarmenelectrax, C8-C12-arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10- (5-alkyl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi or C10-C14- (5-aryl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi;

R6and R7each independently selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, N(R12R13, cyano or halo;

R12and R13each independently selected from H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylsulphonyl, C1-C10- alkylsulfonyl, aryl(C1-C10-alkyl) sulfonyl, arylsulfonyl, heteroarylboronic, heteroarylboronic or aryl, where these arily selectively substituted by 0-3 substituents selected from the group consisting of: C1-C4-alkyl, C1-C4-alkoxy, halo, CF3and NO2;

R15is selected from H, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or-C(=O)N(R5R5a;

R16is selected from: -C(= O)-O-R18a< is selected from: H or C1-C4-alkyl;

R18ais selected from C1-C8of alkyl, substituted 0-2 R19; C2-C8-alkenyl, substituted 0-2 R19; C2-C8-quinil, substituted 0-2 R19; C3-C8- cycloalkyl, substituted 0-2 R19; aryl, substituted 0-4 R19; aryl(C1-C6- alkyl)-, substituted 0-4 R19systems ; heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-4 R19; C1-C6of alkyl, substituted a system of heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl, decree, R19is selected from H, halogen, CF3, CN, NO2, NR12R13C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, C1-C6-alkoxy, C3-C11- cycloalkyl, C4-C11- cycloalkenyl, aryl, heteroaryl, aryl(C1-C6-alkyl) -, or C1-C4- alkoxycarbonyl;

n = 0-4;

q = 1-7;

r = 0-3;

provided that n, q, r are chosen so that the number of atoms between R1and Y is in the range of 8-17.

[12] the Most preferred compounds of the second embodiment of formula Ic are those compounds of formula Ib

< / BR>
where R1is selected from R2(R3)N-, R2NH(R2N=)C-, R2NH(R2N=)CNH-, R2R3N(CH2)p'Z-, R2NH(R2N=)CNH(CH2)p-Z - or

< / BR>
or

< / BR>
n = 0-1;

p' = 4-6;

p = 2-4;

Z is selected from the connection (i.e. is absent), O;

V is a single bond (i.e., not present), -(phenyl)- or -(pyridyl)-;

W is selected from: -(C(R4)2)-C(=O)-N(R5a)- or-C(=O)-N(R5a)-(CH2)-;

X is selected from: -CH2-CNH(R16R17- or-CH2-CHNR5R5a-;

Y is selected from: hydroxy; C1-C10-alkoxy; m is XI; 1-(methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy-; 1-(t-BUTYLCARBAMATE)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; i-propylenecarbonate-; t-butyloxycarbonyl-; 1-(i-propylenecarbonate)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R16is selected from: -C(= O)-O-R18a; -C(= O)-R18b; -S(=O)2-R18aor-SO2-N(R18b)2;

R17is selected from H or C1-C5-alkyl;

R18ais selected from C1-C8of alkyl, substituted 0-2 R19; C2-C8-alkenyl, substituted 0-2 R19; C2-C8-quinil, substituted 0-2 R19; C3-C8-cycloalkyl, substituted 0-2 R19; aryl, substituted 0-4 R19; aryl(C1-C6-alkyl)-, substituted 0-4 R19systems ; heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, Hanania, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-4 R19; C1-C6of alkyl, substituted a system of heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-4 R19.

[13] the Most preferred compounds of formula Ib are those compounds in which R1is R2NH(R2N=)C -, or R2HN(R2N)CNH -, and V is phenylene or peridinin or R1is

< / BR>
V is a single bond (i.e., V is absent);

n = 1 or 2;

R18ais selected from C1-C4of alkyl, substituted 0-2 R19; C2-C4-alkenyl, substituted 0-2 R19; C2-C4-quinil, substituted 0-2 R19; C3-C7-cycloalkyl, substituted 0-2 R19; aryl, substituted 0-4 R19; aryl(C1-C6-Alki Anila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-4 R19; C1-C4of alkyl, substituted a system of heterocyclic rings selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-4 R19.

[14] Especially preferred compounds of formula Ib are compounds or their pharmaceutically acceptable salts, selected from:

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(phenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(4-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(propanesulfonyl)-2,3-(S)-diaminopropanol acid:

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(econsultancy)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(ethoxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(1-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(1-(2-methyl)-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-(2-methyl)-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl] -N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl] -N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-methoxybenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-chlorobenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N the h-5(R, S)-yl} - acetyl] -N2-(forantimicrobial)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-phenoxybenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-(methoxyethyl)-carbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-pyridylcarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-pyridylcarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-pyridinyl-carbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-(2-pyridinyl)-acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-(3-pyridinyl)-acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(2-(4-pyridinyl)-acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

the new acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-thienylmethyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl]-N2-(3-were the N2-(4-iodinesulphur)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-triftormetilfullerenov)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-chlorophenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-2-methoxycarbonylaminophenyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-triftormetilfullerenov)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-triftormetilfullerenov)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-perpenicular)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-perpenicular)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S is)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(2,3,5,6-tetramethylbutylphenol)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(4-cyanobenzylidene)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-propylpentanoic)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-phenylethylamine)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(4-isopropylbenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-phenylpropionyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(phenylenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(2-fluoro-4-formamidine)-isoxazolin-5(R, S)-yl}- acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)-isoxazolin-5(R, S)-yl}- acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)-isoxazolin-5(R, S)-yl}- acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)-isoxazolin-5(R, S)-yl}- acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)-isoxazolin-5(R, S)-yl}- acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(phenylenecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(4-ftorpolimernoj)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(1-naphthalenesulfonyl))-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} - acetyl] -N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, l)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(3-methyl-2-benzothiazolone)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R, S)-yl} - acetyl] -N2-(isobutylketone)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl] -N2-(isobutylketone)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl] -N2-(isobutylketone)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5(R,S)-yl}- acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(R)-yl} - acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5(S)-yl} - acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinium)-isoxazolin-5(R, S)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinium)-isoxazolin-5(R)-yl} - acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinium)-isoxazolin-5(R)-yl} - acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol Kolotova acid.

[15] Also especially preferred are esters prodrugs of especially preferred compounds of formula Ib, the said esters selected from the group comprising: methyl; ethyl; propyl; isopropyl; methylcarbamoylmethyl; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1-(methylcarbonate)ethyl-; 1-(ethylcarbonate)ethyl-; 1-(t-BUTYLCARBAMATE)ethyl-; 1 -(cyclohexyloxycarbonyloxy)ethyl-; i-propylenecarbonate-; cyclohexylcarbodiimide-; t-butyloxycarbonyl-; 1-(i-propylenecarbonate)-; 1-(cyclohexyloxycarbonyloxy)ethyl-; 1-(t-butyloxycarbonyl)ethyl-; dimethylaminoethyl-; diethylaminoethyl-; (5-methyl-1,3-doxacycline-2-he-4-yl)methyl; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methyl; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methyl-; 1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.

[16] the Third embodiment of the present invention provides a compound of formula Id

< / BR>
or a pharmaceutically acceptable salt or prodrug of him,

where R1is selected from R2(R3)N-, R2(R3)N(R2N=)C-, R2(R3)N(R2N=)CN(R2)-,

R2(R3)N(CH2)qZ-, R2(R3)N(R2N=UB>q
Z - or

< / BR>
Z is selected from the connection (i.e. is absent), O, S, S(=O) or S(=O)2;

R2and R3independently selected from: H, C1-C10-alkyl, C2-C6-alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkyl, C6-C10-aryl, C7-C11-arylalkyl, C2-C7- alkylsulphonyl, C7-C11- arylcarbamoyl, C2-C10- alkoxycarbonyl, C4-C11- cycloalkylcarbonyl, C7-C11- bicycloalkanes, C7-C11- aryloxyalkyl or aryl(C1-C10-alkoxy) carbonyl, C1-C6- alkylcarboxylic(C1-C4- alkoxy)carbonyl, C6-C10- arylcarboxylic(C1-C4- alkoxy)carbonyl, C4-C11- cycloalkylcarbonyl(C1-C4- alkoxy)carbonyl;

U is selected from: a single bond (i.e., U is absent); C1-C7- alkylene; C2-C7- Alcanena; C2-C7-akinlana; arylene, substituted 0-3 R6a, perederina, substituted 0-3 R6a;

V is selected from: a single bond (i.e., V is absent); C1-C7- alkylene, substituted 0-6 R6or R7; C2-C7- Alcanena, substituted 0-4 R6
or R7; perederina, substituted 0-3 R6or R7; pyridazinyl, substituted 0-3 R6or R7;

X is selected from: a single bond (i.e. X is absent); -(CH2)nC(= O)N(R12)-; C1-C7- alkylene, substituted 0-6 R4, R8or R15; C2-C7- Alcanena, substituted 0-4 R4, R8or R15; C2-C7- akinlana, substituted 0-4 R4, R8or R15;

Y is selected from: hydroxy, C1-C10-alkoxy, C3-C11- cycloalkane, C6-C10-aryloxy, C7-C11- aralkylated, C3-C10- alkylcarboxylic, C3-C10- alkoxycarbonylmethyl, C2-C10- alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8-C12- aryloxypropanolamine, C8-C12- arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10- (5-alkyl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi, C10-C14- (5-aryl-1,3-dioxa-childname and the same carbon atom and are taken together to form a Spiro-condensed, 5-7-membered ring of the formula

< / BR>
D, E, F and G each independently selected from: C(R6a)2; carbonyl; component containing a heteroatom selected from N, N(R12), O, provided that no more than 2 of D, E, F and G are N, N(R12), O, S, or C(=O); or, the relationship between D and E, E and F or F and G in such a Spiro-condensed ring may have a double bond carbon - nitrogen or a double bond carbon - carbon;

R4is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylcarboxylic or-N(R12R13;

R6and R7each independently selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, -N(R122)R13, cyano, halogen, CF3CHO, CO2R5aC(=O)R5a, CONHR5a, CON(R12)2, OC(=O)R5a, OC(=O)OR5a, OR5a, OC(= O)N(R12)2, OCH2CO2R5a, CO2CH2CO2R5aN(R12)2, NO2, NR12C(= O)R5a, NR12C(= O)OR5a, NR12C(= O)N(R12)2, NR12SO2N(R12)2, NR12SO2R5a, S(O)pR5a, SO2N(R12)2C2-C6-alkenyl, C3 is about 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; C7-C11- arylalkyl specified aryl, optionally substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2; methylendioxy, when R6is the Deputy aryl;

R6ais selected from C1-C4-alkoxy, C1-C4-alkyl, halogen, CF3, NO2or NR12R13;

R8is selected from: H; R6; C1-C10of alkyl, substituted 0-8 R6; C2-C10-alkenyl, substituted 0-6 R6; C2-C10-quinil, substituted 0-6 R6; C3-C8-cycloalkyl, substituted 0-6 R6; C5-C6-cycloalkenyl, substituted 0-5 R6; aryl, substituted 0-5 R6; 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the heterocycle may be saturated, partially saturated or fully unsaturated, said heterocycle is substituted by 0-5 R6;

R12and R13independently are H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylsulphonyl, C13-C11- cycloalkyl, C4-C11- cycloalkyl, C7-C11-arylalkyl, C2-C7- alkylsulphonyl, C7-C11- arylcarbamoyl, C2-C10- alkoxycarbonyl, C4-C11- cycloalkylcarbonyl, C7-C11- bicycloalkanes, C7-C11- aryloxyalkyl, heteroarylboronic, heteroarylboronic or aryl(C1-C10- alkoxy)carbonyl where the specified arily or heteroaryl optional substituted by 0-3 substituents selected from the group consisting of: C1-C4- alkyl, C1-C4-alkoxy, halogen, CF3, NO2;

R5and R5aindependently selected from H, C1-C8-alkyl, C2-C6alkenyl, C3-C11-cycloalkyl, C4-C11- cycloalkenyl, C6-C10-aryl, C7-C11- arylalkyl or C1-C10-alkyl, substituted 0-8 R4;

R15is selected from: H; R6; C1-C10of alkyl, substituted 0-8 R6; C2-C10-alkenyl, substituted 0-6 R6; C1-C10-alkoxy, substituted 0-6 R6; aryl, substituted 0-5 R6; 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where specified, heterocycle the mini-ring substituted 0-8 R6; C1-C10- alkoxycarbonyl, substituted 0-8 R6; CO2R5; or-C(=O)N(R12R13;

n = 0-4;

p = 1-3;

q = 1-7;

r = 0-3,

provided that n, p, q and r are chosen so that the number of atoms between R1and Y is in the range of 8-17.

[17] the Preferred compounds of this third embodiment are the compounds of formula III

< / BR>
where R1is selected from R2NH-, H2N(R2N=)C-, H2N(R2N=)CNH-, R2HN(CH2)qO, H2N(R2N=)CNH(CH2)qO-, piperazinil-(CH2)qO-,

< / BR>
R2is selected from H, aryl(C1-C10- alkoxy)carbonyl or C1-C10- alkoxycarbonyl;

R4is selected from H, C1-C10- alkyl, hydroxy, C1-C10- alkoxy, nitro, C1-C10- alkylcarboxylic or-N(R12R13;

V is selected from: a single bond (i.e., V is absent); C1-C7-alkylene, substituted 0-6 R6or R7; C2-C7- Alcanena, substituted 0-4 R6or R7; C2-C7- akinlana, substituted 0-4 R6or R7; phenylene, substituted 0-3 R6or R7; perederina, substituted 0-3 R6or R7; pyridazinyl>alkylene, substituted 0-1 R4; C2-C7- Alcanena or C2-C7- akinlana:

Y is selected from: hydroxy, C1-C10-alkoxy, C3-C11- cycloalkane, C6-C10-aryloxy, C7-C11- aralkylated, C3-C10- alkylcarboxylic, C3-C10- alkoxycarbonylmethyl, C2-C10- alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl, C5-C10cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8-C12- aryloxypropanolamine, C8-C12- arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10- (5-alkyl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi, C10-C14- (5-aryl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi;

Z is selected from O or CH2;

D, E, F and G each independently selected from: CH2; carbonyl; component containing a heteroatom selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S; or, the relationship between D and E, E and F or F and G in such a Spiro-condensed ring may have a double bond is, 1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, -N(R12R13, cyano or halogen;

R12and R13independently selected from H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylsulphonyl, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonyl, arylsulfonyl, heteroarylboronic, heteroarylboronic or aryl;

n = 0-4;

p = 1-3;

q = 1-7;

r = 0-3,

provided that n, p, q and r are chosen so that the number of atoms between R1and Y is in the range of 8-17.

[18] More preferred compounds of this third embodiment are the compounds of formula II, where R1is R2NHC(=R2)- and V is phenyl or pyridyl, or R1is

< / BR>
V is a single bond (i.e., V is absent);

n = 1 or 2;

X is C1-C4-alkylene, substituted 0-1 R4;

Y is chosen from:

hydroxy1-C10-alkoxy; methylcarbonate-; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1 -(methylcarbonate)ethoxy-; 1 -(ethylcarbonate)ethoxy-; 1 -(t-BUTYLCARBAMATE)ethoxy-; 1 -(cyclohexyl is hydroxy)ethoxy-; 1 -(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t - butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1 -(2-(2-methoxypropyl) carbonyloxy)ethoxy-;

R12and R13each independently selected from H, C1-C6-alkyl, C1-C4- alkoxycarbonyl, C1-C4- alkylsulphonyl, C1-C4- alkylsulfonyl, aryl (C1-C4- alkyl)sulfonyl, arylsulfonyl, heteroarylboronic, heteroarylboronic or aryl; and

R13is H.

[19] Particularly preferred compounds of this third embodiment are compounds, or pharmaceutically acceptable salt or prodrug of them, chosen from:

5(R,S)-3-(4-amidinophenoxy)- 8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4] non-2 - ene-7,9-dione;

5(R, S)-3-(4-amidinophenoxy)-8-(3-carboxypropyl)-1-oxa-2,8 - diazaspiro[4.4]non-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenoxy)-8-(2 - carboxyethyl)-1-oxa-2,8-diazaspiro[4.4] non-2 - EN-5-he;

5(R, S)-3-(4-amidinophenoxy)-8-(3-carboxypropyl)-1-oxa-2,8 - diazaspiro[4.4]non-2-EN-5-he:

5(R,S)-3-(4-amidinophenoxy)-8-(2 - carboxyethyl)-1-oxa-2-azaspiro(R,S)-3-(4-amidinophenoxy)-8-(2-carboxyethyl)-1 - oxa-2,8-diazaspiro[4.4] Dec-2 - ene-7,9-dione;

5(R, S)-3-(4 - amidinophenoxy)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]Dec - 2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenoxy)-8-(2-carboxyethyl)-1 - oxa-2,8-diazaspiro[4.4] Dec-2-EN-5-he;

5(R, S)-3-(4-amidinophenoxy)- 8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]Dec-2-EN-5-he;

5(R,S)-3-(4-amidinophenoxy)-8-(2-carboxyethyl)-1-oxa-2 - azaspiro[4.4]DECA-2,8-Dien-5-he;

5(R, S)-3-(4-amidinophenoxy)-8-(3-carboxypropyl)-1 - oxa-2-azaspiro[4.4] DECA-2.8-Dien-5-he;

5(R,S)-3-(4-amidinophenoxy)- 8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4] undec-2-ene-7,9-dione;

5(R, S)-3-(4-amidinophenoxy)-8-(3-carboxypropyl)-1-oxa-2,8 - diazaspiro[4.4]undec-2-ene-7,9-dione;

5(R,S)-3-(4-amidinophenoxy)-8- (2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4] undec-2-EN-5-he;

5(R, S)-3-(4-amidinophenoxy)-8-(2-carboxypropyl)-1-oxa-2,8 - diazaspiro[4.4]undec-2-EN-5-he;

5(R,S)-3-(4-amidinophenoxy)-8-(2 - carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-Dien-5-he;

5(R, S)-3-(4-amidinophenoxy)-8-(3-carboxypropyl)-1-oxa-2 - azaspiro[4.4] undeca-2,8-Dien-5-he;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl] -8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene - 7,9-dione;

5(R,S)-3-[2-(piperidine-4-yl)ethyl]-8-(3-carboxypropyl)- 1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;

5(R, S)-3-[2-(piperidine-4-yl)ethyl] -8-(2-carboxyethyl)-1-oxa-2,8 - diazaspiro[4.4]non-2-EN-5-he;

5(R, S)-3-[2-(piperidine-4-yl)these are the sa-2 azaspiro[4.4]Nona-2,8-Dien-5-he;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]Nona-2,8 - Dien-5-he;

5(R,S)-3-[2-(piperidine-4-yl)ethyl]-8-(2-carboxyethyl)-1 - oxa-2,8-diazaspiro[4.4]Dec-2-ene-7,9-dione;

5(R, S)-3-[2- (piperidine-4-yl)ethyl] -8-(3-carboxypropyl)-1-oxa-2,8 - diazaspiro[4.4]Dec-2-ene-7,9-dione;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl] -8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]Dec-2-EN-5 - he;

5(R, S)-3-[2-(piperidine-4-yl)ethyl] -8-(3-carboxypropyl)-1-oxa - 2,8-diazaspiro[4.4]Dec-2-EN-5-he;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]DECA-2,8-Dien - 5-he;

5(R, S)-3-[2-(piperidine-4-yl)ethyl] -8-(3-carboxypropyl)-1 - oxa-2-azaspiro[4.4]DECA-2-EN-5-he;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl] -8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene - 7,9-dione;

5(R,S)-3-[2-(piperidine-4-yl)ethyl]-8-(3-carboxypropyl)- 1-oxa-2,8-diazaspiro[4.4]undec-2-EN-7.9-dione:

5(R, S)-3-[2- (piperidine-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8 - diazaspiro[4.4]undec-2-EN-5-he;

5(R, S)-3-[2-(piperidine-4-yl)ethyl] - 8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-EN-5-he;

5(R, S)-3-[2-(piperidine-4-yl)ethyl] -8-(2-carboxyethyl)-1 - oxa-2-azaspiro[4.4]undeca-2,8-Dien-5-he;

5(R, S)-3-[2-(piperidine-4 - yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8 - Dien-5-he:

5(R, S)-3-(4-amidinophenoxy)-8-[2- (benzyloxycarbonyl who provides the compounds of formula 1

< / BR>
or a pharmaceutically acceptable salt or prodrug of them,

where R1is selected from: R2(R3)N(CH2)qZ-, R2(R3)N(R2N=)C(CH2)qZ-. R2(R3)N(R2N=)CN(R2)(CH2)qZ-, piperazinil-(CH2)qZ - or

< / BR>
Z is selected from O, S, S(=O), S(=O)2;

R2and R3independently selected from: H, C1-C10-alkyl, C2-C6-alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkyl, C6-C10-aryl, C7-C11-arylalkyl, C2-C7- alkylsulphonyl, C7-C11- arylcarbamoyl, C2-C10- alkoxycarbonyl, C4-C11- cycloalkylcarbonyl, C7-C11- bicycloalkanes, C7-C11- aryloxyalkyl or aryl(C1-C10- alkoxy)carbonyl, C1-C6- arylcarboxylic(C1- C4- alkoxy) carbonyl, C4-C11- cycloalkylcarbonyl(C1-C4- alkoxy)carbonyl;

U is optional and is selected from C1-C7-alkylene, C2-C7-Alcanena, C2-C7-akinlana, arylene or pirivena;

V is selected from: a single bond (i.e., V is absent); C1-C7; C2-C7- akinlana, substituted 0-4 R6or R7; phenylene, substituted 0-4 R6or R7; perederina, substituted 0-3 R6or R7, pyridazinyl, substituted 0-3 R6or R7;

W is -(aryl)-Z1- where specified aryl substituted 0-6 R6or R7;

Z1is selected from a single bond (i.e., Z1absent), -CH2-, O or S;

X is selected from: a single bond (i.e. X is absent); C1-C7- alkylene, substituted 0-6 R4, R8or R15; C2-C7- Alcanena, substituted 0-4 R4, R8or R15; C2-C7- akinlana, substituted 0-4 R4, R8or R15;

Y is selected from hydroxy, C1-C10- alkoxy, C3-C11- cycloalkane, C6-C10-aryloxy, C7-C11- aralkylated,3-C10- alkylcarboxylic,3-C10- alkoxycarbonylmethyl, C2-C10- alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8- C12- and what carbonylcyanide, WITH5-C10- (5-alkyl-1,3 - dioxa-cyclopenten-2-he-Il) metiloksi; C10-C14- (5-aryl-1,3 - dioxa-cyclopenten-2-he-Il) metiloksi, (R2)(R3)N- (C1-C10- alkoxy)-;

R4is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylcarboxylic or-N(R12R13;

R6and R7each independently selected from H, C1-C10of alkyl, hydroxy, C1-C10- alkoxy, nitro, C1-C10- alkylsulphonyl, -N(R12R13cyano, halo, CF3CHO, CO2R5aC(=O)R5a, CONHR5a, CON(R12)2, OC(=O)R5a, OC(=O)OR5a, OR5a, OC(= O)N(R12)2, OCH2CO2R5a, CO2CH2CO2R5aN(R12)2, NO2, NR12C(=O)R5a, NR12C(= O)OR5a, NR12C(=O)N(R12)2, NR12SO2N(R12)2, NR12SO2R5a, S(O)pR5aSO2N(R12)2C2-C6-alkenyl,3-C11- cycloalkyl, C4-C11- cycloalkenyl; C6-C10-aryl,

optional substituted with halogen, alkoxy, alkyl, CF3, S(O)mMe, or-NMe2; or (C7-C11-Ariel 2
;

R8is selected from: H; R6; C1-C10of alkyl, substituted 0-8 R6;2-C10- alkenyl, substituted 0-6 R6;2-C10-quinil, substituted 0-6 R6;3-C8- cycloalkyl, substituted 0-6 R6; C5-C6- cycloalkenyl, substituted 0-5 R6; aryl, substituted 0-5 R6; 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the heterocycle may be saturated, partially saturated or fully unsaturated, said heterocycle is substituted by 0-5 R6;

R12and R13independently are H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylcarboxylic, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonium, arylsulfonyl, aryl, C2-C6alkenyl,3-C11- cycloalkyl, C4-C11- cycloalkylation, C7-C11- arylalkyl, C2-C7- alkylcarboxylic, C7-C11- arylcarbamoyl, C2-C10- alkoxycarbonyl, C4-C11- cycloalkylcarbonyl, C7-C11- bicycloalkanes, C7-C11- aryloxyalkyl, heteroarylboronic the C1-C10-alkyl, C2-C10-alkenyl, C2-C10- quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or - C(=O)N(R12R13;

R5and R5aindependently selected from hydrogen, hydroxy, C1-C8-alkyl, C2-C6- alkenyl,3-C11- cycloalkyl, C4-C11- cycloalkenyl, C6-C10-aryl, C7-C11- arylalkyl or C1-C10of alkyl, substituted 0-8 R4;

R15is selected from: H; R6; C1-C10of alkyl, substituted 0-8 R6; C2-C10-alkenyl, substituted 0-6 R6;1-C10-alkoxy, substituted 0-6 R6; aryl, substituted 0-5 R6; 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted by 0-5 R6; C1-C10- alkoxycarbonyl, substituted 0-8 R6; CO2R5or - C(=O)N(R12R13;

n = 0-4;

q = 2-7;

r = 0-3;

provided that n, q and r are chosen so that the number of atoms between R1and Y primaraly IV

< / BR>
where R1is selected from R2HN(CH2)qO-, R2HN(R2N=)C(CH2)qZ, piperazinil-(CH2)qZ - or

< / BR>
Z is O;

R2is selected from: H, aryl(C1-C10- alkoxy)carbonyl, C1-C10- alkoxycarbonyl;

V is selected from: a single bond (i.e., V is absent); C1-C7-alkylene, substituted 0-6 R6or R7; C2-C7- Alcanena, substituted 0-4 R6or R7; C2-C7-akinlana, substituted 0-4 R6or R7; phenylene, substituted 0-3 R6or R7; perederina, substituted 0-3 R6or R7; pyridazinyl, substituted 0-3 R6or R7;

Z1is selected from a single bond (i.e., Z1absent), O, or S;

X is selected from: a single bond (i.e. X is absent): C1-C7-alkylene, substituted 0-6 R4, R8or R15; C2-C7- Alcanena, substituted 0-4 R4, R8or R15; C2-C7- akinlana, substituted 0-4 R4, R8or R15;

Y is selected from hydroxy, C1-C10-alkoxy, C3-C11- cycloalkane, C6-C10- aryloxy, C7-C11- aralkylated,3-alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl,5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8-C12- aryloxypropanolamine, C8-C12- arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10- (5-alkyl-1,3-dioxa-cyclopenten-2-he - Il)metiloksi or C10-C14- (5-aryl-1,3-dioxa - cyclopenten-2-he-Il)metiloksi;

R4is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylcarboxylic or-N(R12R13;

R6and R7each independently selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, - N(R12R13, cyano, halogen;

R8is selected from: H; C1-C10-alkyl, C2-C10-alkenyl, C3-C8-cycloalkyl, C5-C6- cycloalkenyl, aryl, 5-6-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the heterocycle may be saturated, partially saturated or fully unsaturated;

R12and R0
- alkylsulphonyl, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonyl, arylsulfonyl, heteroarylboronic, heteroarylboronic or aryl;

R14is selected from H, C1-C10-alkyl, C2-C10-alkenyl, C2-C10- quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or - C(=O)N(R12R13;

R5is selected from hydrogen or C1-C10substituted 0-6 R4;

n = 0-4;

q = 2-7;

provided that n and q are chosen so that the number of atoms between R1and Y is in the range of 8-17.

[22] More preferred compounds of this fourth embodiment are those compounds of formula IV,

where R1is R2HN(CH2)qO - or

< / BR>
V is C1-C3-alkylene;

Z1- single bond (i.e., Z1missing) or;

X - C1-C3-alkylene, substituted 0-1 R4;

Y is selected from: hydroxy; C1-C10-alkoxy; methylcarbonate-; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1- (methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy -; is dicarbonitriles- ; 1-(i-propylenecarbonate)ethoxy-: 1 - (cyclohexyloxycarbonyloxy)ethoxy-; 1-(t - butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4 - yl)methoxy-: (5-(t-butyl)-1,3-doxacycline-2-he-4 - yl)methoxy-; (1,3-dioxa-5-phenyl - cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2-methoxypropyl) carbonyloxy)ethoxy-;

R12and R13independently selected from H, C1-C6-alkyl, C1-C4- alkoxycarbonyl, C1-C4- alkylsulphonyl, C1-C6- alkylsulfonyl, aryl(C1-C4- alkyl)sulfonyl, arylsulfonyl, heteroarylboronic, heteroarylboronic or aryl;

R13- H.

[23] Particularly preferred compounds of this fourth embodiment are compounds, or pharmaceutically acceptable salt or prodrug of them, chosen from:

5(R, S)-4-[3-(piperidine-4-yl)Oxymetazoline-5-yl]hydracarina acid;

5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5 - yl]hydracarina acid:

5(R, S)-4-[3-(3- aminopropylsilyl)isoxazolin-5-yl]hydracarina acid:

5(R, S)-4-[3-(piperidine-4-yl)Oxymetazoline-5 - yl]venexiana acid;

5(R, S)-4-[3-(2- aminoethoxymethyl)isoxazolin-5-yl]f the tx2">

[24] the Fifth embodiment of this invention provides a compound of formula I

< / BR>
or a pharmaceutically acceptable salt or prodrug of him,

where b is a single or double bond;

R1is selected from R2a(R3)N-, R2(R3)N(R2N=)C-, R2a(R3)N(CH2)qZ, R2(R3)N(R2N=)C(CH2)qZ-,

< / BR>
or

< / BR>
Z is selected from the connection (i.e. is absent), O, S, S(=O) or S(=O)2;

R2and R3independently selected from: H, C1-C10-alkyl, C2-C6alkenyl,3-C11- cycloalkyl,4-C11- cycloalkenyl,6-C10- aryl, C7-C11- arylalkyl,2-C7- alkylsulphonyl,7-C11- arylcarbamoyl,2-C10- alkoxycarbonyl,4-C11- cycloalkylcarbonyl,7-C11- bicycloalkanes,7-C11- aryloxyalkyl, aryl(C1-C10- alkoxy)carbonyl, alkylcarboxylic or alkoxycarbonylmethyl, C1-C6- arylcarboxylic(C1-C4- alkoxy)carbonyl, C6-C10- arylcarboxylic(C1-C4- alkoxy)carbonyl, C4-C11- cycloalkyl the N=C;

U is selected from: a single bond (i.e., U is not present), -(C1-C7-alkyl)-, -(C2-C7alkenyl)-, -(C2-C7- quinil)-, -(aryl)-, substituted 0-3 R6aor -(pyridyl)-, substituted 0-3 R6a;

V is selected from: a single bond (i.e., V is not present); -(C1-C7- alkyl)-, substituted 0-3 groups independently selected from R6or R7; -(C2-C7alkenyl)-, substituted 0-3 groups independently selected from R6or R7; (C2-C7- quinil)-, substituted 0-3 groups independently selected from R6or R7; -(phenyl)-, substituted 0-2 groups independently selected from R6or R7; -(pyridyl)-, substituted 0-2 groups independently selected from R6or R7; or(pyridazinyl)-, substituted 0-2 groups independently selected from R6or R7;

W is selected from:

< / BR>
< / BR>
< / BR>
X is selected from: a single bond (i.e., X is not present), -(C(R4)2)n-C(R4)(R8)-C(R4)(R4a)-, provided that when n equals 0 or 1, at least one of R4aor R8is not H or stands;

Y is selected from hydroxy, C1-C10-alkyloxy,3-C11-cycloalkane, SUB>3
-C10- alkoxycarbonylmethyl, C2-C10- alkoxycarbonylmethyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C5-C10- cycloalkylcarbonyl, C7-C11- aryloxypropanolamine, C8-C12- aryloxypropanolamine, C8-C12- arylcarboxylic, C5-C10- alkoxycarbonylmethyl, C5-C10- (5-alkyl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi, C10-C14- (5-aryl-1,3-dioxa-cyclopenten-2-he-Il)metiloksi; (R2)(R3)N-(C1-C10-alkoxy)-;

Z' is-C-, -O - or-NR22-;

Z2is-O - or-NR22;

R4is selected from H, C1-C10-alkyl, C1-C10- alkylsulphonyl, aryl, arrangementsismail or cycloalkylation; or two groups R4on adjacent carbon atoms are connected with bond formation (i.e., double or triple bond carbon - carbon);

R4ais selected from H, hydroxy, C1-C10- alkoxy, nitro, N(R5R5a, - N(R12R13, - N(R16R17C1-C10of alkyl, substituted 0-3 R6, aryl, substituted 0-3 R6-alkenyl, C2-C6-quinil, hydroxy, C1-C6- alkoxy, C1-C6- alkylthio, C1-C6- alkylsulfonyl, C1-C6- alkylsulfonyl, nitro, C1-C6- alkylsulphonyl, C6-C10- aryl, -N(R12R13, halogen, CF3CN, C1-C6- alkoxycarbonyl, carboxy, piperidinyl or pyridyl;

R5is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkenyl, C6-C10-aryl, C7-C11- arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

R5ais selected from hydrogen, hydroxy, C1-C8-alkyl, C2to C6alkenyl, C3-C11-cycloalkyl, C4-C11- cycloalkenyl, C1-C6-alkoxy, benzyloxy, C6to C10aryl, heteroaryl, C7-C11- arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

or R5and R5aas substituents on the same nitrogen atom (as in - NR5R5a) can connect with the nitrogen atom to which they are attached, form a 3-azabicycloalkanes, 1,2,3,4-tetrahydro-1 - chinoline, 1,2,3,4-tetrahed the C1-C6-alkyl, C6-C10-aryl, heteroaryl, C7-C11- arylalkyl, C1-C6- alkylsulphonyl,3-C7- cycloalkylcarbonyl, C1-C6- alkoxycarbonyl, C7-C11- arylethoxysilanes, C1-C6- alkylsulfonyl or C6-C10- arylsulfonyl;

R5bis selected from C1-C8-alkyl, C2-C6-alkenyl,3-C11- cycloalkyl,4-C11- cyclooctylmethyl,6-C10-aryl, C7-C11- arylalkyl or C1-C10of alkyl, substituted 0-2 R4b;

R6is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, - N(R12R13, cyano, halogen, CF3CHO, CO2R5C(= O)R5a, CONR5R5a, OC(= O) R5a, OC(= O)OR5b, OR5, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(=O)OR5b, NR5aC(=O)R5a, NR5aC(=O)NR5R5a, NR5aSO2NR5R5a, NR5aSO2R5, S(O)pR5, SO2NR5R5afrom C2to C6alkenyl, from C3to C11cycloalkyl, C41-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mMe, or-NMe2;7to C11arylalkyl, the above optional aryl substituted by 1-3 groups selected from halogen, C1-C6-alkoxy, C1-C6-alkyl, CF3, S(O)mIU or-NMe2; methylendioxy, when R6is the Deputy aryl; or a 5-10 membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R7;

R6ais selected from C1-C4-alkyl, C1-C4-alkoxy, halogen, CF3, NO2or NR12R13;

R7is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, -N(R12R13, cyano, halogen, CF3CHO, CO2R5C(= O)R5a, CONR5R5a, OC(= O)R5a, OC(= O)OR5b, OR5a, OC(=O)NR5R5a, OCH2CO2R5, CO2CH2CO2R5, NO2, NR5aC(=O)R5a, NR5aC(=O)OR5b, NR5aC(=O)NR5R5a, NR5aSO2NR5Kenya, from C3to C11cycloalkyl, C4to C11cycloalkenyl, C6to C10aryl or C7to C11arylalkyl;

R8is selected from: R6; C2-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C2-C10-quinil, substituted 0-3 R6; C3-C8- cycloalkyl, substituted 0-3 R6; C5-C6- cycloalkenyl, substituted 0-2 R6; aryl, substituted 0-3 R6; 5-10-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R6;

R12and R13independently are H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylcarboxylic, C1-C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonium, arylsulfonyl, aryl, C2-C6- alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkylation, C7-C11- arylalkyl, C7-C11- arylcarbamoyl, C4-C11- cycloalkylcarbonyl, C7-C is)carbonyl, where these arily optional substituted by 0-3 substituents selected from the group consisting of: C1-C4-alkyl, C1-C4-alkoxy, halogen, CF3and NO2;

R14is selected from H, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or-C(=O)N(R5R5a;

R15is selected from: H; R6; C1-C10of alkyl, substituted 0-3 R6; C2-C10-alkenyl, substituted 0-3 R6; C1-C10-alkoxy, substituted 0-3 R6; aryl, substituted 0-3 R6; 5-10-membered heterocyclic ring containing 1-2 heteroatom N, O or S, where the aforementioned heterocyclic ring may be saturated, partially saturated or fully unsaturated specified heterocyclic ring substituted 0-2 R6; C1-C10- alkoxycarbonyl, substituted 0-2 R6; CO2R5or-C(=O)N(R12R13;

provided that when b is a double bond, there is only one of R14or R15;

R16is selected from: -C(= O)-O-R18a; -C(=O)-R18b; -C(=O)N(R18b)2; -C(= O)NHSO2R18a; -NH-C(=O)-NH-R18b; -SO2-O-R18b; -SO2-R18a; -SO2-N(R18b)2; -SO2-NHC(= O)OR18b; -P(=S)(OR18b)2; -P(= O)(OR18a)2; -P(=S)(R18a)2; -P(=O)(R18a)2or

< / BR>
R17is selected from: H, C1-C10-alkyl, C2-C6-alkenyl, C3-C11- cycloalkyl, C4-C15- cycloalkenyl, aryl, aryl(C1-C10-alkyl)-;

R18ais selected from C1-C8of alkyl, substituted 0-2 R19; C2-C8-alkenyl, substituted 0-2 R19; C2-C8-quinil, substituted 0-2 R19; C3-C8- cycloalkyl, substituted 0-2 R19; aryl, substituted 0-4 R19; aryl(C1-C6- alkyl)-, substituted 0-4 R19; 5-10-membered heterocyclic system having 1-3 heteroatoms, selected independently from O, S or N, specified heterocyclic ring, substituted 0-4 R19; C1-C6of alkyl, substituted 5-10-membered heterocyclic system having 1-3 heteroatoms, selected independently from O, S or N, specified heterocyclic ring, substituted 0-4 R19;

R18bis selected from R18aor H;

R19is selected from H, halogen, CF3, CN, NO2, NR< 11- cycloalkyl, C4-C11- cycloalkenyl, aryl, aryl(C1-C6- alkyl)-, C1-C6-alkoxy or C1-C4- alkoxycarbonyl;

R20and R21each independently selected from H, C1-C10-alkyl, CO2R5C(= O)R5aCONR5R5a, NR5C(=O)R5a, NR12R13C2-C6- alkenyl, C3-C11- cycloalkyl, C4-C11- cycloalkenyl, C6-C10-aryl or C7-C11-arylalkyl;

R22is selected from C1-C10-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C15- cycloalkenyl, aryl, aryl(C1-C10- alkyl)-; C(=O)R5a, CO2R5b, -C(=O)N(R5R5aor links to X;

m = 0-2;

n = 0-2;

p = 1-2;

q = 1-7;

r = 0-3;

provided that n, q and r are chosen so that the number of atoms linking R1and

Y is in the range of 8-17.

[25] the Preferred compounds of this embodiment are those compounds of formula IC

< / BR>
where Z is selected from the connection (i.e. is absent), O, or S;

R2is selected from H, aryl(C1-C10-alkoxy)carbonyl or C1-C10- alkoxycarbonyl;
10of alkyl, substituted 0-6 R4b;

R6and R7each independently selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10- alkylsulphonyl, - N(R12R13, cyano or halo;

R12and R13independently selected from H, C1-C10-alkyl, C1-C10- alkoxycarbonyl, C1-C10- alkylsulphonyl, C1- C10- alkylsulfonyl, aryl(C1-C10- alkyl)sulfonyl, arylsulfonyl or aryl, where these arily optional substituted by 0-3 substituents selected from the group consisting of: C1-C4-alkyl, C1-C4-alkoxy, halogen, CF3and NO2;

R15is selected from: H; C1-C10-alkyl, C2-C10-alkenyl, C2-C10-quinil, C1-C10-alkoxy, aryl, heteroaryl or C1-C10- alkoxycarbonyl, CO2R5or - C(=O)N(R5R5a;

R16is selected from: -C(=O)-O-R18a; -C(=O)-R18b; -S(=O)2R18a;

R17is selected from: H or C1-C4-alkyl;

R18ais selected from C1-C8-alkyl; substituted 0-2 R19; C2-C8-alkenyl, substituted 0-2 R19; C2-C8
19; aryl(C1-C6- alkyl)-, substituted 0-4 R19; heterocyclic system selected from pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring, substituted 0-2 R19; C1-C6of alkyl, substituted 5-10 membered heterocyclic system, pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring substituted 0-2 R19.

[26] More preferred compounds of this embodiment are the compounds of formula Ib

< / BR>
where R1is selected from R2(R3)N-, R2NH(R2N=)C-, R2R3N(CH2)p-Z-, R2NH(R2N= )CNH(CH2)p'Z-
< or C1-C5-alkyl;

V is a single bond (i.e., V is absent) or -(phenyl)-;

X is selected from: -CH2-, -CHN(R16R17or-CNHR5R5a;

Y is selected: hydroxy; C1-C10-alkoxy; methylcarbonate-; ethylcarboxylate-; t-BUTYLCARBAMATE-; cyclohexylcarbodiimide-; 1-(methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy-; 1-(t-BUTYLCARBAMATE)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; i-propylenecarbonate-; t-butyloxycarbonyl-; 1-(i-propylenecarbonate)ethoxy-; 1 -(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2- methoxypropyl)carbonyloxy)ethoxy-;

R18ais selected from C1-C4of alkyl, substituted 0-2 R19; C2-C4-alkenyl, substituted 0-2 R19; C2-C4-quinil, substituted 0-2 R19; C3-C4-cycloalkyl substituted 0-2 R19; aryl, substituted 0-2 R19; aryl(C1-C4- alkyl)-, substituted 0-2 R19; heterocyclic testsoterone, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring substituted 0-2 R19; C1-C6of alkyl, substituted 5-10 membered heterocyclic system, pyridinyl, furanyl, thiazolyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, chinoline, izochinolina, isoxazoline, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl or morpholinyl specified heterocyclic ring substituted 0-2 R19.

[27] More preferred compounds of this fifth embodiment are the compounds of formula Ib where R1- R2NH(R2N=)C -, or R2NH(R2N=)CNH -, and V is phenyl or pyridyl; or R1is

< / BR>
V is a single bond (i.e., V is absent),

n = 1-2;

R3- H or C1-C5-alkyl;

X is selected from: -CH2-, CHN(R16R17or CHNR5R5a-;

W is selected from

< / BR>
< / BR>
or

< / BR>
m = 1-3;

is carbonyloxy-; cyclohexylcarbodiimide-; 1-(methylcarbonate)ethoxy-; 1-(ethylcarbonate)ethoxy-; 1-(t-BUTYLCARBAMATE)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; i-propylenecarbonate-; t-butyloxycarbonyl-; 1-(i-propylenecarbonate)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyl)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-doxacycline-2-he-4-yl)methoxy-; (5-(t-butyl)-1,3-doxacycline-2-he-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-he-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R19- H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, cyclopropylmethyl, aryl or benzyl;

R20and R21both are H;

R22is H, C1-C4-alkyl or benzyl.

[28] Particularly preferred compounds of this fifth embodiment are the compounds of formula 1b or form of their pharmaceutically acceptable salts, selected from:

2-(R, S)-2-carboxymethyl-1-{ 5-(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5 - ylacetic] piperidine;

2-(R, S)-2-carboxymethyl-1-{ 5-(R,S)-N-[3- (4-amidinophenoxy)isoxazolin-5-ylacetic]azepin;

2-(R, S)-2-carboxymethyl-1-{ 5-(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5 - ylacetic]pyrrolidin;

5-(R, S)-carboxymethyl-1-{ 5-(R,S)-N- [3-(4-amidinophenoxy)isoxazolin-5-ylacetic]pyrrolidin-2-he;

7-(R, S)-carboxymethyl-1-{ 5-(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]azetidin-2-he;

2-(R, S)-carboxymethyl-1-{ 5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5 - ylacetic]pyrazolidine;

3-(R, S)-carboxymethyl-4-{ 5-(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]morpholine.

In the present invention discovered that the above-mentioned compounds of formula I are suitable as inhibitors of the processes of adhesion between the cell and the matrix and between cells. The present invention includes new compounds of formula I and methods of using such compounds for the prevention or treatment of diseases, developing as a result of abnormal adhesion of cells to extracellular matrix, including the introduction of a host in need of such treatment, a therapeutically effective amount of compounds of formula I.

The present invention also discovered that the above-mentioned compounds of formula I are suitable as inhibitors of glycoprotein IIb/IIIa (IIb/IIIa). Compounds of the present invention inhibit the activation and aggregation of platelets caused by all known endogenous agonist of platelets.

rmaceuticals acceptable filler.

The compounds of formula I of the present invention is suitable for the treatment (including prevention) of thromboembolic complications. Used here

the term "thromboembolic complications" includes a state in which the activation and aggregation of platelets, such as arterial or venous cardiovascular or cerebral vascular thromboembolic complications, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, sudden death from coronary heart disease, heart attack, stroke, atherosclerosis, thrombophlebitis, venous thrombosis, thrombosis of deep veins, arterial embolism, thrombosis cardiac and cerebral arteries, myocardial infarction, cerebral embolism, kidney embolism, pulmonary embolism or similar diseases associated with diabetes, including the introduction in need of such treatment to the mammal a therapeutically effective amount of the compounds of formula I, described above.

The compounds of formula I of the present invention may be suitable for treating or preventing other diseases in which processes are clumping of cells, including, but not limited to, inflammatory process, resorption ctiv master", the rejection of transplanted organs, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, tumors, metastases, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases. The compounds of formula I of the present invention may also be useful in the healing of wounds.

Compounds of the present invention are suitable for inhibiting the binding of fibrinogen to platelets, inhibition of platelet aggregation effects on the formation of thrombus or pitch or prevent the formation of thrombus or pitch in mammals. The compounds of this invention can be used as a medication that blocks the effects of fibrinogen to its receptor in mammals.

Compounds of the present invention can be administered to patients of the need to prevent thrombosis by inhibiting the binding of fibrinogen to glycoprotein IIb/IIIa receptor membrane of platelets. They are suitable in surgery on peripheral arteries (arterial of graft, carotid endartectomy) and in cardiovascular surgery where correction of arteries and organs, and/or the interaction of platelets with artificial surfaces shall thromboemboli. Compounds of the present invention may be imposed in such surgical patients to prevent blood clots and thromboembolic.

In cardiovascular surgery for oxygenation of blood is usually used extracorporeal circulation. Platelets stick to the surfaces of the equipment for extracorporeal circulation. The adhesion depends on the interaction between IIb/IIIa on the membranes of platelets and fibrinogen adsorbed on the surface of the equipment. Platelets are taken with artificial surfaces, show impaired homeostatic function. The compounds of this invention can be administered to prevent such aggregation in vivo.

Compounds of the present invention can be used for other in vivo applications to prevent adhesion of cells in biological samples.

Other possible applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic treatment and prevention of platelet thrombosis, thromboembolism and reocclusion after plastic surgery on the coronary and other arteries after coronary artery bypass. Connected the present invention are suitable as thrombolytics for the treatment of thromboembolic complications.

Compounds of the present invention can also be administered in combination with one or more additional drug selected from: anticoagulants, or suppress a coagulation compounds, such as heparin or warfarin; antiplatelet, or suppress platelet compounds, such as aspirin, piroxicam or ticlopidine; thrombin inhibitors, such as biopeptide, hirudin or argatroban; or thrombolytic or fibrinolytic compounds, such as plasminogen activators, anistreplase, urokinase or streptokinase.

The compounds of formula I of the present invention can be administered in combination with one or more of the aforementioned additional drugs in order to reduce the dose of each drug needed to achieve the desired therapeutic effect. Thus, combined treatment of the present invention allows the use of lower doses of each component while reducing toxic side effects of each component. Lower dose reduces the likelihood of side effects joints, providing, thus, an increased factor of safety compared with the coefficient b is to imeetsya for synergistic or additive therapeutic effects in the treatment of thromboembolic complications.

By "therapeutically effective amount" means the amount of the compounds of formula I that, when introduced individually or in combination with an additional drug into the cell or mammal is effective to prevent or decrease the intensity of thromboembolic complications or progression of the disease.

Under "introduced in combination" or "combination therapy" means that the compound of formula I and one or more additional drugs are administered together to a mammal undergoing treatment. With the introduction of the combination of each component may be administered simultaneously or sequentially in any order at different points in time. Thus, each component is entered separately, but close enough in time of introduction in order to provide the desired therapeutic effect.

Used herein, the term "anti-clotting medicines (or suppress a coagulation funds") refers to the tools that interfere with blood clotting. These tools include warfarin (available as CoumadinTM) and heparin.

Used herein, the term "antiplatelet is alaysia aggregation, adhesion or secretion of platelet granular content. These drugs include various known non-steroidal anti-inflammatory drugs (spit), namely aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamic, droxicam, diclofenac, sulfinpirazon and piroxicam, including pharmaceutically acceptable salts or prodrugs. From spit aspirin (acetylsalicylic acid or ASA) and piroxicam. Piroxicam for sale Pfizer Inc. (New York, NY) as FeldonTM. Other suitable antiplatelet drugs include ticlopidine, including pharmaceutically acceptable salts or prodrugs. Ticlopidine is also the preferred connection because it is known that he has when using a weak effect on the gastrointestinal tract. Other suitable inhibit platelet drugs include antagonists of thromboxane A2 receptor and inhibitors of thromboxane A2 synthetase, as well as pharmaceutically acceptable salts or prodrugs of him.

Used herein, the term "thrombin inhibitors (or protivotumanki drugs) denotes the inhibitors of serine protease thrombin. By inhibiting thrombin violated various incidental the platelets and/or secretion granules inhibitor-1 plasminogen activator and/or serotonin and/or fibrin formation. Such inhibitors are derivatives of moreargentina and biopeptide, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs of them. Derivatives moreargentina and biopeptide include N-acetyl and peptide derivatives of Bronevoy acid, namely C-terminal derivatives of alpha-aminoboronic acid, lysine, ornithine, arginine, homoarginine, and the corresponding isothiouronium counterparts. Used here, the term hirudin includes corresponding derivatives or analogs of hirudin, designated here as chirology, namely desulfatohirudin. Biopeptide of thrombin inhibitors include compounds described in Kettner et A1. in U.S. patent N 5187157 and European patent N 293881 A2, the opening of which is incorporated by reference. Other relevant derivatives moreargentina and biopeptide-thrombin inhibitors include those that are open PCT N 92/07869 and European patent N 471651 A2, the opening of which is incorporated herein by reference in full.

Used herein, the term "thrombolytic (or fibrinolytic) connection (or thrombolytics or fibrinolitiki") refers to compounds that dissolve the clot (thrombus). Such compounds include tissue plasminogen activator. Tissue plasminogen activator (TAP) sold Genentech. Inc., South San Francisco, California. Used herein, the term "anistreplase" refers to Anatolievna activating plasminogen streptokinase complex, as described, for example, in European patent N 028489, the opening of which is here incorporated fully by reference. Anistreplase sold as AminataTM. Have in mind that when used herein, the term "urokinase" means urokinase having two and one polypeptide chain, the latter also designated here as the PUK.

Introduction the compounds of formula I of this invention in combination with such additional drug may have advantages in effectiveness compared to the use of compounds and drugs separately and can ensure this by using lower doses of each drug. Lower dose reduces the likelihood of adverse effects, providing, thus, an increased safety factor.

It is known that the expression of IIb/IIIa increased in tumor cell metastasis. Connection or combination products of the present invention may also be useful in the treatment, including prevention of m is in or compounds for comparison, for example, as a quality standard or control, in tests or assays involving binding of fibrinogen to platelet IIb/IIIa. Such compounds can be represented in the form of a sales kit, for example, for use in pharmaceutical research involving IIb/IIIa. Compounds of the present invention can also be used in diagnostic methods, including IIb/IIIa.

These compounds may have asymmetric centers. Unless otherwise stated, all chiral, diastereomeric and racemic forms are included in the present invention. The compounds described herein may exist many geometric isomers of olefins, double bond C= N, etc., All such stable isomers are assumed in this invention. It should be noted that the compounds of the present invention containing asimmetricheskii substituted carbon atoms can be isolated in optically active or racemic forms. It is well known how to obtain optically active form, namely the separation of racemic mixtures or by synthesis from optically active starting materials. Assumed all chiral, diastereomeric, racemic forms and all geometric Saka any variable (for example, but not limited to, R2, R4, R6, R7, R8, R12and R14, n and so on) appears more than once in any item or in any formula, its definition in each case does not depend on its determination for each different case. For example, if it is shown that the group is substituted by 0-2 R4, the above-mentioned group may optionally be substituted with from 0 to 2, R4and in each case, R4is selected independently from the defined list of possible R4. Also, for example for a group-N(R5a)2each of the two substituents R5aN is selected independently from the defined list of possible R5a. Also, for example for a group-C(R7)2- each of the two substituents R7C independently is selected from the defined list of possible R7.

When it is shown that the connection to the Deputy crosses the bond connecting two atoms in the ring, such Deputy may be associated with any atom in the ring. When the link connecting the Deputy with the other group, not specifically shown or specifically not specified atom is attached to another group, such Deputy may form a relationship with any atom in such other group.Inoi part of the compounds of formula I, such Deputy may communicate via any atom in such substituent. For example, when a Deputy is piperazinil, piperidinyl or tetrazolyl, unless otherwise stated, the above piperazinilnom, piperidinyl, tetrataenia group can communicate with the rest of the compounds of formula I via any atom in such piperazinilnom, piperidinyloxy, tetrazolyl group.

The combination of the substituents and/or variables are permissible only if such combinations provide for a stable connection. Under stable connection or stable structure here refers to a connection that is strong enough to withstand the allocation to a suitable degree of purity from a reaction mixture and turn into an effective drug.

Used herein, the term "substituted" means that one or more hydrogen atom in the designated atom is replaced by the selection of a specified group under the condition that you are not exceeding the indicated normal valency of the atom and that the substitution leads to the formation of stable compounds. When a Deputy is keto (i.e., =O), then on the atom are replaced by two hydrogen atoms.

Have in mind that the COI is levoberegnyi radicals, having the specified number of carbon atoms (e.g., "C1-C10" denotes alkyl having 1 to 10 carbon atoms); it is understood that "haloalkyl" includes both branched and unbranched, saturated aliphatic hydrocarbon radicals with the specified number of carbon atoms, substituted by one or more halogen atom (for example-CvFw where v=1-3 and w= 1 to(2v+1)); "alkoxy" represents an alkyl radical with the specified number of carbon atoms attached through an oxygen bridge; have in mind that "cycloalkyl" includes saturated cyclic radical, including mono-, bi - or polycyclic system of rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and substituted; and have in mind that "bicycloalkyl" includes a saturated bicyclic radicals, namely [3.3.0] bicicletta, [4.3.0] bicycleand, [4.4.0]bellocan (decalin), [2.2.2]bicicletta, etc. mean that "alkenyl" includes either branched or unbranched hydrocarbon chain with one or more unsaturated bond carbon - carbon which may be in any stable point in the chain, namely ethynyl, propenyl and so on; and we mean that "quinil includes prosvetlennogo to be in any stable point in a circuit namely ethinyl, PROPYNYL, etc.

The terms "alkylene", "albaniles", "phenylene", etc. denote alkyl, alkeline or phenyl radicals respectively, which are connected by two bonds to the rest of the structure of formula I. Such "alkylen", "albaniles", "phenylene", etc. can alternately and equivalently be referred to here as "-(alkyl)-", "-(alkenyl) - and-(phenyl) -", etc.

Used herein, "halo" or "halogen" refers to fluorine-, chlorine-, bromine - and iodine; and "counterion" is used to denote a small, negatively charged particles, such as chloride, bromide, hydroxide, acetate, sulfite, etc.

Have in mind that when used herein, the term "aryl" or "aromatic residue" refers to phenyl or naphthyl; "arylalkyl" represents an aryl radical attached through an aryl bridge.

Have in mind that when used herein, the term "carbocycle" or "carbocyclic residue" refers to any stable 3-7-membered monocyclic or bicyclic, or 7-14 membered bicyclic or tricyclic or to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles fork or tetrahydronaphthyl (tetralin).

It is implied that used here, the term "heterocycle" or "heterocyclic" refers to a stable 5 to 7-membered monocyclic or bicyclic 7-10 - membered bicyclic heterocyclic ring which may be saturated, partially unsaturated or aromatic, and which consists of carbon atoms and 1-4 heteroatoms independently selected from the group consisting of N, O and S, and where the heteroatoms nitrogen and sulfur may be optionally oxidized, and the nitrogen may optionally have four links, and including any bicyclic radical, in which any of videopreteen heterocyclic ring condensed to the benzene ring. Heterocyclic ring may be attached to it additional group at any heteroatom or carbon atom that results in a stable structure. Described here heterocyclic ring can be substituted on the carbon atom or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophene, indolyl, indolinyl, isoxazolyl, chinoline, ethenolysis, benzopyranyl, tetrahydroisoquinolines, decahydroquinoline or octahydronaphthalene, azocines, triazinyl, 6H-1,2,5-thiadiazine, 2H,6H-1,5,2-detainer, thianthrene, pyranyl, isobenzofuranyl, bromanil, xantener, phenoxethanol, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazole, purinol, 4H-hemolysins. ethenolysis, chinoline, phthalazine, naphthyridine, honokalani, hintline, cinnoline, pteridine, an-carbazole, carbazole, β-carboline, phenanthridine, acridine, pyrimidinyl, phenanthrolines, phenazines, phenarsazine, phenothiazinyl, furutani, phenoxazines, isopropanol, bromanil, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidine, piperazinil, indolinyl, isoindolyl, hinokitiol, popolini or oxazolidinyl. Also included are condensed ring and spiraeoideae containing, for example, the above-mentioned heterocycles.

Used herein, the term "heteroaryl" refers to aromaticheski heterocyclic radicals. Such heteroaryl radicals are preferably 5-6 membered monocyclic radical, but not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothiazol, benzimidazolyl, chinoline or ethenolysis.

Used herein, the term "pharmaceutically acceptable salts" refers to derivatives of open connections where the source compound of formula I is modified by the formation of acidic or basic salts of the compounds of formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids of the basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, etc.

Assume that "prodrugs are any covalently linked fillers, which release the active source drug according to formula I in vivo introduction of such prodrugs mammals. Prodrugs of compounds of formula I are prepared by modifying functional groups of the compounds so that the modified group was tsapralis either the normal way or in vivo from the parent compounds. Prodrugs include compounds EU, which when administered to a mammal cleaved with the formation of free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetates, vomity, benzoate alcohol and functional amino groups of the compounds of formula I, etc. are Examples of typical carboxyl and amino prodrugs are included under the definitions of R2, R3and y

Pharmaceutically acceptable salts of compounds of formula I include the conventional nontoxic salts or Quaternary ammonium salts and the compounds of formula I formed by, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric, etc., and salts derived from organic acids such as acetic, propionic, succinic, glycol, stearic, lactic, malic, tartaric, citric, ascorbic, pamelia, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, econsultation, saugat to be synthesized from compounds of the formula I, which contain a basic or acidic component, conventional chemical methods. Usually salt is produced by interaction of the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in an appropriate solvent or various combinations of solvents.

Pharmaceutically acceptable salts of the acids of formula I with a suitable base, such as hydroxide of alkali or alkaline-earth metal, for example sodium, potassium, lithium, calcium or magnesium, or organic bases, such as amino, such as dibenziletilendiaminom, trimethylamine, piperidine, pyrrolidine, benzylamine etc., or Quaternary ammonium hydroxide, such as hydroxide of Tetramethylammonium.

As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be obtained by the interaction of forms of these compounds in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or mixtures thereof; most preferred non-aqueous environment, such as ether, utilicemos Publishing Company, Easton, PA, 1985, p. 1418, incorporated herein by reference.

All sources mentioned here are incorporated fully by reference.

Synthesis of

Compounds of the present invention can be obtained in different ways, known to experts in the field of organic synthesis. Compounds of the present invention can be synthesized by methods described below, as well as methods known in organic synthesis or varieties known to specialists in this field. Preferred methods include, but are not limited to, methods described below. All these sources are incorporated fully by reference.

In the text the following abbreviations are used:

-Ala - 3-aminopropionic acid

Boc - tert-butyloxycarbonyl

Boc2O - di-tert-BUTYLCARBAMATE

BSTFA - N,O-bis(trimethylsilyl)cryptomelane

Cbz - benzyloxycarbonyl

DCC - 1,3-dicyclohexylcarbodimide

DEAD - diethylazodicarboxylate

DEC hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DIEA - diisopropylethylamine

DCHA - dicyclohexylamine

DCM - dichloromethane

DMAP - 4-dimethylaminopyridine

DMF - N,N-dimethylformamide

EtOAc - ethyl acetate

EtOH - ethanol

clinimed

NMM is N-methylmorpholine

PPh3- triphenylphosphine

pyr is pyridine

TBTU - 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate

TFA - triperoxonane acid

THF - tetrahydrofuran

The traditional method of synthesis of compounds of this invention include dipolar cycloaddition of nitrile oxides to the corresponding dipolarophiles to get isoxazoline rings present in the compounds of formula I (for reviews of the chemistry of 1,3-dipolar cycloaddition, see 1,3-Dipolar Cycloaddition Chemistry (Padwa. ed. ), Wiley, New York. 1984; Kanemasa and Tsuge, Heterocycles 1190,30,719).

In scheme I (see below) shows the sequence of the synthesis of compounds of the second embodiment of this invention. Accordingly substituted hydroxylamine is processed NCS in DMF according to the method of Liu et al. (J. Org. Chem. 1980, 45, 3916). The resulting chloride of hydroximino then dehydrohalogenated in situ using TEA to obtain a nitrile oxide, which undergoes 1,3-dipolar to ticlopidine to respectively replaced with the alkene, giving isoxazolin. Or the oxime may be oxidizing chlorinated, dehydrochlorination and the resulting nitrile oxide catch the corresponding alkene in terms of transfer phases in accordance with the laws of the Sabbath. ical synthesis, gives the desired acid. The intermediate compounds containing alkali sensitive functional groups such as nitrile, can be chipped off the ether with excellent hemispherically using trimethylsilanol sodium in accordance with the method Laganis and Ehenard (Tetrahedron Lett. 1984, 25, 5831). The connection of the resulting acid with appropriately substituted alpha - or beta-aminoethanol using standard reagents, such as DCC/HOBt to obtain nitriloside. Then the nitrile is converted to amidin through imidate or thioimidate under standard conditions with subsequent saponification of the ester (LiOH, THF/H2O).

An example of a related method of producing compounds of the second embodiment of the present invention is presented in scheme Ia (see the end of the description). The conversion of 3-(4-cyanophenyl) -isoxazolin-5-yl-acetic acid in the corresponding amidin with further protection in the form of Re-derived and saponification gives 3-(4-BOC-lidinopril)isoxazolin-5-yl-acetic acid, which is connected, as shown, with ether beta-amino acids. The office of the protector gives the desired beta-aminoadenine esters isoxazolecarboxylic acid. Described saponification gives the free acid.

Another example of the synthesis of compounds of Deuteronomy is formyloxy method, described Gree et al. (Bioorganic and Med. Chem. Lett. , 1994, 253) gives t-butyl[5-(4-cyanophenyl)isoxazolin-3 - yl] acetate. Using the described methods, this intermediate compound is converted into a compound of formula I, where isoxazoline ring back is oriented with respect to the compounds obtained in schemes I and Ia.

Other isoxazolidinone, suitable as starting compounds for preparing compounds of the formula I, in which V is - (phenyl)-Q -, and Q is a single bond, can be obtained by cyclopentadiene respectively substituted by chlorine or Bromhexine to air vinylalcohol acid as shown in scheme IB (see below), using the literature methods or their modifications (D. P. Curran & J. Chao, J. Org. Chem. 1988, 53, 5369-71; J. N. Kim & E. K. Ryu, Heterocycles, 1990, 31, 1693-97).

Compounds of the present invention, where R2or R3is, for example, alkoxycarbonyl, can be obtained by the interaction of free amidines, amines or guanidines with activated derivatives of carbonyl, such as alkylphosphoric. The compounds of the second embodiment of the transformation of the free amines, amidines and guanidines in such groups acyl-nitrogen can optional be done before connection isoxazolines kislotami Y - oxoalkoxide radical, for example alkoxycarbonylmethyl, can be obtained by the interaction of the correspondingly substituted carboxylic acid of the formula I, for example alkoxycarbonylmethyl, in the presence of a source of iodine, such as tetrabutylammonium iodide or potassium iodide, and acid acceptor, such as triethylamine or potassium carbonate, using methods known in the art.

Accordingly substituted racemic beta amino acids can be bought or, as shown in scheme II (see end of description), method 1, to obtain from the corresponding aldehyde, malonic acid and ammonium acetate according to the method of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299). Esters of racemic beta-substituted-beta-amino acids can be obtained through interaction dialkylamino or alkylate 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol (scheme II, method 2) or by reductive amination of beta-ketoesters, as described in WO 9316038 (see also Rico et al., J. Org. Chem. 1993, 58, 7948-51). Enantiomerically pure beta-substituted-beta-amino acids can be obtained through the optical splitting mixtures of racemates or you can get them using numerous methods, including: obtaining homologs to meet the TOD 3 (see Meier and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32: Rodriquez et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and quoted them in the sources); and through enantioselective hydrogenation of dehydrolinalool, as shown in scheme II, method 4 (see Asymmetric Synthesis. Vol. 5, (Morrison, ed.) Academic Press, New York 1985). A comprehensive survey of obtaining derivatives of beta-amino acids can be found in the patent application WO 9307867, the opening of which is here incorporated by reference.

The synthesis of derivatives of N2-substituted diaminopropionic acid can be performed through the Hoffmann rearrangement of the different derivatives of asparagine as described in Synthesis, 266-267 (1981).

Accordingly substituted pyrrolidin-, piperidine -, and hexahydroazepin acetic acid can be obtained using a large number of methods. Pyrrolidine usually get the reaction of the Arndt-Eistert from the corresponding Proline, as shown in scheme III (see the end of the description), method 1 (see Meier and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriquez et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and quoted them in the sources). Piperidine can be obtained by recovering the corresponding pyridine, as shown in scheme III, method 2. Hexahydroazepin receive the appropriate recovery winlogonexe amide using tzia is installed heterocycles are commercially available or can be easily modified by methods known in the art. Accordingly substituted morpholines can be obtained from amino acids through the sequence of steps shown in scheme IIIA (see the end of the description), method 1 (see Brown et al., J. Chem. Soc. Perkin Trans I, 1987, 547; Bettoni et al. Tetrahedron 1980, 36, 409; Clarke, F. H. J. Org. Chem. 1962, 27, 3251 and cited sources).

N-ethoxycarbonylmethyl-1,2-dietetically get condensation respectively substituted dibromide with benzylpiperazine with subsequent reaction Mitsunobu with ethyl acetate and removal of the protector, as shown in scheme IIIa, method 2 (see Kornet, et al. J. Pharm. Sci 1979, 68, 377; Barcza, et al. J. Org. Chem. 1976, 41, 1244 and cited sources).

General Protocol for the synthesis of compounds of the first embodiment of this invention depicted in scheme IV (see the end of the description). Is the connection of the appropriate BOC-protected amerosport with appropriately substituted phenol under conditions Mitsunobu (see Mitsunobu, Synthesis 1981, 1), followed by oxymorphine at participation means of hydrochloric acid hydroxylamine in ethanol/pyridine (1: 1). The formation of isoxazoline, saponification of the ester and Boc cleavage (33% TFA/DCM) gives compounds of this invention with good yield.

Synthesis pyrocondensation imides of isoxazoline the third embodiment of the present invention presents absimiliard to alpha-methylene ether, dibasic acid gives isoxazolines fluids, which otscheplaut ether using silanolate. Dehydration to the anhydride by Ishihara et al. (Chem. Pharm. Bull. 1992, 40, 1177-85) with subsequent formation of imide using correspondingly substituted aminoether gives spirits. Or imide can be obtained directly from diapir of isoxazoline according to Culbertson et al. (J. Med. Chem. 1990, 33, 2270-75). Education amidine or Boc cleavage with subsequent saponification of the ester gives the compounds of this invention with good yield.

Synthesis pyrocondensation isoxazolines amides of the third embodiment of the present invention represented by the General Protocol depicted in scheme VI (see end of description). Dipolar cycloaddition of hydroxymandelate to alpha metilenlaktony gives isoxazolines, which interacts with a corresponding aminoethanol with the formation of the amide (see The Chemistry of The Amides (Zabicky, ed. ), p. 96, Interscience, New York, 1970; Prelog et al. Hely. Chim. Acta. 1959, 42, 1310; Inubushi wr al., J. Chem. Soc., Chem. Commun. 1972, 1252). Education amidine or Boc cleavage with subsequent saponification of the ester gives the compounds of this invention with good overall yield.

Synthesis pyrocondensation isoxazolines of cycloalkenes the third embodiment of the present invention represented by the General Protocol, the image is substituted on the alpha metilenlaktony gives isoxazolines. Then spend the interaction of the lactone with the corresponding dimethylaminophenol lithium, followed by PCC oxidation. The resulting dicationic undergoes intramolecular reaction of Witting in the presence of K2CO3/18-crown-6 in accordance with the method described by Lim and Marquez (Tetrahedron Lett. 1983, 24, 5559). Education amidine or cleavage of the BOC with subsequent saponification of the ester gives the compounds of this invention with good overall yield.

Dipolarophiles used to obtain the compounds of the present invention, it is possible to get numerous methods. Ether-albanology acid, one of the classes of dipolarophiles, you can buy or get by oxidation of the corresponding-alkenols by the method of Corey and Schmidt (Tetrahedron Lett. 1979, 399, scheme VIII (see the end of the description), method 1). Alpha-methylene ester of dibasic carboxylic acids and alpha-metilenlaktony, another class of dipolarophiles, you can buy or be obtained in various ways from the corresponding ester of dibasic acid (see Osbond., J. Chem. Soc. 1951, 3464; Ames and Davey, J. Chem. Soc. 1958, 1794; Hiroi, J. Che. Soc., Chem. Commun. 1972, 1317, scheme VIII, method 2). 3-(styrene)propionic ester can be obtained catalyzed by palladium cross-coupling respectively substituted bromine - or iodine-beta-pen, 25, 508, scheme VIII, method 3).

The compounds of formula I in which b is a double bond, can be obtained using one of the paths listed in scheme IX (see the end of the description). Bromination and subsequent dehydrobrominated correspondingly substituted methyl 3- (cyanophenyl)isoxazolin-5-ilaclama obtained as described above, using the method Elkasaby & Salem (Indian J. Chem., 1980, 1913, 571-575), gives the corresponding intermediate compound isoxazol. Or this intermediate product can be obtained 1,3-dipolar-cyclopentadiene oxide cyanoaniline (obtained from the corresponding chloroxine as described in scheme I) to the corresponding alcino education directly isoxazol. Hydrolysis of the ester traditional methods known to experts in the field of organic synthesis, gives acetic acid. The connection of the resulting acid with appropriately substituted alpha - or beta - aminoethanol using standard reagents such as TBTU, gives the nitrile-amide. Then the nitrile seem imidan through imidate or thioimidate under standard conditions with the formation of ester prodrugs. Saponification leads to the formation of acids.

The compounds of formula I, where R1is (R2)(R3)N(REnie correspondingly N-substituted aminophenylalanine to t-butyl ether

vinylalcohol acid under the conditions described above gives t-butyl[3-(4-t - butyloxycarbonyl)isoxazolin-5-yl]acetate. Hydrolysis of the ester with lithium hydroxide gives the free acid which can be coupled with appropriately substituted methyl 3-aminopropionic, as described previously. After removal of the protective group of the aniline is converted to the corresponding guanidine according to the method described by Kim et al. (Tetrahedrom Lett., 1993, 48, 7677). The final stage of removal of Boc-group gives guanidinoacetate formula I.

The compounds of this invention and obtaining them can be further understood from the following methods and examples, which illustrate but do not limit the scope of this invention.

Example 1

3-[4-(2-piperidine-4-yl)ethoxyphenyl] -(5R, S)- isoxazolin-5-yl-acetic acid, salt triperoxonane acid

Part A. Obtaining 2-(4-N-t-butyloxycarbonyl)ethanol.

This substance was obtained from 4-piperidine-2-ethanol in accordance with European patent application, publication number 478363 A2.

Part B. 4-[(2-N-t-butyloxycarbonyl-4 - yl) ethoxy]benzaldehyde.

To a solution of 2-(4-N-t-butyloxycarbonyl)ethanol (7,71 g, 33.6 mmol), 4-hydroxybenzaldehyde (4.11 g, 33.6 mmol) and Rocesse adding the formed solution of saturated red color, which changed the color to gold when heated overnight (18 h) to room temperature. At this point, the solution was concentrated and pererestorani in EtOAc. Then it was washed with water, 0.1 M HCl, 1 M NaOH, saturated NaCl and dried (MgSO4). Concentration gave a solid residue (about 20 g) which was purified flash chromatography (stepwise gradient 10-20-30-40-50% EtOAc/hexane) to give after reaching constant weight of 7.82 g (70%) of the desired ether; tPL76,4 -79,7oC;1H NMR (300 MHz, CDCl3) 9,88 (s, 1H), 7,83 (d, J=8,4 Hz, 2H), 6,98 (d, J=8,4 Hz, 2H), 4,10 (bd, J= 12,8 Hz, 2H), Android 4.04 (t, J=6.6 Hz, 2H), 2,69 (bt, 2H), of 1.84 (m, 2H), 1,70 (bd, J=14,3 Hz, 2H), of 1.46 (s, 9H, overlapping with m, 2H), 1,10 (m, 2H).

Part C. 4-[(2-N-t-butyloxycarbonyl-4 - yl)ethoxy]benzaldoxime.

To a solution of 4-[(2-N-t-butyloxycarbonyl-4-yl)ethoxy]benzaldehyde (3,16 g, 9,48 mmol) in MeOH (20 ml) was added hydrochloric acid hydroxylamine (1.27 g, and 18.3 mmol) and 2 M NaOH (7 ml, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 h). the pH of the mixture was brought to 1 M HCl and 4, and then the mixture was filtered and washed with water. The crystals were dried under vacuum over P2O5getting 2,88 g (87%); tPLto 114.4-116,1oC;1H NMR (300 MHz, CDCl3) of 8.09 (s, 1H), 7,51 (d, J=8,8 Hz, 2H), 6.89 in (d, J=8,8 Hz, 2H), 4,10 (b, 2H)si] benzaldoxime chloride.

To a solution of 4-[(2-N-t - butyloxycarbonyl-4-yl)ethoxy] benzaldoxime (955 mg, is 2.74 mmol) in DMF (5 ml) was added in three portions NCS (366 mg, is 2.74 mmol). After 2 h, the solution was diluted with EtOAc and washed with water, saturated NaCl, dried (MgSO4) and concentrated. The resulting solid residue was recrystallized from ether/hexane, getting 548 mg (52%) of oxymyoglobin; tPL119,3-119,9oC;1H NMR (300 MHz, CDCl3) of 8.37 (bs, 1H), to 7.77 (d, J= 8,8 Hz, 2H), to 6.88 (d, J=8,8 Hz, 2H), 4,12 (bd,J=13,2 Hz, 2H), Android 4.04 (t, J= 6.2 Hz, 2H), 2,72 (bt, J=12.1 Hz, 2H), 1.70 to (m, 5H), of 1.46 (s, 9H), 1,10 (m, 2H).

Part D. Methyl 3-[4-{(2-N-t-butyloxycarbonyl-4 - yl)ethoxy}phenyl]-(5R,S) -isoxazolin-5-ylacetic.

To a solution of 4-[(2-N-t-butyloxycarbonyl-4-yl)ethoxy] benzaldoxime chloride (400 mg, 1,045 mmol) and methyl 3-butenoate (200 mg, 2.00 mmol) was added TEA (0.15 ml, 1.1 mmol). The resulting suspension was heated under reflux 5 h, cooled to room temperature and diluted with EtOAc. Then washed with 0.1 M HCl, water, saturated NaCl, dried (MgSO4) and concentrated. The resulting solid residue was recrystallized from DCM/hexanol getting 357 mg (77%) of isoxazoline; tPL139,1 - 140,9oC;1H NMR (300 MHz, CDCl3) to 7.59 (d, J=8,8 Hz, 2H), make 6.90 (d, J=8,8 Hz, 2H), 5,08 (m, 1H), 4,10 (bd, J5,8, 7.7 Hz, 1H), 1,72 (m, 5H), of 1.46 (s, 9H), of 1.08 (m, 2H).

Part E. 3-[4-{(2-N-t-butyloxycarbonyl-4 - yl)ethoxy}phenyl]-(5R,S) -isoxazolin-5-yl-acetic acid.

To a solution of 3-[4-{(2-N-t-butyloxycarbonyl-4-yl)ethoxy} phenyl]- (5R, S)-isoxazolin-5-ilaclama (47 mg, 0,105 mmol) in THF (2 ml) was added 0.5 M LiOH (1 ml, 0.5 mmol). The mixture was stirred 5 h at room temperature, then acidified to pH 3 with 0.1 M HCl. The mixture is washed with DCM and the combined organic fraction was dried (MgSO4) and concentrated. The resulting solid residue was recrystallized from EtOAc/hexanol. receiving 34 mg (74%) carboxylic acid; tPL169,1-170,6oC;1H NMR (300 MHz, CDCl3) 7,60 (d, J= 8,8 Hz, 2H), 6,91 (d, J=8,8 Hz, 2H), 5,10 (m, 1H), 4,08 (bd, 2H, overlapping with t, J=5,9 Hz, 2H), 3,55 (dd, J=16.5, and a 10.2 Hz, 1H), 3,11 (dd, J=16,8, 7,0 Hz, 1H), 2,93 (dd, J=16,1, 6.2 Hz, 1H), 2,71 (m, 3H), 2,00 (m, 2H), 1,72 (m, 5H), of 1.46 (s, 9H).

Part G. of 3-[4-(2-piperidine-4-yl) ethoxyphenyl]-(5R,S)- isoxazolin-5-yl-acetic acid, salt triperoxonane acid.

To a solution of 3-[4-{(2-N-t-butyloxycarbonyl-4 - yl) ethoxy}phenyl]- (5R, S)-isoxazolin-5-yl-acetic acid (53 mg, 0.12 mmol) in DCM (2 ml) was added TFA (1 ml, 13 mmol). After 1.5 h the product was led by addition of ether, receiving 33 mg (60%) amino acids; tPL142,4-143,1oC;1 is C, 2H), and 3.16 (ddd, J=17,2, 7,7, 2.2 Hz, IH), 2,98 (bt, J=13,2 Hz, 2H), 2,69 (m, 2H), 2,01 (bd, J=14,3 Hz, 2H), 1.91 a (m, 1H), 1,80 (m, 2H), 1,46 (m, 2H).

Example 4

(2S)-(5R, S)-[3-[4-{ (2-piperidine-4 - yl)ethoxy} phenyl]isoxazolin-5 - yl{ [(benzyloxy)carbonyl] amino}]acetate, salt triperoxonane acid

Part A. Benzyl-L-2-[[(benzyloxy)carbonyl] amino]-3-butenoate.

This compound was obtained from alpha-benzyl ester of N-Cbz-L - glutamic acid according to Krol et al. (J. Org. Chem. 1991, 728).

Part b: Benzyl (2S)-(5R,S)-[3-[4-{(N-t - butyloxycarbonyl-4 - yl)ethoxy} phenyl] isoxazolin-5 - yl{[benzyloxy)carbonyl] amino}]acetate.

To a solution of 4-[(2-N-t - butyloxycarbonyl-4-yl)ethoxy]benzaldoxime (852 mg, 2,44 mol) and benzyl L-2- [[benzyloxy)carbonyl]amino]-3-butenoate (612 mg, 1.88 mmol) in DCM (10 ml) was added 5% NaOCl (common household bleach, 4 ml, 2.8 mmol). The mixture was rapidly stirred at room temperature for 22 h, then was diluted with water and DCM. After separation of the layers the aqueous layer washed with DCM (3x). The combined organic extracts were dried (MgSO4) and concentrated in vacuo, obtaining 1,4, Subsequent purification with flash chromatography (10% EtOAc/hexane - 30% EtOAc/hexane) gave 886 mg (70%) of oily product in the form of a mixture of 2.5:1 Erythro - and threo-isomers is with a 4.03 t, J=6,1 Hz, 4H), to 3.36 (m, 2H), 2,71 (bt, J=a 12.7 Hz, 2H), 1.70 to (m, 5H), 1,45 (s, 9H), of 1.18 (m, 2H).

Calculated for C38H45N3O8: 67,93; H 6,76; N 6,26. Found: 67,95; H 6,77; N 6,17.

Part C. (2S)-(5R, S)-[3-[4-{ (2-N-t - butyloxycarbonyl-4-yl)ethoxy} phenyl] isoxazolin-5 - yl{[(benzyloxy)carbonyl] amino}] acetic acid.

A solution of benzyl (2S)-(5R, S)-[3-[4- {(N-t-butyloxycarbonyl-4 - yl)ethoxy}phenyl] isoxazolin-5 - yl{[benzyloxy)carbonyl] amino}]acetate (875 mg, 1,302 mmol) in THF (5 ml) omilami for 5 h with 0.5 M LiOH (3.5 ml) according to example 1, part g To the crude product was added methanol, causing the crystallization of one of the diastereomers. Filtering and pumping to constant weight gave 295 mg (39%); tPL216,1oC;1H NMR (400 MHz, DMSO-d6, 80oC) to 7.50 (d, J=8,9 Hz, 2H), 7.23 percent (s, 5H), of 6.96 (d, J=8,9 Hz, 2H), 6,17 (bs, 1H), 4,99 (m, 3H), 4,07 (t, J=6,1 Hz, 2H), 3,90 (m, 3H), 3,35 (d, J=9,3 Hz, 2H), 2,72 (bt, J=12,4 Hz, 2H), 1,67 (m, 5H), of 1.39 (s, 9H), of 1.08 (m, 2H). The filtrate was concentrated in vacuo and pumped until reaching constant weight, receiving 200 mg (26%) of carboxylic acids in the form of a mixture of Erythro - and threo-isomers; TLC (silica gel 60; 20% MeOH/CHCl3) Rf= 0,23. Mass spectrum (ESI, e/z, relative abundance) 582 (M+N)+, 32%; 526 (M-C4H9+ H2)+, 100%; 482 (M-Boc + H2)+, 91%.

From (2S)-(5R, S)-[3-[4-{(2-N-t - butyloxycarbonyl-4-yl) ethoxy} phenyl] isoxazolin-5-yl{ [(benzyloxy) carbonyl]amino}]acetic acid (23 mg, 0,039 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part 3, receiving 15 mg (79%); tPL302oC (decomposition); 1H NMR (400 MHz, DMSO-d6, 60oC) EUR 7.57 (d, J=8,8 Hz, 2H), 7,30 (s, 5H), of 6.99 (d, J=8,8 Hz, 2H), of 5.05 (s, 2H, coincides with m, 1H), 4,35 (d, J=4.9 Hz, 1H), 4.09 to (t, J=6,l Hz, 2H), 3,52 (dd, J=17,3 and 10.7 Hz, 1H), 3,26 (m, 3H), 2,88 (dt, J=12,7, 2.7 Hz, 2H), 1,88 (bd, J=14,4 Hz, 2H), 1,80 (m, 1H), 1,72 (m, 2H), 1,38 (m, 2H).

Part G'. (2S)-(5R,S)-[3- [4-{(2-piperidine-4 - yl)ethoxy} phenyl]isoxazolin-5 - yl{[(benzyloxy) carbonyl]amino}]acetic acid (isomer B).

From (2S)-(5R, S)-[3-[4-{(2-N-t-butyloxycarbonyl-4-yl) ethoxy} phenyl] isoxazolin-5-yl{ [(benzyloxy) carbonyl]amino}]acetic acid (23 mg, 0,039 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part 3, receiving 3 mg (2%) TFA salt; tPL> 400oC;1H NMR (400 MHz, DMSO-d6, 60oC) 8,48 (bs, 0.5 H), 8,15 (bs, 0.5 H), 7,55 (d, J=8,9 Hz, 2H), 7,30 (m, 5H), 6,97 (d, J=8,9 Hz, 2H), of 5.05 (s, 2H), 4,96 (m, 1H), 4,33 (m, 1H), 4,07 (t, J= 6.3 Hz, 2H), 3,38 (m, 2H), 3,26 (bd, J=12.0 Hz, 2H), 2,87 (m, 2H), 1,86 (bd, J= 14,2 Hz, 2H), 1,78 (m, 1H), 1.70 to (apparent q, J=6.3 Hz, 2H), 1,36 (bq, J= 13,2 Hz, 2H).

Example 6

3-(3-[4-(piperidine-4-ylethoxy) phenyl] -(5R, S)- isoxazolin-5-yl)propionic acid, salt Proc. of UEMOA solution utilityperson (20,01 g, 0,1273 mol) in EtOAc (100 ml) at 0oC was added dropwise a solution of Boc2On (27,76 g, 0,1272 mol) in EtOAc (50 ml). The mixture was allowed to warm to room temperature over night. After 20 h the mixture was washed with water, 0.1 M HCl, saturated NaHCO3, saturated NaCI, and dried (MgSO4). Concentration and pumping under vacuum until reaching constant weight gave 32,54 g (99%) of the desired carbamate in the form of low-viscosity oil;1H NMR (300 MHz, CDCl3) of 4.13 (q, J=7,0 Hz, 2H), 4,03 (dm, J=13,6 Hz, 2H), 2,81 (m, 2H), 2,41 (m, 1H), 1,86 (dm, J= 13,6 Hz, 2H), 1,62 (m, 2H), of 1.44 (s, 9H), 1,24 (t, J=7.0 Hz, 3H).

Part B. N-t-butyloxycarbonyl-4-ylmethanol.

To a solution of ethyl N-t-butyloxycarbonyl-4-carboxylate (32,34 g, 0,1257 mol) in THF (100 ml) was added dropwise at 0oC 1 M LAH in THF (87,9 ml, 0,0879 mol). After 2 h, the excess hydride was suppressed by addition of water (3.2 ml), 2 M NaOH (3.2 ml) and water (10 ml). The mixture was filtered, washed with EtOAc and the filtrate was washed with water, feast upon. NaCl, dried (MgSO4) and concentrated. Pumping to constant weight gave 22,72 g (84%); tPL79,2-81,1oC;1H NMR (300 MHz, CDCl3) 4,12 (bd, J= 12,8 Hz, 2H), 3,49 (d, J=6.2 Hz, 2H), 2,68 (dt, J= 13,2 Hz, 2H), 1.69 in (m, 3H), of 1.44 (s, 9H overlap of the c m, 1H), 1.14 in (m, 2H).

Part C. 4-(N-t-butyloxycarbonyl-4-ylethoxy)- benzal is,5 mmol) and PPh3(9,59 g of 36.5 mmol) in THF (100 ml) at -20oC was added DEAD (of 5.75 ml of 36.5 mmol) in THF (50 ml) according to example 1, part B, getting to 8.14 g (70%); tPL115,6-116,8oC; 1H NMR (300 MHz, CDCl3) 9,86 (s, 1H), 7,81 (d, J=8,8 Hz, 2H), of 6.96 (d, J= 8.8 Hz, 2H), 4,15 (bd, J=13,2 Hz, 2H), a 3.87 (d, J=6.6 Hz, 2H), 2,74 (dt, J= 12,4, 1.8 Hz, 2H), of 1.97 (m, IH), 1,81 (bd, J=12,8 Hz, 2H), 1,45 (s, 9H), 1.27mm (dq, J= 12,1, 4.0 Hz, 2H).

Part, 4-(N-t-butyloxycarbonyl-4 - ylethoxy)benzaldoxime.

A mixture of 4-(N-t-butyloxycarbonyl-4 - ylethoxy)-benzaldehyde (3,16 g, 9,89 mol) and hydrochloric acid hydroxylamine (1.27 g, and 18.3 mmol) in MeOH/pyridine (9: 1, 30 ml) was heated under reflux for 18 hours the Mixture was cooled to room temperature and concentrated until dry. The residue was dissolved in EtOAc and washed with 0.1 M HCl (3x), water, saturated CuSO4(2x), water, saturated NaCl, dried (MgSO4) and concentrated, obtaining 3,19 g (96%) of oxime; tPL140,1-141,8oC;1H NMR (300 MHz, CDCl3) 8,07 (s, 1H), of 7.48 (d, J=8,8 Hz, 2H), 6,86 (d, J=8,8 Hz, 2H), 4,14 (bs, 2H), 3,80 (d, J=6.2 Hz, 2H), 2,71 (bt, J= 12,4, Hz, 2H), 1,95 (m, 1H), 1,80 (bd, J= 12,4 Hz, 2H), 1,45 (s, 9H), 1.26 in (m, 2H).

Part D. 4-(N-t-butyloxycarbonyl-4-ylethoxy) benzaldoxime chloride.

4-(N-t-butyloxycarbonyl-4 - ylethoxy)benzaldoxime (3,19 g, 9,54 mmol what I hydroxyisovalerate (1,17 g, 33%); tPL178,0-179,8oC; 1H NMR (300 MHz, CDCl3) of 7.75 (d, J= 9.0 Hz, 2H), 6,86 (d, J=9.0 Hz, 2H), 4,17 (bd, J=12,4 Hz, 2H), 3,80 (d, J= 6.2 Hz, 2H), 1,95 (m, 1H), 1,81 (bd, J=12.1 Hz, 2H), of 1.46 (s, 9H), 1.27mm (dq, J=12,5, 4.0 Hz, 2H).

Part E. Methyl 3-(3-[4-(N-t - butyloxycarbonyl-4 - ylethoxy)phenyl] -(5R,S)-isoxazolin-5-yl)propionate.

4-(N-t-butyloxycarbonyl-4-ylethoxy)benzaldoxime chloride (738 mg, 2.00 mmol), methyl 4-pentenoate (230 mg, 2.02 mmol) and TEA (of 0.28 ml, 2.0 mmol) was heated under reflux for 1 h in accordance with example 1, part D. Crystallization from ether/hexanol give 537 mg (60%); tPLis 97.9 to 99.9oC;1H NMR (300 MHz, CDCl3) EUR 7.57 (d, J=9.0 Hz, 2H), 6.87 in (d, J= 9.0 Hz, 2H), 4,74 (m, 1H), 4,15 (bd, J=13,2 Hz, 2H), 3,81 (d, J=6.2 Hz, 2H), to 3.67 (s, 3H), 3,40 (dd, J=16.5, and a 10.2 Hz, 1H), 2,95 (dd, J=l6,5, and 7.3 Hz, 1H), 2,73 (dt, J= 13,2, 1,1 Hz, 2H), 2,52 (t, J=7,3 Hz, 2H), 1,98 (q, J=7,0 Hz, 2H, overlapping m, 1H), 1,81 (bd, J=12,8 Hz, 2H), 1,45 (s, 9H), 1.26 in (dq, J=12,4, and 3.7 Hz, 2H).

Part G. of 3-(3-[4-[N-t-butyloxycarbonyl-4 - ylethoxy) phenyl] -(5R,S)-isoxazolin - 5-yl)propionic acid.

Methyl 3-(3-[4-(N-t-1 - butyloxycarbonyl-4 - ylethoxy) phenyl]-(5R, S)- isoxazolin-5-yl)propionate (250 mg, 0,560 mmol) omilami using a 0.5 M LiOH (2 ml, 1 mmol) in THF (2 ml). The reaction mixture was stirred for 3 h at room temperature according to note the acid; tPL146,5-a 147.7oC;1H NMR (300 MHz, CDCl3) EUR 7.57 (d, J=8,8 Hz, 2H), to 6.88 (d, J=8,8 Hz, 2H), and 4.75 (m, 1H), 3,81 (d, J=6.2 Hz, 2H), 3,41 (dd, J=16.5, and 10.3 Hz, 1H), 2,95 (dd, J=16.5, and 7,3 Hz, 1H), 2,75 (bt, J=12,4 Hz, 2H), 2.57 m (t, J=7,3 Hz, 2H), of 1.97 (m, 3H), 1,81 (bd, J= 12.1 Hz, 2H), 1,45 (s, 9H), 1,24 (m, 2H).

Part z 3-(3-[4-(piperidine-4-ylethoxy) phenyl]-(5R,S)- isoxazolin-5 - yl)propionic acid, salt triperoxonane acid.

From 3-(3-[4-(N-t - butyloxycarbonyl-4 - ylethoxy) phenyl]-(5R,S)- isoxazolin-5-yl)propionic acid (103 mg, 0,238 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part G, receiving 88 mg (83%) TFA salt; tPL179,1 - 181,8oC;1H NMR (400 MHz, MeOH-d4) 7,60 (d, J=9.0 Hz, 2H), 6,97 (d, J=9.0 Hz, 2H), 4,73 (m, 1H), 3,94 (d, J=6,1 Hz, 2H), 3.46 in (m, 3H), 3,06 (m, 3H), of 2.45 (dt, J=7,3, 1.2 Hz, 2H), 2,16 (m, 1H), 2,08 (bd, J=15,4 Hz, 2H), was 1.94 (q, J=6,6 Hz, IH), 1,64 (dq, J=14,2 Hz, 2H).

Example 7

3-[4-(piperidine-4-ylethoxy)phenyl] -(5R,S)- isoxazolin-5-ilocana acid, salt triperoxonane acid

Part A. Methyl 3-[4-((N-t - butyloxycarbonyl-4 - ylethoxy)phenyl]- (5R,S)-isoxazolin-5-ylacetic.

Chloride 4-(N-t-butyloxycarbonyl-4-ylethoxy) benzaldoxime (412 mg, 1.12 mmol), methyl 3-butenoate (200 mg, 2.00 mmol) and TEA (of 0.18 ml, 1.3 mmol) was heated under reflux for 2 h according to example 1, part D. Krystallis,8 Hz, 2H), to 6.88 (d, J=8,8 Hz, 2H), 5,04 (m, 1H), 4,15 (bd, J=13,2 Hz, 2H), 3,81 (d, J= 6.2 Hz, 2H), 3,71 (s, 3H), of 3.54 (dd, J=16,8, 10,3 Hz, 1H), is 3.08 (dd, J= 16,8, 7,3 Hz, 1H), 2,86 (dd, J=16,l, 5,9 Hz, 1H), by 2.73 (dt, J=12,8, 1.8 Hz, 2H), 2,62 (dd, J=15,8, 7.7 Hz, 1H), 1,95 (m, IH), 1,81 (bd, J=13,2 Hz, 2H), 1,45 (s, 9H), 1,25 (dq, J=12,8, 4,4 Hz, 2H).

Part B. 3-[4-(N-t-butyloxycarbonyl-4 - ylethoxy)phenyl] -(5R, S)- isoxazolin-5-yl-acetic acid.

Methyl 3-[4-((N-t - butyloxycarbonyl-4-ylethoxy)phenyl] -(5R,S)- isoxazolin-5-ylacetic (329 mg, 0,762 mmol) omilami using a 0.5 M LiOH (3 ml, 1.5 mmol) in THF (5 ml). The reaction mixture for 4 h was stirred under reflux according to example 1, part E, receiving 72 mg (22%) carboxylic acid; tPL164,0-164, 8mmoC;1H NMR (300 MHz, CDCl3) 7,58 (d, J= 8,8 Hz, 2H), to 6.88 (d, J=8,8 Hz, 2H), 5,07 (m, 1H), 4,15 (bd, J=13,6 Hz, 2H), 3,82 (d, J= 6.2 Hz, 2H), 3,53 (dd, J=16,8, 10,3 Hz, 1H), 3,10 (dd, J=16,8, 7,0 Hz, 1H), only 2.91 (dd, J=16,1, 5,9 Hz, 1H), by 2.73 (dt, J=14,6, 1.8 Hz, 2H), 2,68 (dd, J=16,1, 7,3 Hz, 1H), 1,97 (m, 1H), 1,81 (bd, J=13,2 Hz, 2H), 1,45 (s, 9H), 1.26 in (dq, J=12,8, 4,4 Hz, 2H).

Part C. 3-[4-piperidine - 4-ylethoxy) phenyl]-(5R,S)- isoxazolin-5-ilocana acid, salt triperoxonane acid.

From 3-[4-(N-t-butyloxycarbonyl-4-ylethoxy)phenyl] -(5R, S)- isoxazolin-5-yl-acetic acid (72 mg, 0,172 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part G, receiving 64 mg (94%) TFA salt; t

Example 8

3-[4-(2-piperidine-4-yl)ethoxyphenyl] -(5R,S)- isoxazolin-5-ylpropionic acid, salt triperoxonane acid

This substance was obtained by analogy with example 1, obtaining the desired connection; tPL114,8-by 115.7oC;1H NMR (300 MHz, CDCl3) to 7.59 (d, J=8,4 Hz, 2H), 6,95 (d, J=8,4 Hz, 2H), 4.72 in (m, 1H), 4,07 (t, J=5,9 Hz, 2H), 3,47 (dd, J= 16,8, 10,2 Hz, 1H), 3,37 (dd, J=16,8, 7.7 Hz, 1H), 2,98 (m, 2H), 2,44 (t, J= 7,3 Hz, 2H), 2,01 (bd, J=15,0 Hz, 2H), 1.93 and (m, 3H), of 1.80 (m, 2H), 1,44 (m, 2H).

Example 9

Erythro - and threo-3-[3-[4-[(piperidine-4 - yl)methoxy]phenyl]isoxazolin-5-yl {[butanesulfonyl] amino]propionate, salt triperoxonane acid

Part A. Dicyclohexylammonium D,L-2-[(butanesulfonyl)amino]- 4 - pontenova acid.

To a suspension of D, L-2-amino-4-pentenol acid (2,54 g, representing 22.06 mmol) in acetonitrile (35 ml) was added BSTFA (7.3 ml, 27.5 mmol). The suspension was heated for 2 h at 55oC, then a solution of a Golden-yellow color. To this solution was added pyridine (2.2 ml, to 27.2 mmol) and n-butanesulfonate (3.0 ml, of 23.1 mmol). The mixture for 20 h was heated at 70oC, then cooled to room temperature. Concentration under vacuum gave Kariya organic extracts were washed with saturated NaCl, dried (MgSO4), concentrated and the resulting oil was dissolved in ether (5 ml). To this solution was added DCHA (of 4.38 ml, 22,0 mmol), causing immediate precipitation of salts of dicyclohexylamine. The solid residue was collected by filtration and was pumped to constant weight, getting 8,42 g (92%); tPL207,1-208,6oCo;1H NMR (300 MHz, MeOH-d4) of 5.84 (m, 1H), 5,09 (dm, J=17,1 Hz, 1H), 5,04 (dm, J=10,2 Hz, 1H), 3,80 (dd, J=7,1, 5,1 Hz, 1H), 3,18 (m, 2H), to 3.02 (m, 2H), 2.49 USD (m, 2H), 2.06 to (m, 4H), of 1.78 (m, 8H), of 1.55 (m, 12H), were 0.94 (t, J=7,3 Hz).

The part b Methyl D,L-2-[(butanesulfonyl) amino]-4-pentenoate.

To a solution of D, L-2-[(butanesulfonyl) amino]-4-pentenoate of dicyclohexylamine (at 8.36 g, 20,07 mmol) in MeOH (50 ml) was added HCl, saturated MeOH (50 ml). The resulting suspension was stirred 18 h at room temperature, was diluted with ether and filtered. After concentration of the filtrate under vacuum followed by the addition of ether, the second filtering and washing of the filtrate with 0.1 M HCl, saturated NaHCO3saturated NaCl. The solution was dried over anhydrous MgSO4concentrated and placed under vacuum until reaching constant weight, getting of 4.49 g (90%) of the desired ester as a light brown oil; 1H NMR (300 MHz, CDCl3) of 5.68 (m, 1H), 5,19 (bd, J=l,5 Hz, 1H), 5,15 (m, 1H), 4,78 (bd, J= 8,4 Hz, 1H), 4,20 (dt, J=8,8, 5.8 Hz, 1H), 3.7 km threo-3-(3-[4- {(butyloxycarbonyl-4-yl) methoxy}phenyl]isoxazolin-5 - yl{[butanesulfonyl] amino})propionate.

To a solution of 4-[(N-t - butyloxycarbonyl-4-yl)methoxy]- benzaldoxime (2,680 g, 8,01 mmol), methyl-D,L-[(butanesulfonyl)amino]-4 - pentenoate (2,000 g, 8,02 mmol) and TEA (of 0.11 ml, 0.79, which mmol) in THF (10 ml) was added a 5% solution of NaOCl (common household bleach, 15 ml, 10.5 mmol). The resulting mixture was intensively stirred at room temperature for 20 hours the Mixture was diluted with EtOAc and water and the layers were separated. The aqueous portion washed with EtOAc and the combined organic fractions were washed a feast upon. NaCl and dried over MgSO4. Concentration in vacuo gave a light brown oil (4.8 g) which was purified flash chromatography (0-50% EtOAc/hexane in 5 stages), receiving four components. The least polar of these compounds (fractions 8-11) determined1H NMR as the original olefin (1,520 g, 76%). The next component is selected in order of increasing polarity (fractions 12-15), was determined1H NMR as a source oxime (1,423 g, 53%). The next component down from the column (fraction 20), was defined as two diastereoisomer (317 mg). This substance was coming off the column with an impurity having a1H NMR profile similar to the original oxime, and probably has about 50% purity. The most polar selected component (fractions 22-25) is defined as a second diaster 1H), to 4.87 (m, 1H), 4,35 (dt, J= 9,2, and 3.7 Hz, 1H), 4,15 (bs, 2H), 3,81 (d, J=6.2 Hz, 2H), of 3.78 (s, 3H), 3,49 (dd, J= 16.5, and 10.3 Hz, 1H), 3,05 (t, J=7.7 Hz, 2H), 2,97 (dd, J=16.5, and a 7.0 Hz, 1H), 2,73 (bt, J=12.1 Hz, 2H), of 2.21 (m, 1H), was 1.94 (m, 2H), equal to 1.82 (m, 4H), 1,45 (s, 9H), 1,24 (m, 3H), of 0.92 (t, J=7,3 Hz, 3H).

Part, 3-(3-[4-{ ( butyloxycarbonyl-4-yl)methoxy) phenyl] isoxazolin-5-yl{ [butanesulfonyl] amino})-propionic acid (more polar diastereoisomer).

The solution of the more polar diastereoisomer of methyl 3-(3-[4- { (butyloxycarbonyl-4 - yl)methoxy}phenyl]isoxazolin-5 - yl{ [butanesulfonyl] amino} )propionate (200 mg, 0,344 mmol) in THF (1 ml) omilami using a 0.5 M LiOH (1 ml, 0.5 mmol) for 4 h as in example 1, part E. the Crude carboxylic acid was recrystallized from EtOAc/hexanol getting 77 mg (39%) of the desired compound; tPL137,3-139,0oC;1H NMR (300 MHz, CDCl3) of 7.55 (d, J=8,8 Hz, 2H), 6.87 in (d, J=8,8 Hz, 2H), of 5.45 (d, J= 9.5 Hz, 1H), 4,87 (m, 1H), 4.92 in (m, 1H), 4,37 (m, 1H), 4,15 (b, 2H), 3,81 (d, J= 6.2 Hz, 2H), 3,47 (dd, J=16.5, and 9.9 Hz, 1H), is 3.08 (t, J=8,1 Hz, 2H), 3,01 (dd, J=16.5, and a 7.0 Hz, 1H), 2,74 (bt, J=12.1 Hz, 2H), and 2.26 (m, 1H), 2,01 (m, 2H), is 1.81 (m, 4H), 1,45 (s, 9H, overlapping with m, 1H), 1,24 (m, 3H), of 0.91 (t, J=7,3 Hz, 3H).

Part G'. 3-(3-[4-{ (butyloxycarbonyl-4-yl) methoxy}phenyl] isoxazolin-5-yl{ [butanesulfonyl] amino} )- propionic acid (less polar diastereoisomer).

A solution of the crude methanesulfonyl] amino})propionate (309 mg) in THF (5 ml) omilami, using 0.5 M LiOH (2 ml, 1 mmol) for 6 h as in example 1, part E. the Crude carboxylic acid was purified flash chromatography (CHCl3- 5-15% MeOH/CHCl3a step gradient), followed by crystallization from tOAc/hexanol getting 169 mg of the desired compound; tPL155oC (decomposition);1H NMR (400 MHz, DMSO-d6) 7,56 (d, J=8,8 Hz, 2H), 6,98 (d, J=8,8 Hz, 2H), 4,80 (m, 1H), 3.96 points (bd, J=13,2 Hz, 2H), 3,90 (d, J=6.3 Hz, 2H), of 3.77 (bs, 3H), 3,52 (t, J=7.8 Hz, 1H), 3,38 (dd, J=14,4, 10,0 Hz, 1H), 2.98 (t, J=7.8 Hz, 2H)that was 2.76 (dt, J=12,2, 1.7 Hz, 2H), 1,95 (m, 2H), of 1.75 (m, 4H), of 1.41 (s, 9H), to 1.38 (d, J=7,6 Hz, 1H), 1,25 (m, 4H), to 0.88 (t, J=7,3 Hz, 3H).

Part D. 3-(3-[4-{ piperidine-4-yl)methoxy} phenyl]isoxazolin - 5-yl { [butanesulfonyl] amino} )propionic acid, salt triperoxonane acid (more polar diastereoisomer).

From the more polar diastereoisomer 3-(3-[4-{(butyloxycarbonyl-4 - yl)methoxy} phenyl] isoxazolin-5-yl{ [butanesulfonyl] amino} )- propionic acid (40 mg, 0,070 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part G. Recrystallization from ethanol gave 4 mg (10%) TFA salt: tPL263,5oC (decomposition).

Part D.'. 3-(3-[4-{ piperidine-4 - yl)methoxy} phenyl]isoxazolin-5-yl) { [butanesulfonyl] amino} )propionic acid, salt triperoxonane acid (less polar Diaz is isoxazolin-5-yl{[butanesulfonyl] amino})- propionic acid (98 mg, 0,173 mmol) was tsalala Boc, using 33% TFA/DCM according to example 1, part G, receiving 40 mg TFA salt. Recrystallization from methanol gave 28 mg (29%) of pure amino acids; tPL239,4-240,7oC.

Example 33

4-carboxymethyl-3-[4-(2-piperidine-4 - yl)ethoxyphenyl]-(5R,S)-isoxazolin-5-yl-acetic acid, salt triperoxonane acid

This substance was obtained analogously to example 1, obtaining the desired substance; tPL141,4oC (decomposition); 1H NMR (400 MHz, CD3OD, 60oC) 7,60 (d, J=8,8 Hz, 2H), of 6.96 (d, J=8,8 Hz, 2H), 3,84 (d, J=17.3 Hz, 2H), 3,66 (s, 3H) and 3.59 (d, J=17.3 Hz, 1H), 3,38 (bd, J=12,9, Hz, 1H), 3,24 (t, J=1.7 Hz, 2H), 3,21 (dm, J= 20,3 Hz, 1H), 3.04 from (d, J=1.5 Hz, 2H), 3.00 and (dt, J=12,9, 2,9 Hz, 2H), 2,02 (bd, J=14,4 Hz, 2H), 1,95 (m, 1H), is 1.81 (m, 2H), 1,48 (m, 2H).

Example 43

3(R, S)-{ 5(R,S)-N-[3- (4-amidinophenoxy)isoxazolin - 5-ylacetic] amino}-3-phenylpropane acid

Part A. 4-cyanobenzylidene.

This substance was obtained from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc. Perkin Trans 1 1979, 643).

The part b Methyl 3-(3-butenyl)amino-3-phenylpropionate.

To a solution of vinylalcohol acid (861 mg, 10.0 mmol), hydrochloric acid methyl 3-amino-3-phenylpropionate (2.37 g, 11.0 mmol) and TEA (1.6 ml, 12 mmol) in DCM (20 ml) at -10oC added DEC (2,11 g, 11.0 mmol). The resulting mixture was stirred 15 h at t is over anhydrous MgSO4. Concentration under vacuum, followed by pumping until reaching constant weight gave a 2.36 g (95%) of the desired amide in the form of oil is Golden in color appropriate purity for the next reaction;1H NMR (300 MHz, CDCl3) 7,28 (m, 5H), 6,78 (bd, J=7.7 Hz, 1H), 5,95 (m, 1H), 5,43 (dt, J=8,4, 5,9 Hz, 1H), 5.25 in (m, 2H), 3,61 (s, 3H), 3.04 from (d, J=7,0 Hz, 2H), 2,88 (dq, J=15,0, 5,9 Hz, 2H).

Part C. Methyl 3(R,S)-{5(R,S)-N-[3- (4 - cyanophenyl)isoxazolin-5 - ylacetic]amino} -3-phenylpropanoate.

This substance was obtained from methyl 3-(3-butenyl)amino-3-phenylpropionate (816 mg, 3,30 mmol) and 4-cyanobenzaldehyde (438 mg, 3.00 mmol) according to example 4, part B. the Crude product was purified flash chromatography (70% EtOAc/hexane), getting 731 mg (62%) of the desired isoxazolines in a 1:1 mixture of diastereoisomers;1H NMR (300 MHz, CDCl3) 7,74 (m, 8H), 7,29 (m, 10H), 6,92 (bm, 2H), 5,42 (m, 2H), 5,16 (m, 2H), to 3.64 (s, 3H), of 3.60 (s, 3H), of 3.48 (m, 2H), 3,26 (dd, J=17,3, 7.7 Hz, 1H), 3.15 in (dd, J=16,8, 8,1 Hz, 1H), 2,85 (m, 2H), 2,69 (m, 2H).

Part G of Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy) isoxazolin-5-ylacetic] amino)-3-phenylpropanoate.

Through a solution of methyl 3(R,S)-{5(R,S)-N-[3- (4-cyanophenyl)isoxazolin-5 - ylacetic] amino} -3-phenylpropanoate (587 mg, 1.50 mmol) in 10% DCM/methanol (55 ml) propulsively dry gaseous HCl for 2 h the Mixture was stirred 18 h, then continu the mixture was stirred 18 h, then filtered. The filtrate was concentrated under vacuum and the residue was purified flash chromatography (CHCl3-20% methanol/CHCl3). Concentration of the appropriate fractions in vacuo, followed by the location of the residue under vacuum until reaching constant weight gave 193 mg (32%) of the desired amidino; mass spectrum (NH3-DCI, e/z, relative abundance) 409 (M+H)+, 100%.

Part D. 3(R,S)-{5(R,S)-N-[3-(4-amidinophenoxy) isoxazolin-5 - ylacetic] amino}-3-phenylpropane acid, salt triperoxonane acid.

Methyl 3(R, S)-{ 5(R, S)-N-[3- (4-amidinophenoxy)isoxazolin-5 - ylacetic] amino} -3-phenylpropanoate (45 mg, 0,113 mmol) omilami using a 0.5 M LiOH (0.6 ml, 0.3 mmol) according to example 1, part E, receiving 28 mg (49%); mass spectrum (NH3-DCI, e/z, relative abundance) 412 (M+H)+, 100%.

Example 120A

Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]amino} -3-ethoxypropionate

Part A. (E)-methyl-phenyl-2-pentenoate.

The solution hydracarina aldehyde (13,42 g, 0.1 mol) and methyl(triphenylphosphonium)acetate (33,44 g, 0.1 mol) in THF was stirred under reflux for 20 hours the Reaction mixture was concentrated under vacuum and the residue was purified flash chromatography using hexane:EtOAc::9:1. The desired ve who 2H), to 7.2, and 7.1 (m, 3H), 7,1-6,9 (m, 1H), to 5.85 (d, 1H, J=5.8 Hz in), 3.75 (s, 3H), 2.8 (t, 2H, J=7,7 Hz) to 2.55 (q, 2H, J=7.4 Hz); mass spectrum (NH3-DCI) 191 (M+H)+.

The part b Methyl 3-(R)-[N-(1-(R) -1-phenylethyl)amino]-5 - phenylpentane.

A mixture of (E)-methyl-5-phenyl-2 - pentenoate (5,70 g, 0.03 mol) and R-methylbenzylamine (14,54 g, 0.12 mol) was heated for 94 hours at 110oC. the Cooled reaction mixture was purified flash chromatography using hexane:EtOAc::8:2 to obtain 1.18 g (0,0038 mol, 12%) of the desired substance in the form of a transparent liquid;1H NMR (300 MHz, CDCl3) between 7.4 to 7.0 (m, 11H), a 3.9 (q, 1H, J=6.5 Hz), the 3.65 (s, 3H), 2,9-to 2.65 (m, 2H), 2,6-of 2.35 (m, 3H), 1,75-1,6 (m, 2H), of 1.35 (d, 3H, J=6.2 Hz); mass spectrum (NH3-DCI) 312 (M+H)+.

Part C. Methyl 3-(R)-amino-5-phenylpentane, salt of acetic acid.

A mixture of methyl 3-(R)-[N-(1-(R)-1-phenylethyl) amino]-5 - phenylpentane (0,72 g, 2.3 mmol), 20% Pd(OH)2/C (0,38 g), cyclohexene (8.2 ml), ice ukusnoj acid (0,13 ml, 2.3 mmol) and MeOH (15 ml) was heated under reflux for 20 h under nitrogen atmosphere. After cooling, the catalyst was removed by filtration through a plug of celite, washed with MeOH and the solution was concentrated under vacuum. The residue is triturated with hexane to obtain 0,46 g (96%) of a white solid residue; tPL73-75oC;1H NMR (300 MHz, DMSO) of 8.3 (bs, 2H), 7,35-to 7.15 (m, 5H), 3,6 R)-{5(R,S)-N- [3-(4-cyanophenyl)isoxazolin - 5-ylacetic] amino} heptanoate.

To a suspension of 3-(4 - cyanophenyl)isoxazolin-5-yl-acetic acid (460 mg, 2.0 mmol) in EtOAc (15 ml) were added salt acetic acid, methyl 3-(R)-amino-5 - phenylbutanoate (410 mg, 2.0 mmol), TBTU (640 mg, 2.0 mmol) and Et3N high (0.56 ml, 400 mg, 4.0 mmol). After stirring at room temperature for 16 h the reaction mixture was concentrated under vacuum, then purified flash chromatography using EtOAc getting 690 mg (83%) of colorless oil.1H NMR (300 MHz, DMSO) with 8.05 (brs, 1H), 7.95 is to 7.9 (m, 2H), 7,85 one-7.8 (m, 2H), 7,3-7,25 (m, 2H), 7,2, and 7.1 (m, 2H), 5,15-5,0 (m, 2H), 4,15 to 4.0 (m, 1H), 3,6 (d, 3H, J= 9.9 Hz), and 3.3 (d, 2H, J=6.9 Hz), 3.25 to 3.15 in (m, 1H), 2,75 to 2.35 (m, 6H), 1,8-1,6 (m, 2H); MC (NH3-DCl) 420 (M+H)+.

Part D. Methyl 3(R)-{5(R,S)-{[3- (4 - amidinophenoxy) isoxazolin-5-ylacetic] amino}-3 - ethoxypropionate.

This compound was obtained from methyl 3(R)- { 5(R, S)-N-[3-(4 - cyanophenyl)isoxazolin-5 - ylacetic] amino} of heptanoate (670 mg, 1.6 mmol) according to example 43, part, the Crude product is triturated with cold ether, getting 272 mg (39%) of white solid residue of the indicated compound in the form of 1:1-mixture of diastereomers; tPL76-78oC;1H NMR (300 MHz, DMSO) of 8.1 to 8.0 (m, 1H), 8.0 to about 7.8 (m, 4H), 7.95 is-a 7.85 (m, 5H), 7,35 to 7.2 (m, 5H), from 5.1 to 5.0 (m, 1H), 4,1 to 4.0 (m, 1H), 3,6 (s, 3H), 3,3 - 3,15 (m, 2H), 2,7-2,4 (m, 6H), to 1.8-1.7 (m, 2H); MC (NH3-ESI), 437 (M+H)+.

Example b

Meth is)-1-phenylethyl)amino]-5 - phenylpentane.

A mixture of (E)-methyl-5-phenyl-2-pentenoate (5,70 g, 0.03 mol) and R-methylbenzylamine (14,54 g, 0.12 mol) was heated for 94 hours at 110oC. the Cooled reaction mixture was purified flash chromatography using hexane:EtOAc::8:2 to obtain 1.20 g (to 0.0039 mol, 13%) of the desired compound in the form of a transparent liquid;1H NMR (300 MHz, CDCl3) 7,35-of 7.0 (m, 11H), a 3.9 (q, 1H, J=6.6 Hz), the 3.65 (s, 3H), 2.95 and is 2.8 (m, 1H), 2,75-2,5 (m, 2H), 2,45 to 2.35 (m, 2H), 1,9-of 1.65 (m, 2H) and 1.3 (d, 3H, J=6.6 Hz); MC (NH3-DCI) 312 (M+H)+.

The part b Methyl 3-(S)-amino-5-phenylpentane, salt of acetic acid.

Methyl 3(S)-[N-benzyl-N-(1-R-1-phenylethyl) amino] heptanoate (0,93 g, 2.9 mmol), 20% Pd(OH)2/C (0,47 g), cyclohexene (10.1 ml), glacial acetic acid (0.17 ml, 2.9 mmol) and MeOH (20 ml) was heated under reflux in nitrogen atmosphere for 48 hours After cooling, the catalyst was removed by filtration through a plug of celite, washed with MeOH and the solution was concentrated under vacuum. The residue is triturated with hexane, getting 0.65 g (80%) of the solid residue of a white colour; tPL86-88oC;1H NMR (300 MHz, CDCl3) 7,35-to 7.15 (m, 5H), 5,3 (brs, 2H), the 3.65 (s, 3H), 3,35-3,2 (m, 1 H), 2,8-to 2.55 (m, 3H), 2,5-2,4 (m, 1H), 2,0 (s, 3H), 1.8 m (q, 2H, J=7.4 Hz); []2D5+of 9.55o(C=0,220, MeOH).

Part C. Methyl 3(S)-{5(R,S)-N- [3-(4-cyanophenyl)isoxazolin-5 - ylacetic] A15 ml) was added methyl 3-(S)-amino-5-phenylbutanoate, salt acetic acid (600 mg, 2.6 mmol), TBTU (830 mg, 2.6 mmol) and Et3N (1,09 ml, 790 mg, 7.8 mmol). After stirring for 16 h at room temperature the reaction mixture was concentrated under vacuum, then purified flash chromatography using EtOAc getting 420 mg (38%) of colorless oil.1H NMR (300 MHz, CDCl3) 8,05 to 8.0 (m, 1H), 7.95 is to 7.9 (m, 2H), 7,85 one-7.8 (m, 2H), 7,3 to 7.2 (m, 2H), 7,2, and 7.1 (m, 3H), 5,15 to 5.0 (m, 1H), 4,15 to 4.0 (m, 1H), 3,6-3,55 (m, 3H), 3,3-3,1 (m, 1H), 2,7 - 2,4 (m, 6H), 1,8 - 1,6 (m, 2H); MC (NH3-DCI) 420 (M+H)+.

Part G of Methyl 3(S)-{5(R,S)-N-[3- (4 - amidinophenoxy)isoxazolin-5 - ylacetic]amino}-3-ethoxypropionate.

This substance was obtained from methyl 3(S)-{5(R,S)-N-[3-(4 - cyanophenyl)isoxazolin-5-ylacetic]amino}-3-ethoxypropionate (360 mg, 0.86 mmol) according to example 43, part, the Crude product is triturated with cold ether, receiving 230 mg (62%) of the indicated compound as an amorphous solid residue of a mixture of diastereoisomers, tPL84-86oC;1H NMR (300 MHz, DMSO) of 8.1 to 8.0 (m, 1H), 8.0 to about 7.8 (m, 4H), of 7.75 to 7.7 (m, 1H), and 7.3, and 7.1 (m, 6H), from 5.1 to 5.0 (m, 1H), 4,15 to 4.0 (m, 1H), the 3.65 (s, 3H), 3,3-3,1 (m, 1H), 2,7-2,6 (m, 3H), 2,5-2,4 (m, 3H), 1,8-of 1.65 (m, 2H), 1,1-1,0 (m, 2H); MC (NH3-ESI) 437 (M+H)+.

Example 189

5(R, S)-(2-piperidine-4-yl)ethyl-8-(2-carboxyethyl)- 1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione

Part A. 3-(N-t-butyloxycarbonyl a solution of 3-(N-t - butyloxycarbonyl-4-yl)propanol (10,00 g, 41,09 mmol) in DCM (20 ml). After standing for 4 h at room temperature the mixture was diluted with ether and passed through a short column with Florisil (fluorisil (R)) with ether as eluent. The eluate was concentrated in vacuo and placed under vacuum until reaching constant weight, getting 8,32 g (84%) of the desired aldehyde as a colourless oil;1H NMR (300 MHz, CDCl3) 9,76 (t, J=1.5 Hz, 1H), of 4.05 (bs, 2H), 2,64 (bt, J= 11.7 Hz, 2H), 2,45 (dt, J=7,3, 1.5 Hz, 2H), 1,60 (m, 3H), USD 1.43 (s, 9H, overlapped with m, 2H), 1,08 (dq, J=12,1, 4.0 Hz, 2H).

Part B. Reaction of (E,Z)-3-(N-t-butyloxycarbonyl-4 - yl)propanal.

To a solution of 3-(N-t-butyloxycarbonyl-4 - yl)propanal (3,905 g, 16,18 mmol) in ethanol:pyridine=1:1 (20 ml) was added hydrochloric acid hydroxylamine (1,701 g, 24,48 mmol) and the resulting solution was stirred 20 h at room temperature. Concentration in vacuo gave an oil which was dissolved in EtOAc and washed with 0.1 M HCl (3x), water, saturated CuSO4(2x), water and brine. The solution was dried over MgSO4concentrated in vacuo and placed under vacuum until reaching constant weight, getting 4,071 g (98%) 1:1 mixture of the (E, Z)-oxime as a colorless oil;1H NMR (300 MHz, CDCl3) 7,42 (t, J=6.2 Hz, 0.5 H), 6,70 (t, J=5,5 Hz, 0.5 H) 4,06 (bs, 2H), 2,67 (bt, J=12,8 Hz, 2H), 2,41 (m, 1H), 2,23 (m, 1H), 1,66 (b, 2H), 1,45 (s, 9H, peracre isoxazolin - 5-yl} acetate

To a solution of the oxime (E,Z)-3-(N-t - butyloxycarbonyl-4-yl)propanal (503 mg, a 1.96 mmol) and dimethylcarbonate (620 mg, to 3.92 mmol) in DCM (3 ml) was added a 5% solution of sodium hypochlorite (common household bleach, 3 ml, 2 mmol). The resulting mixture was stirred at room temperature overnight (19 h). Separated the layers and the aqueous layer washed with DCM (2x). The combined DCM fraction was dried over MgSO4and concentrated in vacuum. Purification with flash chromatography (hexane - 10% EtOAc/hexane to 50% EtOAc), followed by concentration and pumping to constant weight gave the desired isoxazoline (510 mg, 63%) as a colourless oil;1H NMR (300 MHz, CDCl3) 4,06 (bd, J=13,6 Hz, 2H), of 3.78 (s, 3H), to 3.67 (s, 3H), 3,57 (d, J=l7,6 Hz, 1H) and 3.15 (d, J=16.5 Hz), 3,06 (d, J=17.6 Hz, 1H), 2,86 (d, J=16.5 Hz, 1H), 2,65 (bt, J= 12.1 Hz, 2H), a 2.36 (m, 2H), 1,65 (m, 2H, overlap with H2O, 2H), USD 1.43 (s, 9H), of 1.07 (m, 2H).

Part, 5(R,S)-{[2- (N-t-butyloxycarbonyl-4 - yl)ethyl]-5 - carboxipenicilin-5-yl} acetic acid.

A solution of methyl (5R,S)-3-{[2-(N-t-butyloxycarbonyl-4-yl)ethyl]-5 - carboxymethylchitin-5-yl} acetate (380 mg, 0,921 mmol) in THF (5 ml) omilami of 0.5 M LiOH (5 ml, 2.5 mmol). The reaction mixture was stirred at ambient temperature for 5 h according to example 1, part E, to obtain a 2.8 Hz, 1H), 3,18 (d, J= 17,8 Hz, 1H), 2,97 (AB Quartet, = 32,6, J=16,8 Hz, 2H), 2,72 (b, 2H), 2,39 (m, 2H), 1,71 (bd, J=13,2 Hz, 2H) and 1.51 (m, 3H), USD 1.43 (s, 9H), of 1.05 (m, 2H).

Part D. 5(R, S)-2-(N-t - butyloxycarbonyl-4-yl)ethyl- 8-[(2-(1,1- dimethylethoxysilane) ethyl] -1-oxa-2,8 - diazaspiro[4,4]non-2-ene-7,9-dione.

To a solution of 5(R,S)-{[2-(N-t - butyloxycarbonyl-4-yl)ethyl]-5-carboxipenicilin-5-yl} acetic acid (700 mg, 1.82 mmol) in THF (5 ml) was added DCC (378 mg and 1.83 mmol) and the resulting suspension was stirred 30 min at room temperature. To this mixture was added a suspension of hydrochloric acid t-butyl ester of beta-alanine (372 mg, 2.05 mmol) and TEA (300 μl, of 2.15 mmol) in THF (5 ml). The mixture was stirred overnight (18 h) at room temperature. After dilution with EtOAc, the mixture was filtered and the filtrate was washed with 0.1 M HCl, saturated NaHCO3saturated NaCl. Was dried over anhydrous MgSO4concentrated and placed under vacuum until reaching constant weight, getting 430 mg (46%) dirty amide. Part of this substance (420 mg, 0,821 mmol) was dissolved in THF (4 ml). To the solution was added HOSuc (100 mg, 0,869 mmol) and then DCC (180 mg, 0,872 mmol). The resulting suspension was stirred at room temperature for 18 hours, the Filtrate was dried over anhydrous MgSO4concentrated and placed under vacuum until reaching constant DMF (5 ml) at 0oC. To this solution was added NaH (16 mg, 0.66 mmol). After 3 h at 0oC the reaction was stopped HOAc. After dilution with EtOAc, the mixture was washed with water (4x), saturated NaHCO3, water, 0.1 M HCl and saturated NaCl. Was dried over anhydrous MgSO4concentrated and placed under vacuum until reaching constant weight, getting 230 mg (70%) of crude imide. The crude substance was purified flash chromatography (CHCl3- 5% MeOH/CHCl3) to give 149 mg (46%) of a colorless oil after concentration of appropriate fractions and pumping until reaching constant weight;1H NMR (300 MHz, CDCl3) 4.09 to (b, 2H), 3,82 (t, J=7,3 Hz, 2H), 3,54 (d, J=and 17.2 Hz, 1H), 3,12 (d, J=18.7 Hz, 1H), 2,98 (d, J=and 17.2 Hz, 1H), and 2.83 (d, J=18.7 Hz, 1H), 2,69 (m, 2H), 2.57 m (t, J=7,3 Hz, 2H), 2,42 (m, 2H), by 1.68 (m, 2H), of 1.57 (m, 2H), 1,45 (s, 9H, c coincides m, 1H), 1,11 (m, 2H).

E. part 5(R, S)-(2-piperidine-4-yl)ethyl-8-(2-carboxyethyl)-1 - oxa-2,8-diazaspiro [4.4]non-2-ene-7,9-dione.

To a solution of 5(R,S)-2-(N - t-butyloxycarbonyl-4-yl)ethyl-8-[(2-(1,1- dimethylethoxysilane)ethyl] -1-oxa-2,8-diazaspiro[4.4] non-2-ene - 7,9-dione (75 mg, 0,152 mmol) in DCM (1 ml) was added TFA (0.5 ml, 8 mmol). The reaction mixture was stirred 2 h at room temperature, then concentrated in vacuo. The excess TFA was off on a rotary evaporator with toluene (2x). Crystallization from MC;1H NMR (300 MHz, DMSO-d6, 60oC) 12,15 (bs, 1H), compared to 8.26 (bs, 2H), to 3.64 (m, 2H), 3,39 (d, J= 17,8 Hz, 1H), 3,26 (m, 3H), 2,98 (AB Quartet, =71,3, J=18.3 Hz, 2H), 2,85 (m, 2H), 2,50 (m, 1H, coincides with DMSO-d5), is 2.37 (t, J=7,6 Hz, 2H), 1,84 (bd, J= 11.7 Hz, 2H), 1,58 (m, 1H), 1,52 (t, J=7,6 Hz, 2H), 1,29 (m, 2H).

Example 190

5(R,S)-(2-piperidine-4-yl)ethyl-8-(3-carboxypropyl)-1-oxa - 2,8-diazaspiro[4.4]non-2-ene-7,9-dione

This substance was obtained by the methods described in example 189, receiving the specified connection; tPL133,4-135,1oC; 1H NMR (400 MHz, CD3OD, 55oC) 3,59 (t,

J= 6,8 Hz, 2H), 3,50 (d, J=17.7 and Hz, IH), 3,38 (bd, J=12.9 Hz, 2H), 3,18 (d, J= 17.7 and Hz, 1H), 2,98 (m, 4H), 2,85 (m, 2H), 2,50 (m, 1H, coincides with DMSO-d5), a 2.45 (m, 2H), 2,31 (t, J=7,1 Hz, 2H), 2,00 (m, 2H), 1,98 (pentuple, J=7,1 Hz, 2H), 1,40 (m, 2H).

Example 275

N3-[3-(4-amidinophenoxy)isoxazolin-5(R, S)-ylacetic]-L-2,3 - t diaminopropionic acid, TFA salt

Part A. 3-(4 - cyanophenyl)isoxazolin - 5(R,S)-yl-acetic acid.

To a solution of 4-cyanobenzaldehyde (see example 43, part a) (312 g, 2,13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyloxy acid (552 g, 6,41 mol). The yellow solution was cooled in an ice bath was added dropwise over 2 h a solution of sodium hypochlorite (5200 ml). After stirring over night at room temperature the reaction extinguish the Auteuil to pH 4. The acidic layer was twice washed with 200 ml of ether, the ether layers were combined and carried out the extraction with a saturated solution of sodium bicarbonate. After acidification of the alkaline layer citric acid the product was extracted with 400 ml of ether. The organic phase is 3 times washed with 150 ml of water, once with brine, dried (MgSO4and focused, getting 220 g of 3-(4-cyanophenyl)isoxazolin-5-yl - acetic acid as a white solid residue. Recrystallization from 25% solution of water/ethanol gave 165 g of analytically pure substance.

Calculated for C12H10N2O3: C 62,61; H TO 4.38; N 12,16. Found: 62,37; H 4,47; N 11,71.

1H NMR (300 MHz, CDCl3) to 7.77-7,76 (d, 2H, J=1,8 Hz), 7,72-7,71 (d, 2H, H= 1.8 Hz), 5,22-5,14 (m, 1H), 3,63-of 3.54 (dd, 1H, J=10,6 Hz, is 16.8 Hz), 3,19-3,11 (dd, 1H, J= 7,3 Hz, is 16.8 Hz), 3.00 and-of 2.93 (dd, 1H, J=6.2 Hz, 16.5 Hz), 2,79-of 2.72 (dd, IH, J=7,3 Hz, 16.5 Hz); IR-spectrum (KBr sediment): 3202, 2244, 1736, 1610, 1432, 1194, 1152, 928, 840, 562 cm-1.

The part b Methyl N2-bz-L-2,3-diaminopropionic, HCl salt.

N2-Cbz-L-2,3-diaminopropionic acid (10 mmol, 2,39 g) was dissolved in 20 ml methanol and 20 ml of 4 N HCl in dioxane and the solution was stirred 4 h and then concentrated to obtain a solid residue. The solid residue was washed several times with ether, receiving 2.50 g (87%) of product. NMR (DMSO-dAnafanil) isoxazolin - 5(R,S)-ylacetic] -L-2,3-diaminopropionic.

To a solution of 3-(4 - cyanophenyl)isoxazolin -5(R,S)-yl-acetic acid (19 mmol, 4,37 g), methyl N2-bz-L-2,3-diaminopropionic, HCl salt (20 mmol, 5,76 g) and triethylamine (60 mmol, at 8.36 ml) was added TBTU (20 mmol, 6.42 per g) and the solution was stirred for 2 hours was Added ethyl acetate and washed with a solution of dilute citric acid, brine, NaHCO3and brine, dried (MgSO4) and concentrated. Crystallization from ethyl acetate/ether to give 6.85 g (78%) 3 product. NMR (DMSO-d6) is 8.16 (t, 1H), 7,92 (d, 2H), 7,82 (d, 2H), 7,68 (d, 1H), was 7.36 (m, 5H), 5,04 (m, 3H), 4,20 (m, 1H), to 3.64 (s, 3H), 3,50 (m, 2H), 3,26 (m, 2H), 2,50 (m, 2H).

Part G of Methyl N3-[3-(4-amidinophenoxy)isoxazolin -5(R,S)- ylacetic] -L-2,3 - diaminopropionic, HCl salt.

Gaseous HCl propulsively through a solution of methyl N2-Cbz-N3-[3-(4-cyanophenyl) isoxazolin-5(R, S)-ylacetic] -L-2,3-diaminopropionic (2.1 mmol, 1.0 g) 1 h, stirred solution overnight and then concentrated. The residue was dissolved in 30 ml of 2 M ammonia in methanol and the solution was stirred overnight, concentrated, obtaining 1.2 g of the crude product.

Part of that is, N3-[3-(4-amidinophenoxy)isoxazolin -5(R,S)- ylacetic]-L-2,3-diaminopropionic acid, TFA salt.

Methyl N3- [3-(4-amidinophenoxy) isoxazolin-5(R,S)-ylacetic] -L-2,3 - diaminopropionic HPLC gave 40 mg of the product. ESI (M+N)+: calculated 334,2; found: 334,2.

Example 276

N2-Cbz-N3-[3- (4-amidinophenoxy)isoxazolin -5(R,S)- ylacetic]-L-2,3-diaminopropionic acid, TFA salt

Part A. Methyl N2-Cbz-N3-[3- (4-amidinophenoxy)isoxazolin - 5(R,S)-ylacetic] -L-2,3-diaminopropionic, TFA salt.

To a solution of compound of example 275, part D (1.0 mmol, 385 mg) and sodium bicarbonate (5.0 mmol, 400 mg) in 2 ml water, 2 ml of acetonitrile and 1 ml DMF was added benzylchloride (1 mmol, 143 μl) and the mixture was stirred 2 h at room temperature. The solution was filtered, acidified TFA and purified by reversed-phase HPLC, receiving 150 mg (25%) of the product. NMR (DMSO-d6) 9,40 (s, 2H), 9,20 (s, 2H), 8,18 (t, 1H), 7,86 (m, 4H), to 7.68 (d, 1H), 7,35 (m, 5H), 5,02 (m, 3H), 4,20 (m, 1H), to 3.64 (s, 3H), 3,52 (m, 2H), 3,26 (m, 2H), 2,50 (m, 2H).

Part B. N2-Cbz-N3-[3- (4-amidinophenoxy)isoxazolin-5(R,S)- ylacetic]-L-2,3-diaminopropionic acid, TFA salt.

Methyl N2-Cbz-N3-[3- (4-amidinophenoxy)isoxazolin -5(R,S)-ylacetic]-L-2,3-diaminopropionic, TFA salt (0.12 mmol, 70 mg) was dissolved in 2 ml methanol and 1 ml of 1 N NaOH and after 1 h the solution sekilala acetic acid. Purification by reversed-phase HPLC gave 50 mg (74%) of product. ESI (M+H)+: calculated 468,2; found 468,2.

Example 278

N2-n-butyloctyl A. Methyl N2-n-butyloxycarbonyl-N3- [3-(4-amidinophenoxy) isoxazolin-5(R,S) -ylacetic]-L-2,3-diaminopropionic, TFA salt.

To a solution of compound of example 275, part E (1.0 mmol, 385 mg) and sodium bicarbonate (2.5 mmol, 200 mg) in 2 ml water, 2 ml of acetonitrile and 1 ml of DMF, cooled in an ice bath, was added n-butylchloroformate (1 mmol, 127 μl). After stirring 1 h, the solution sekilala acetic acid and was purified by reversed-phase HPLC, receiving 150 mg (27%) of product. NMR (DMSO-d6) 9,40 (s, 2H), 9,20 (s, 2H), 8,16 (t, 1H), 7,86 (m, 4H), 7,47 (d, 1H), 5,02 (m, 1H), 4,16 (m, 1H), 3,94 (t, 2H), 3,62 (s, 3H), 3,50 (m, 2H), 3,26 (m, 2H), 2,50 (m, 2H), of 1.52 (m, 2H), 1,32 (m, 2H), to 0.88 (t, 3H). ESI (M+H)+: calculated 448,3; found 448,3.

Part B. N2-n-butyloxycarbonyl-N3- [3-(4 - amidinophenoxy)isoxazolin -5(R,S)-ylacetic]-(S)-2,3 - diaminopropionic acid, TFA salt.

Methyl N2-n-butyloxycarbonyl - N3-[3-(4-amidinophenoxy)isoxazolin -5(R, S)-ylacetic] -L-2,3 - diaminopropionic, TFA salt (0,107 mmol, 60 mg) was dissolved in 2 ml methanol and 2 ml of 1 N NaOH and after 1 h the solution sekilala acetic acid. Purification by reversed-phase HPLC gave 53 mg (89%) of product. ESI (M+H)+: calculated 434,3; found 434,3.

Example 314A

Methyl N2-n-butyloxycarbonyl-N3- [3-(4-amidinophenoxy)isoxazolin -5(S)-ylacetic]-(S)Astaro methyl N2-Cbz-(S)-2,3-diaminopropionic, HCl salt (916,3 mmol, 4.7 g) and di-tert-BUTYLCARBAMATE (16.3 mmol, of 3.56 g) in 30 ml of chloroform, cooled in an ice bath, was added triethylamine (34 mmol, 4,7 ml) and the solution was stirred 1 h in an ice bath and 3 h at room temperature and concentrated. The residue was collected with ethyl acetate and the solution washed with dilute citric acid, brine, NaHCO3and brine, dried (MgSO4) and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) of the final product. NMR (DMSO-d6) 7,60 (d, 1H), 7,35 (m, 5H), to 6.88 (t, 1H), 5,02 (s, 2H), 4,14 (m, 1H), 3,60 (s, 3H), of 3.28 (m, 2H), of 1.37 (s, 9H), to 0.88 (t, 3H).

The part b Methyl N3-Boc-(S)-2,3-diaminopropionic, salt HCO2H.

A mixture of methyl N2-Cbz-N3-Boc-(S)-2,3-diaminopropionic (14 mmol, 5.0 g), formic acid (42 mmol, 1.6 ml) and 10% Pd/C (500 mg) in 40 ml of methanol was stirred at room temperature for 1 h and filtered through celite. The filtrate was concentrated and the residue triturated with ether/petroleum ether, gaining 3.7 g (100%) of solid product. NMR (DMSO-d6) to 8.20 (s, 1H), 6.90 to (t, 1H), are 5.36 (b, 3H), 3,61 (s, 3H), 3,51 (t, 1H), 3,18 (t, 2H), to 1.38 (s, 9H).

Part C. Methyl N2-n-butyloxycarbonyl-N3-Boc-(S)-2,3 - diaminopropionic.

To a mixture of methyl N3-Boc-(S)-2,3-diaminobutane, slowly over 15 min was added butylchloroformate (16 mmol, 2 ml). After stirring for 1 h was added ethyl acetate and washed with a solution of dilute citric acid, brine, NaHCO3and brine, dried (MgSO4) and concentrated, obtaining 4.4 g (100%) of oily product. NMR (DMSO-d6) 7,37 (d, 1H), at 6.84 (t, 1H), 4,20 (m, 1H), 3.96 points (t, 2H), 3,60 (s, 3H), 3,26 (m, 2H), of 1.52 (m, 2H), to 1.38 (s, 9H), of 1.36 (m, 2H), from 0.88 (t, 3H).

Part G of Methyl N2-butyloxycarbonyl- (S)-2,3 - diaminopropionic, TFA salt.

Methyl N2-n-butyloxycarbonyl-N3-Boc-(S)- 2,3-diaminopropionic (a 13.9 mmol, 4.4 g) was dissolved in 25 ml of dichloromethane and 35 ml of TFA and after 1 h the solution was concentrated, obtaining an oily product. Yield 4.8 g (100%). NMR (DMSO-d6) 8,02 (b, 3H), 7,68 (d, 2H), to 4.38 (m, 1H), 3,99 (t, 2H), 3,68 (s, 3H), up 3.22 (m, 1H), 3,06 (m, 1H), 1.55V (m, 2H), of 1.34 (m, 2H), 0,89 (t, 3H).

Part D. Methyl-N2-n-butyloxycarbonyl-N3-[3(4 - cyanophenyl)isoxazolin-5(S)-ylacetic] -(S)-2,3-diaminopropionic.

To a solution of 3-(4-cyanophenyl)isoxazolin-5(S)-yl-acetic acid (5.2 mmol, 1.2 g) [chiral starting material was obtained from racemic compound of example 275, part a, the separation column (Chiralpak AD, h cm, using a 0.1% TFA/EtOH, 10oC yield of the isomer A (comes with the speakers before) and isomer B (tone, leaving 5(R) isomer in the mother solution; the absolute stereochemistry of salt crystals was determined by x-ray crystallography to identify 5(S) isoxazoline] and methyl N2-butyloxycarbonyl-(S)-2,3 - diaminopropionic, TFA salt (6 mmol, 1,53 g) in 20 ml of DMF, cooled in an ice bath, was added diisopropylethylamine (20 mmol, 3.5 ml), and then the THIEF (5.5 mmol, 2,43 g). After stirring for 3 h at room temperature was added ethyl acetate and the solution was washed with 0.5 N HCl, brine, NaHCO3and brine, dried (MgSO4) and concentrated, obtaining 1.9 g (87%) of the final product. NMR (DMSO-d6) to 8.12 (t, 1H), 7,94 (d, 2H), 7,83 (d, 2H), 7,46 (d, 1H), 5,04 (m, 1H), 4,16 (m, 1H), 3.96 points (t, 2H), to 3.64 (s, 3H), to 3.58 (dd, 1H), 3,40 (m, 2H), 3,20 (dd, 1H), 2,56 (dd, 1H), 2,43 (dd, 1H), of 1.52 (m, 2H), of 1.32 (m, 2H), from 0.88 (t, 3H).

Part G. Methyl-N2-n-butyloxycarbonyl-N3-[3-(4-amidinophenoxy) isoxazolin-5(S)-ylacetic] -(S)-2,3-diaminopropionic, TFA salt.

Through a solution of methyl-N2-n - butyloxycarbonyl-N3-[3(4-cyanophenyl) isoxazolin - 5(S)-ylacetic]-(S)-2,3-diaminopropionic (4.4 mmol, 1.9 g) in 50 ml of methanol propulsively gaseous HCl at 0oC for 1 h, the solution was stirred for 5 h at room temperature and concentrated. The residue was collected 20 ml of methanol was added carbonate is astoral in methanol/water/TFA. Purification by reversed-phase HPLC gave 1.0 g (40%) of the final product. ESI (M+N)+: calculated 448,3; found 448,3.

Example B

Methyl N2-n-butyloxycarbonyl-N3- [3-(4 - amidinophenoxy)isoxazolin -5(R)-ylacetic]-(S)-2,3-diaminopropionic, TFA salt

Part A. 3-(4-cyanophenyl)-5(R)-yl-acetic acid.

This substance was separated from 3-(4-cyanophenyl)isoxazolin-5(R,S)-yl - acetic acid as described above in the method of example 314A, part E.

The part b Methyl-N2-n-butyloxycarbonyl-N3- [3-(4 - cyanophenyl)isoxazolin -5(R)-ylacetic]-(S)-2,3-diaminopropionic.

This substance was synthesized from 3-(4-cyanophenyl)-5(R)-yl-acetic acid (4.3 mmol, 1.0 g), methyl N2-butyloxycarbonyl-(S)-2,3 - diaminopropionic, TFA salt (5 mmol, 1.27 g), THIEF (4.5 mmol, 2 g) and diisopropylethylamine (16 mmol, 2.8 ml) using the same method as for the XVII, the output of 1.75 g (95%). NMR (DMSO-d6) to 8.12 (t, 1H), 7,94 (d, 2H), 7,83 (d, 2H), 7,46 (d, 1H), 5,04 (m, 1H), 4,16 (m, 1H), 3.96 points (t, 2H), to 3.64 (s, 3H), to 3.58 (dd, 1H), 3,40 (m, 2H), 3,20 (dd, 1H), 2,56 (dd, 1H), 2,43 (dd, 1H), of 1.52 (m, 2H), of 1.32 (m, 2H), from 0.88 (t, 3H).

Part C. Methyl N2-n-butyloxycarbonyl-N3-[3-(4 - amidinophenoxy)isoxazolin - 5(R)-ylacetic]-(S) -2,3-diaminopropionic, TFA salt.

This compound was synthesized from methyl-N2-n - butyloxycarbonyl in example 314A, part J. the Output of 1.0 g (45%). ESI (M+H)+: calculated 448,3; found 448,3.

Example 344

Methyl 3(R)-{5(R,S)-N- [3-(4 - amidinophenoxy)isoxazolin-5-ylacetic] amino} heptanoate

Part A. (E)-methyl 2-heptanoate.

To a solution of diethylaminoacetate (19 ml, 104 mmol) in anhydrous THF (800 ml) at -4oC was added to 64 ml of n-Buli (of 1.6 M in hexane, 102 mmol) dropwise within 45 minutes the resulting solution was stirred 1 h at room temperature. Added valeric aldehyde (10.0 ml, 94 mmol) and stirred for 3.5 h at room temperature. The reaction was stopped with 25 ml saturated NH4Cl. The solvents were released at atmospheric pressure and the resulting solid residue was collected EtOAc. was extracted with water and brine and dried over Na2SO4. The solvents again drove at atmospheric pressure and the resulting yellow liquid was distilled in a vacuum unit with the release of 7.2 g of a transparent liquid, boiling range in a vacuum unit 90-125oC. MS BP, e/z calculated (M+H)+: 143,1072; found 143,1070; IR (film) 1728, 1658 cm-1.

Part B. N-(l-(R)-1-phenylethyl)benzamide.

A solution of benzoyl chloride (22.5 ml, to 0.19 mol) in dichloromethane (10 ml) was added dropwise over 1.5 h to a cooled to 0oC R is h at 0oC the mixture was concentrated in vacuo, then diluted with EtOAc. This mixture was extracted with water, 1 M HCl, water and brine, then dried (MgSO4) and concentrated to yield of 43.4 g of a colorless crystalline solid residue; tPLto 121.0-121,5oC; IR spectrum (KBR) 3332, 1636 cm-1; []2D5-2,30o(C=1,002, CH2Cl2).

Calculated for C15H15NO: 79,97; H OF 6.71; N 6,22. Found: 79,88; H Of 6.65; N 6,16.

Part C. N-(1-(R)-1-phenylethyl)-N-benzylamine.

BH3/THF (1 M in THF, 220 ml, 220 mmol) was added dropwise over 1 h to a cooled to 0oC the solution of the above benzamide (20 g, 89 mmol) in anhydrous THF (200 ml). The ice bath was removed and the mixture was heated under reflux for 40 hours TLC Analysis showed that the reaction is not completely gone, so I added another BH3/THF (1 M in THF, 30 ml, 30 mmol) and continued heating for another 22,5 hours After cooling, carefully dropwise over 5 h was added MeOH (250 ml). The resulting mixture was boiled for 2 hours, then cooled and concentrated in vacuo. Re-concentration of MeOH (2x500 stretch-forming press ml) and drying under high vacuum gave 19.3 g of oil containing a small amount of sediment. This crude product was stirred with hot 2 M HCl (140 ml) to obtain the I crystalline solid residue, as described Simpkins (Tetrahedron 1990, 46(2), 523). The solid residue was collected by filtration and washed with a small amount of water. After drying in air for 3 days, got 16,35 g muriate; tPL178,5-179,5oC; []2D1+18,9o(C=4,0, EtOH). Salt was converted to free base by extraction Et2O and aqueous KOH, then drove away, the temperature of the oven 120-140oC (1 mm RT.article) to give 12.5 g oil; []2D1+61,2o(C= 3,98, EtOH).

Calculated C15HN: FROM 85,26; H 8,11; N 6,63. Found: 84,93; H Of 7.75; N 6,58.

Part G of Methyl 3-(R)-[N-benzyl-N-(1-(R)-1 - phenylethyl) amino]heptanoate.

According to the method of Davies asymmetric joining Michael (Tetrahedron: Asymmetry 1991, 2(3), 183), n-utility (1.6 M in hexane, 4.4 ml, 7.0 mmol) was added dropwise over 3 min to a cooled to 0oTo a solution of N- (1-(R)-1-phenylethyl)-N - benzylamine (1.5 g, 7.0 mmol) in anhydrous THF (35 ml). After 30 min the obtained dark pinkish-red solution was cooled to -78oC and was added dropwise a solution of methyl 2-heptanoate (0.50 g, 3.5 mmol) in THF (10 ml). After 13 minutes the cold reaction mixture is extinguished saturated ammonium chloride and brine, dried (MgSO4) and concentrated in vacuo. The product was purified by chromatography the channels at mixed fractions) was concentrated in vacuo, receiving of 0.91 g of light yellow oil, which by NMR shows the presence of a single diastereoisomer with the newly obtained asymmetric center, designated as 3(R) by analogy with Davies, linked above;13With NMR (300 MHz, CDCl3) 173,31, 143,40, 141,78, 128,40, 128,27, 128,11, 128,00, 126,91, 126,67, 57,90, 54,22, 51,32, 50,05, 36,83, 33,28, 29,32, 22,72, 19,40, 14,12; []2D5+12,96o(c=0,602, MeOH).

Part D. Methyl 3(R)-aminoheptanoic, salt of acetic acid.

Methyl 3-(R)-[N-benzyl - N-(1-(R)-1-phenylethyl)amino]heptanoate (0,70 g, 2.0 mmol), 20% Pd(OH)2/C (0.35 g), cyclohexene (7 ml), glacial acetic acid (to 0.12 ml, 2.1 mmol) and MeOH (14 ml) was heated under reflux in a nitrogen atmosphere in the course of 20.5 hours After cooling, the catalyst was removed by filtration through a plug of celite, washed with MeOH and the solution was concentrated in vacuo. Drying overnight under high vacuum gave of 0.43 g of a viscous oil;13With NMR (300 MHz, CDCl3) 177,64, 171,52, 51,97, 48,22, 37,24, 33,08, 27,50, 23,31, 22,29, 13,76; []2D5-10,6o(c=0,602, MeOH).

Part E. Methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin - 5-ylacetic] amino}heptanoate.

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-luxusni acid (300 mg, 1.3 mmol) in EtOAc (10 ml) was added methyl 3(R)-aminoheptanoic, salt explainitory the reaction mixture was extracted with 5% KHSO4saturated NaHCO3and brine, then dried Na2SO4. Evaporation followed by chromatography on silica gel, 50-100% EtOAc/hexane gave 245 mg of a colorless glass. MS (NH3-DCI). Calculated: (M+N)+372; (M+NH4)+389. Found: 372, 389.

Part g of Methyl 3(R)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin - 5 - ylacetic]amino}heptanoate.

To a solution of methyl 3(R)-{5(R,S)-N-[3-(4 - cyanophenyl)isoxazolin-5-ylacetic] amino} of heptanoate (179 mg, 0.48 mmol) in 15 ml anhydrous MeOH at 0oC was added in a stream of gaseous HCl obtained by adding two 20 ml of sulfuric acid to solid sodium chloride, within 35 minutes After stirring for 20 h at room temperature the solvent was removed at a rapid stream of nitrogen. Added Et2O and removed at a rapid stream of nitrogen. The resulting oil with a high content of resinous substances collected in 15 ml of anhydrous MeOH, to which was added (NH4)2CO3(1.1 g, to 11.4 mmol). After stirring for a period of 19.5 hours at room temperature the solvent was removed at a rapid stream of nitrogen and the resulting white solid residue was purified by chromatography on silica gel by elution of 0-20% MeOH/CHCl3. The purified product was collected in 5% MeOH/CHCl3and f> MC BP, e/z calculated (M+N)+389,2189; found: 389,2192.

Example 348

Ethyl 3(R)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]amino}-5-methylhexanoate, salt triperoxonane acid

Part A. (E)-ethyl 5-methyl-2-hexanoate.

Received as methyl 2-heptanoate using triethylphosphate, stirring 17 hours at room temperature before adding isovalerianic aldehyde. Distillation in a vacuum unit gave 72% transparent oil boiling range in a vacuum unit 80-130oC; IR (film) 1724, 1656 cm-1.

Part b: Ethyl 3-(R)-[N-butyl-N-(1-(R)-1-phenylethyl)amino]-5 - methylhexanoate.

Received likewise through asymmetric joining Michael example 344, part G (see above). Output viscous light yellow oil (65%);13C NMR (300 MHz, CDCl3) 172,83, 143,56, 142,71, 128,27, 128,21, 128,15, 128,03, 126,96, 126,60, 60,10, 58,56, 52,43, 50,09, 43,23, 36,72, 24,76, 23,48, 22,13, 20,20, 14,21; []2D5+5,12o(c=0,606, EtOH).

Part C. Ethyl 3-(R)-amino-5-methylhexanoate, salt of acetic acid.

Received as described previously, except that the solvent used ethanol. Output waxy solid residue (94%); tPL57-61oC; BP MS, e/z calculated: (M+H)+ The above salt of acetic acid (1.1 g, 4.7 mmol) was stirred 4 min in 4 M HCl/dioxane (5.0 ml). The resulting solution was rubbed Et2O, cooled and transparent solution decantation, leaving an orange oil which hardened under high vacuum with the formation of 960 mg waxy solid residue.1H NMR (300 MHz, CDCl3) 8,49 (br, 3H), 4,20 (q, J=7,3, 2H), 3,70-the 3.65 (m, 1H), 2,86 is 2.80 (m, 2H), 1,83 and 1.80 (m, 2H), 1,58-and 1.54 (m, 1H), 1.30 and 1.26 in (t, J=7,3, 3H), 0,99 - of 0.91 (m, 6H).

Part D. Ethyl 3(R)-{ 5(R, S)-N- [3-(4-(N-t - butyloxycarbonyl) phenyl)isoxazolin-5-ylacetic]amino}-5 - methylhexanoate.

To a suspension of 3-[4-(N-t-butoxycarbonylamino) phenyl]isoxazolin-5-yl-acetic acid (78 mg, 0.22 mmol) in EtOAc (5 ml) was added ethyl 3-(R)-amino-5-methylhexanoate, salt of hydrochloric acid (47 mg, 0.22 mmol), TBTU (72 mg, 0.22 mmol) and Et2N (100 μl, to 0.72 mmol). After stirring for 6 h at room temperature, the reaction mixture was extracted with a buffer with a pH of 4 (hydroptila potassium), saturated NaHCO3and brine, then dried with Na2SO4. Evaporation followed by chromatography on silica gel with 100% EtOAc gave 33 mg of colorless glass;1H NMR (300 MHz, CDCl3) of 7.90 (d, J=8,4, 2H), of 7.70 (dd, J= 8,5, J'=1,9, 2H), 6,32-6,28 (m, 1H), 5,13-5,11 (m, 1H), 4,34-to 4.33 (m, 1H), 4,17-4.09 to (m, 2H), 3,56-3,47 (m, 1H), 3,25-3,17 (m, 1H), 2.71 to the 2.46 (m, 4H), 1,66 to 1.47 (m, 2H), of 1.56 (s, 9H), 1,31-of 1.23 (m, 4H), to 0.92 (dd, J, salt triperoxonane acid.

The product of part D (29 mg, 0,058 mmol) was dissolved in DCM (300 ml) to which was added TFA (100 μl). The resulting solution was stirred at room temperature CaSO4shitennou tube for 3.5 h and triturated with Et2O. was Collected by filtration 24 mg of white solid residue.1H NMR (300 MHz, CDCl3) to 9.4 (br, 1H), and 9.0 (br, 1H), and 7.8 (s, 4H), 5,0 (m, 1H), 4,2 (m, 1H), 4,0 (m, 2H), 3,6 (m, 1H), 3,3 (m, 2H), 2,4 (m, 3H), 1,6 (m, 1H), 1,4 (m, 1H), 1,2 (m, 4H), 0.8 a (m, 6H); MC BP, e/z Rasch.: (M+H)+403,2345; found: 403,2363.

Example 350

Methyl 3(R,S)- {5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino} -4-(phenylthio)butanoate, salt of hydrochloric acid

Part A. Methylphenylacetic.

To a solution of thiophenol (5,00 ml, to 48.6 mmol) in DMF (20 ml) was added potassium carbonate (of 10.09 g, 73 mmol) and methylacetoacetate (5,93 ml, 48.6 per mmol). The reaction mixture was stirred 6 h at 50oC, diluted with EtOAc and extracted with saturated Na2SO4, water and brine, then dried (Na2SO4) and concentrated. The resulting oil was chromatographically with 20% EtOAc in hexane to yield 9,40 g yellow oil; MS (CH4-DCI) is calculated: (M+N)+224; found: 224; IR-spectrum (KBr) 2954, 1656, 1438, 626 cm-1.

The part b Methyl-3(R,S)-amino-4-phenylthiourea.

2
SO4and concentrated, receiving and 0.61 g of a yellow oil; MS (NH3-CI/DDIP) calculated: (M+N)+226; found: 226;1H NMR (300 MHz, CDCl3) 7,39 (d, J=7, 2H), 7,32-7,26 (m, 3H ), 7,22 (d, J=10, 1H), 3,74 (s, 3H), 3,39-of 3.31 (m, 1H), 3,13-of 3.07 (dd, J=13, J'=9, 1H), 2.91 in-and 2.83 (dd, J= 12, J'=6, 1H), 2,65-of 2.58 (dd, J=12, J'=6, 1H), 2,46-of 2.38 (dd, J=16, J'=8, 1H).

Part of the Century Methyl-3-(R,S)-{5(R,S)-N-[3-(4-cyanophenyl) isoxazolin-5 - ylacetic]amino}-4-((phenylthio)butanoate.

To a suspension of 3-(4-cyanophenyl)isoxazolin-5-yl-acetic acid (0.50 g, 2 mmol) in EtOAc (10 ml) was added methyl-3-(R,S)amino-4- (phenylthio)butanoate (0.51 g, 2 mmol), TBTU (0.71 g, 2 mmol) and Et3N (1,24 ml, 8.9 mmol). The reaction mixture was stirred 2 h at room temperature, diluted with EtOAc, washed with 5% citric acid, saturated NaHCO3and brine, dried over Na2SO4concentrated and the oil obtained was chromatographically on silica gel, 100% EtOAc, receiving and 0.61 g of a yellow glass, MS (NH3-CI/DDIP) calculated for (M+N)+: 438,1; found: 438,1.

Calculated for C32H23N3O

The product of part b (0,30 g of 0.68 mmol) was dissolved in anhydrous MeOH (20 ml) at 0oC. After the resulting solution was passed gatabazi HCl from a source described in example 344, G, within 2 hours Source was removed and the reaction mixture was stirred at 0oC 18 h, then concentrated and triturated with CHCl3. The resulting precipitate was collected by filtration and pererestorani in anhydrous MeOH (20 ml). To this solution was added ammonium carbonate (0,99 g, 10 mmol) and the mixture was stirred 18 h at room temperature. The solution was concentrated and recrystallized from DCM/MeOH to yield 0.14 g of a white solid residue; MS, BP, e/z Rasch. for (M+N)+: 455,1753; found: 455,175.1H NMR (300 MHz, d6-DMSO) 9,44 (br s, 1H), 9,18 (br s, 1H), they were 8.22 (d, J =10, 1H), 7,86 (m, 4H), 7,41-7,25 (m, 4H), 7,2 (m, 1H), to 5.03 (m, 1H), 4,2 (m, 1H) and 3.59 (s, 3H) 3,29 was 3.05 (m, 4H), 2,8-2,39 (m, 4H).

Example 359

Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]amino} -4- (phenylsulfonyl)butanoate, salt triperoxonane acid

Part A. Methyl 3(R,S)-hydroxy-4-aminobutanoic, salt of hydrochloric acid.

Chloromethylene (100 ml, of 0.79 mol) was added dropwise over 1.5 h to stir at 0oC suspension of 4-amino-3-(R,S)- hydroxybutiric acid (25 g, 0.21 mol) in MeOH (1 l). oritel evaporated in vacuo and the resulting residue was concentrated again from MeOH (2x500 stretch-forming press ml). Drying under high vacuum gave 37 g of viscous oil.13With NMR (300 MHz, d6-DMSO) 171,42, 90,14, 64,67, 51,89, 44,39.

Calculated for C5H16ClNO3: 35,41; H 7,13; N Compared To 8.26; Cl 20,90. Found: 35,18; H To 7.09; N 8,18; Cl 20,77.

The part b Methyl 3(R,S)-hydroxy-4-(phenylsulfonyl)butanoate.

The solution benzosulfimide (7.5 ml, 59 mmol) in dichloromethane (10 ml) was added dropwise over 55 min to a cooled to 0oC the amine salt solution of part a (10 g, 50 mmol) and Et3N (17 ml, 120 mmol) in dichloromethane (110 ml). The mixture was let to slowly warm to room temperature and continued stirring for output. After removal in vacuo of the solvent the mixture was diluted with EtOAc and extracted with water, 0.1 M HCl and brine. Drying (MgSO4and removal in vacuo of the solvent gave 14.6 g of a viscous oil:13With NMR (300 MHz, CDCl3) 172,67, 139,79, 132,78, 129,22, 127,02, 66,77, 52,01, 47,72, 38,31.

Calculated for C11H15NO5S: 48,34; H OF 5.53; N 5,13; S 11,73. Found: 48,44; H 5,61; N 4,90; S 11,34.

Part C. Methyl 3-oxo-4-(phenylsulfonyl)butanoate.

The alcohol Part B (2.8 g, 10 mmol) was oxidized with Jones reagent under standard conditions. The ketone was purified by chromatography on silica gel by elution 0-100% EtOAc in hexane, getting 1,11 is, 27,17, 52,71, 51,91, 46,15.

Calculated for C11H13NO5S: 48,70; H A 4.83; N 5,16; S 11,82. Found: 48,77; H 4,69; N 5,08; S 11,88.

Part G of Methyl 3-(R,S)-3-amino-4-(phenylsulfonyl)butanoate.

At room temperature to a solution of ketone side In (0.71 g, 2.6 mmol) in MeOH (7 ml) and THF (3 ml) was added ammonium formate (2.5 g, 39 mmol) and cyanoborohydride sodium (0.25 g, 3.9 mmol). Through 45,5 h the solvent is evaporated and the residue was diluted with EtOAc (70 ml). This solution was extracted with 1.0 M NaOH, water and brine. After concentration the product was purified by chromatography on silica gel by elution 0-100% EtOAc in hexane, then 1-20% MeOH in EtOAc, getting 0.16 g of a viscous oil, which eventually hardened; 1H NMR (300 MHz, CDCl3) 9,79 (br, 2H), to 7.84 (d, 2H, J=8 Hz), 7,81 (br, 1H), 7.68 per-7,53 (m, 3H), 4,05-to 3.92 (m, 1H, in), 3.75 (s, 3H), 3.33 and-3,17 (m, 2H), 2,89-of 2.72 (m, 2H); MCBP e/z calculated (M+H)+: 273,0909; found: 273,0916.

Part D. Methyl 3-(R,S)-{5(R,S)-N-[3- (4-N-t - butyloxycarbonyl) phenyl)isoxazole-3-ylacetic]amino}- (phenylsulfonyl)butanoate.

This compound was obtained in analogy with example 348, part D, stirring 24 h in 5 ml of EtOAc and 1 ml DMF. Chromatography 5% MeOH/CHCl3gave 80% orange solid residue; IR-spectrum (KBr) 3296, 2338, 1736, 1660, 1618 cm-1; MC BP, e/z calculated for (M+N)+: Alcolholic)butanoate, salt triperoxonane acid.

From the product of part D was tsalala protection as in example 348, part E, receiving 86% pink solid residue; IR-spectrum (KBr) 3312, 3104, 1734, 1670; MS, BP, e/z calculated for (M+N)+: 502,1760; found: 502,1761. More active diastereoisomer (based on PRP analysis) was isolated from the above mixture SFC HPLC, Chiralpak AD - h cm by elution with 0.1% TFA/25% MeOH/75% CO2. Under these conditions, a more active diastereoisomer was elyuirovaniya last.

Example 362

Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]amino} -4-(n - butylsulfonyl)butanoate, salt triptocaine acid

Part A. Methyl 3-(R,S)-hydroxy-4- (n - butylsulfonyl)butanoate.

This compound was obtained similarly as in example 359, part B, using n-butylsulfonyl. Colorless waxy solid residue of excellent purity was obtained with 65% yield without purification; tPL46-50oC;13With NMR (300 MHz, CDCl3) 172,64, 67,29, 52,56, 51,99, 47,83, 38,40, 25,57, 21,52, 13,55.

Calculated for C19H19NO5S: 42,67; H TO 7.59; N OF 5.53; S 12,66. Found: 42,69; H To 7.59; N Are 5.36; S 12,78.

The part b Methyl-3-oxa-4-(n-butylsulfonyl)butanoate.

The resulting alcohol was immediately oxidized as described in example 359, part b, St>H17NO5S: 43,02; H 6,82; N 5,57; S OF 12.76. Found: 42,68; H 7,03; N 5,74; S 13,06.

Part C. Methyl 3(R,S)-3-amino-4-(n - butylsulfonyl)butanoate.

The compound was obtained in analogy with example 350, part B, using the above product of part B (1.20 g, 4.8 mmol) to give 0.26 g of a yellow oil; 1H NMR (300 MHz, CDCl3) 3,70 (s, 3H), 3,38 (m, 1H), 3,24-3,13 (m, 1H), to 3.02 (m, 4H), 2,58-2,52 (dd, J=16, J'= 11, 1H), 1,79 (m, 2H), 1,24 (m, 2H), of 0.95 (t, 3H); MC (NH4-DCI) calculated for (M+H)+: 271; found: 271.

Part G of Methyl 3(R,S)-{5(R,S)-N-[3-(4-N-t - butoxycarbonylamino) phenyl)isoxazolin-5-ylacetic]amino}-4-(n - butylsulfonyl)butanoate.

To a solution of 3-[4-(N-t - butoxycarbonylamino)phenyl)isoxazolin-5-luxusni acid (0.24 g, 0.83 mmol) in DMF (20 ml) was added the product from Part b (0,29 g, 0.83 mmol), TBTU (0.27 g, 0.83 mmol) and Et3N ones (0.46 ml, 3.3 mmol). After stirring for 4 h at room temperature the reaction mixture was diluted in EtOAc, was extracted with buffer pH 4 (hydroptila potassium), saturated NaHCO3brine, then dried (NaSO4). Concentration followed by chromatography on silica gel, 100% EtOAc gave 1,17 g of a white foam; MS (NH3-DCI)wycislo for (M+N)+: 582,3; found: 582; IR-spectrum (KBr) 3312, 2338, 1620, 1144 cm-1.

Part D. Methyl 3(R,islote.

To a solution of the product of part G (0,22 g, and 0.37 mmol) in DCM (10 ml) was added triperoxonane acid. The reaction mixture was stirred 2 h at room temperature, triturated with Et2O and the resulting precipitate was chromatographically on silicalite in 20% MeOH in CHCl3with the release of 0.20 g of a white solid residue; MS, BP, e/z calculated for (M+N)+: 482,2073; found: 482,2090; tPL178-184oC.

Example 365

Methyl { 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5 - ylacetic]amino}-4-(methoxycarbonyl) butanoate, salt triperoxonane acid

Part A. Dimethyl 3-aminoglutaric, salt of hydrochloric acid.

This product was received as described in example 359, part a, beta-glutamic acid, obtaining fluids in the form of a colourless resin with a quantitative yield; MS, BP, e/z calculated for (M+N)+: 176,0923; found: 176,0933.

The part b Methyl { 5(R, S)-N-[3-(4-(N-t - butoxycarbonylamino) phenyl)isoxazolin-5-ylacetic]amino}-4- (methoxycarbonyl)butanoate.

Received by analogy with example 359, part D, with the release of 32% of the white solid residue; MS, BP, e/z calculated for (M+N)+: 505,2298; found: 505,2283.

Part C. Methyl { 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5 - ylacetic] amino}-4-(methoxycarbonyl)butanoate, triperoxonane acid.

-1; MS, BP, e/z Rasch. for (M+N)+: 405,1774; found: 405,1775.

Example 368

Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]amino} -4- (methoxycarbonyl)pentanoate, triperoxonane acid

Part A. Dimethyl 3-(R,S)-aminoadipate, salt of hydrochloric acid.

This product was obtained as in Example 359, part a, beta-aminoadipic acid with the formation of a colourless resin with a quantitative yield; MS, BP, e/z calculated for (M+N)+: 190,1079; found: 190,1080.

The part b Methyl-3(R,S)-{5(R,S)-N-[3-(4-N-t - butoxycarbonylamino) phenyl)isoxazolin-5-ylacetic]amino}-4- (methoxycarbonyl)pentanoate.

This substance was obtained by analogy with example 362, part G using the above-mentioned connection part a (to 0.70 g, 3.1 mmol) with a yield of 1.17 g of a white foam; MS, BP, e/z calculated for (M+N)+: 519,2454; found: 519,2459.

Calculated for C25H34N4O8: 57,90; H IS 6.61; N 10,80. Found: 57,73; H 6,51; N 10,86.

Part C. Methyl 3(R,S)-{5(R,S)-N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic] amino}-4- (methoxycarbonyl)pentanoate, triperoxonane acid.

This product was obtained as in example 362, part D using the above product of part b (1,00 g, 1.9 mmol) to yield 0.9 g of a white solid fuel is ptx2">

Example 375

Getting 2-(R, S)-2-carboxymethyl-1-{ 5-(R, S)-N- [3-(4-amidinophenoxy) isoxazolin-5-ylacetic]} piperidine

Part A. Obtaining 2-(methoxy-2-oxoethyl)piperidine.

Hydrochloric acid pyridyloxy acid (10,00 g, 57.6 mmol) and platinum oxide (IV) (1,00 g, 4.4 mmol) was dissolved in a mixture of 75 ml of acetic acid, 75 ml of methanol and 10 ml of concentrated HCl at Parr under 60 hsi hydrogen at room temperature overnight. Then the mixture was filtered through Celite and the filtrate evaporated under reduced pressure to yield 8,42 g (75,9%) of the above compound in the form of not-quite-white solid residue. MS (NH3- CI/DDIP): m/e 158 (M+N)+.1H NMR (300 MHz, CDCl3) 1,50 is 1.96 (m, 6H), 2,80 (m, 2H), 3,20-of 3.60 (m, 3H), 3,76 (s, 3H).13With NMR (60 MHz, d6-DMSO): 21,94, 28,05, 37,46, 40,49, 44,12, 57,33, 52,74, 170,39.

Part B. Obtaining 2-(R,S)-2-(methoxy-2-oxoethyl) -1-{5- (R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetic)} piperidine.

To 2.00 g (8.69 mmol) of 3-(4-cyanophenyl)-isoxazolin-5-luxusni acid in anhydrous DMF was added to 1.36 g (8.69 mmol) of 2-(methoxy-2 - oxoethyl)piperidine, 2,80 g (8.69 mmol) TBTU and 6,05 ml (to 34.7 mmol) diisopropylethylamine. After stirring for 6 h the reaction mixture was diluted with ethyl acetate and washed with 5% aqueous citric acid solution, water, 5% in travali. The filtrate is evaporated under reduced pressure, obtaining the crude product as a yellow foam. Purification column flash chromatography on silica gel with 25-75% ethyl acetate in hexane gave 1.54 g (48%) of the indicated compound as a yellow foam. Of the mixture was allocated a single diastereoisomer (racemic). MS (NH3-CI/DDIP): m/e 370 (M+H)+.1H NMR (300 MHz, CDCl3) of 1.42 to 1.76 (m, 6H), 2,60 (m, 2H), 2.77-to a 3.01 (m, 3H), 3,05-3,26 (m, 2H), 3,56-3,70 (m, 4H), 4,50 (m, 1H), 5,20 (m, 1H), 7,69 (d, J=8,4 Hz, 2H), to 7.77 (d, J=8,4 Hz, 2H).

Part of the Century, Obtaining 2-(methoxy-2-oxoethyl)-1-{N-[3-(4 - amidinophenoxy) isoxazolin-5-ylacetic]) piperidine (racemic diastereoisomer A).

Gaseous HCl propulsively through a solution of 1.02 g (2,80 mmol) of the product of part B in 30 ml of anhydrous MeOH, cooled in an ice bath for 2 hours Then the reaction flask was sealed with Teflon tape and warmed to room temperature, stirring overnight. Evaporated MeOH under reduced pressure and then under vacuum, obtaining the intermediate imidate in the form of a yellow foam. MS (ESI): m/e 402 (M+H)+. Then it was mixed with 8,07 g (of 84.0 mmol) (NH4)2CO3in 30 ml of anhydrous EtOH overnight in a sealed reaction flask. After filtration the filtrate is evaporated under reduced pressure, obtaining the crude product is 9 g (26.8 per cent) of the specified compound as a yellow solid residue. MS (ESI): m/e 387 (M+H)+.1H NMR (300 MHz, d6-DMSO) of 1.57-1,67 (br, 6H), 2,46-2,90 (m, 5H), and 3.16 (m, 2H), 3,53-to 3.64 (m, 4H), 4,36 (br. m, 1H), 5,07 (br. m, 1H), 7,89 (m, 4H), 9,38 (br. s, 3H).

Part Was Getting 2-carboxymethyl-1-{N-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic)} piperidine (racemic isomer A).

To a solution of 0.08 g (0.2 mmol) of the product selected in part b, in 5 ml of anhydrous THF at ambient temperature was added 0.5 ml (0.5 mmol) of 1.0 M solution NaOTMS in THF. After stirring overnight the solvent is evaporated under reduced pressure, obtaining a yellow solid residue, which was recrystallized from MeOH and Et2O receiving 0.05 g (64,9%) of the named compound as a yellow powder. MS (ESI): m/e 373 (M+H)+.1H NMR (300 MHz, CD3OD) 1,68 (br., 6H), of 2.56 (m, 2H), 2,72 (m, 3H), equal to 2.94 (m, 2H), only 3.57 (m, 4H), 4,46 (br., 1H), 5,18 (br., 1 (H), to 7.84 (m, 4H).

Example 377

Getting 2-(R, S)-2-carboxymethyl-1-{ 5-(R, S)-N- [3-(4-amidinophenoxy) isoxazolin-5-ylacetic]} azepine

Part A. Obtaining 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)- N-[3-(4-cyanophenyl)isoxazolin-5-ylacetic]}azepine.

Received 0.73 g (84,6%) of the compounds of 0.50 g (2,17 mmol) 3-(4 - cyanophenyl)isoxazolin-5-luxusni acid, using 0.40 g (2,17 mmol) 2-(ethoxy-2-oxoethyl)azepine, 0,70 g (2,17 mmol) TBTU and is 1.51 ml (to 8.70 mmol) Cl3) of 1.26 (m, 11H) and 1.83 (br., 2H), 2.05 is (m, 1H), 2,18-to 2.65 (m, 2H), was 2.76-to 2.85 (m, 1H), 3.04 from (m, 2H), 3,62 (s, 1H), 4,08 (m, 2H), 5,22 (m, 1H), 7,68 (d, J=8,4 Hz, 2H), 7,78 (d, J= 8,4 Hz, 2H).

Part B. Obtaining 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)- N-[3-(4 - amidinophenoxy) isoxazolin-5-ylacetic]} azepine.

0,42 g (61.1 per cent) of these compounds were obtained according to the method of example 375, part b, of 0.73 g (of 1.84 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1- {5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetic] } azepine, using as solvent EtOH. MS (NH3-CI/DDIP): m/e 415 (M+H)+.1H NMR (300 MHz, d6-DMSO) of 1.18 (m, 3H), of 1.38 (m, 2H), 1.70 to (m, 4H), 2,08 (br., 2H), 2,66 (m, 2H), 3,02-3,26 (m, 2H), 3,60 (br. m, 1H), of 4.05 (m, 2H), 4,58 (m, 1H), 5,10 (m, 1H), of 7.90 (m, 4H), 9,38 (br. s, 3H).

Part of the Century, Obtaining 2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3- (4-amidinophenoxy) isoxazolin-5-ylacetic)} azepine.

0.12 g (82,9%) of the indicated compound was obtained according to the method of example 375, part G, 0.16 g (0.35 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N- [3-(4-amidinophenoxy) isoxazolin-5-ylacetic] } azepine using 0,89 ml (0.89 mmol) of 1.0 M solution NaOTMS in THF. MS (NH3-DCI): m/e 387 (M+N)+.

Example 400

Obtaining 3-(R,S)-(methoxy-2-oxoethyl)-4-{5- (R,S)-N-[3-(4-amidinophenoxy) isoxazolin-5-ylacetic]}piperazine-2 - it

Part A. 3-(R, S)-(ethoxy-2-oxoethyl)-4-{ 5-(R,S)-N- [3-(4 - cyanophenyl) isoxazolin-5-ylacetic]}Pipa) 3-(4-cyanophenyl)isoxazolin-5-yl-acetic acid, using 0,81 g (4,34 mmol) ethyl 2-piperazine - 3-one acetate, 1,39 (4,34 mmol) TBTU and to 3.02 ml (17,40 mmol) diisopropylethylamine. MS (NH3-CI/DDIP): m/e 399 (M+N)+.1H NMR (300 MHz, CDCl3) of 1.26 (m, 3H), 2.71 to the 3.65 (br., 9H), a 3.87 (br., m, 1H), 4,16 (m, 2H), 5,01 & 5,09 (two t, J= 5.0 and 5.1 Hz, 1H), 5,20 (m, 1H), 7,00 & 7,12 (two br, 1H), to 7.77 (m, 4H).

Part B. 3-(R, S)-(methoxy-2-oxoethyl)-4-{ 5-(R,S)- [3-(4 - amidinophenoxy) isoxazolin-5-ylacetic]} piperazine-2-it.

0,30 g (27.6 per cent) of the indicated compound was obtained according to example 375, part b, of 1.08 g (a 2.71 mmol) 3-(R,S)-(ethoxy-2-oxoethyl)- 4-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetic]}piperazine-2 - it. MS (NH3-CI/DDIP): m/e 402 (M+H)+.1H NMR (300 MHz, d6-DMSO) 2,70-to 3.67 (m, 12H), 3,91 (br., 1H), 4,87 & with 4.64 (two m, 1H), is 5.06 (m, 1H), 7,88 (m, 4H), 8,16 (br., 1H), 9,40 (br. s, 3H).

Example 434

Obtain (S)- N-[3-(4-amidinophenoxy)isoxazolin - 5-(R, S)-ylacetic] - aspartate-N- (2-phenylethyl)amide, salt triperoxonane acid

Part A. Obtaining (S)- N(benzyloxycarbonyl)- -(O-t-butyl) - aspartate-N-(2-phenylethyl)amide.

To a solution of (S)-N-(benzyloxycarbonyl)-- (O-t-butyl)-aspartic acid (BACHEM-Bioscience Inc) (3,20 g, 9.9 mmol) in DCM (25 ml) was added amoxifillin (1,34 g, 11.1 mmol) was then added DEC (2.10 g, 10.9 mmol). The reaction mixture was stirred at3and saturated NaCl, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum, obtaining 4,28 g (100%) of the amide, which was of sufficient purity for use in the next step;1H NMR (300 MHz, CDCl3) to 7.35 (s, 5H), 7,17-to 7.35 (bm, 5H), of 6.52 (bs, 1H), 5,93 (bd, J=8,1 Hz,

1H), 5,10 (s, 2H), 4,46 (bm, 1H), 3,50 (dd, J=13,9, 6.2 Hz, 2H), 2,92 (dd, J=17,0, 4,2 Hz, 2H), 2.57 m (dd, J=17,0, 6.4 Hz, 1H), of 1.42 (s, 9H); mass spectrum (NH3-DCl, e/z, relative abundance) 444 (M+NH4)+, 100%; 427 (M+H)+, 4%.

Part b Claim (S)--(O-t-butyl) - aspartate-N- (2 - phenylethyl)amide.

Carried out the hydrogenation reaction in a solution of (S)-M-(benzyloxycarbonyl)--(O-t-butyl) - aspartate-N-(2-phenylethyl)amide (4.09 g, 9,58 mmol) in ethanol (30 ml) at atmospheric pressure, using as catalyst 10% palladium on carbon (1.0 g) for 90 minutes, the Catalyst was removed by filtration and the filtrate was concentrated under vacuum to obtain 2,80 g amber oil, which was purified flash chromatography (5% MeOH/DCM), getting to 2.13 g (76%) of free amine in the form of solids;1H NMR (300 MHz, CDCl3) 7,44 (bs, 1H), 7,20-to 7.35 (m, 5H), 3,61 (dd, J=8,4, and 3.7 Hz, 1H), 3,52 (dd, J=13,2, 7,0 Hz, 1H), 2,80-2,90 (m, 3H), 2,46 (dd, J=16,7, and 8.4 Hz, 1H), 1,58 (bs, 2H), 1,45 (s, 9H); mass spectrum (ESI, e/z, relative abundance) 293, (M+N)+, 37%; 237, (M+acetate, salt of hydrochloric acid.

A suspension of 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-luxusni acid (23.1 g, 100 mmol) in 200 ml of anhydrous methanol was cooled in an ice bath and propulsively through the reaction mixture with dry gaseous HCl until a clear solution is formed. The total reaction time of joining about 3 hours the Reaction flask was sealed and given the reaction mixture to warm to room temperature with stirring for approximately 24 hours After deposition of the reaction product of the methanol solution was poured into 600 ml of anhydrous ether and the resulting slurry was cooled to -25oC for 2.5 hours and Then the slurry was diluted with 100 ml of chilled anhydrous ether. The precipitate was filtered off, washed with two portions of 100 ml of cold ether and the residue was dried in nitrogen atmosphere, receiving 23.3 g (73%) salt of hydrochloric acid;1H NMR (300 MHz, CDCl3) to 12.9 (bs, 1H), and 12.2 (bs, 1H), 8,46 (d, J=8,8 Hz, 2H), 7,86 (d, J=8,8 Hz, 2H), 5,20 (bm, 1H), 4,59 (s, 3H), 3,74 (s, 3H), 3,53 (dd, J=16,8, a 10.6 Hz, 1H), 3.15 in (dd, J=16,8, 7.7 Hz, 1H), 2,90 (dd, J=16,l, 6.2 Hz, 1H), 2,70 (dd, J=16,l, 7,3 Hz, 1H), 1.77 in (bs, 1H); mass spectrum (NH3-CI/DDIP, e/z, relative abundance) 277, (M+H)+, 100%.

Part, Obtain methyl 3-(4-amidinophenoxy)-(5R,S)- isoxazolin-5-ylacetic, salt of hydrochloric acid.

Suspension salancik the OLE was stirred at room temperature for 14 h, during which the solid residue was completely dissolved. The solution was concentrated in vacuo, getting 22.1 g (100%) of the crude salt of hydrochloric acid in the form of a reddish-brown solid residue;1H NMR (300 MHz, CDCl3) 9,6-9,2 (b), to $ 7.91 (d, J=8,8 Hz, 2H), 7,87 (d, J= 8,8 Hz, 2H), 5,08 (bm, 1H), to 3.64 (s, 3H), 3,3-3,1 (m, 2H), 2,8 (m, 2H); mass spectrum (ESI, e/z, relative abundance) 264, (M+H)+, 100%.

Part D. Obtain methyl 3-(4-N-BOC-lidinopril)isoxazolin-5-racette.

To a solution of 21.6 g (72,5 mmol) methyl 3-(4-amidinophenoxy)isoxazolin-5-ilaclama (obtained according to example 434, part D) in 350 ml of DMF, cooled in an ice bath, was added to 20.2 ml (145 mmol) of triethylamine and 17.4 g (79,8 mmol) di-tert-BUTYLCARBAMATE. The mixture was heated to room temperature and stirred 16 hours the Reaction mixture was poured into 1500 ml of water with stirring. After the formation of the precipitate and the mixture was filtered and dried on the filter under nitrogen atmosphere, receiving, and 19.6 g (74.8 percent) of the compounds in the form of a white solid. MS (ESI): m/e 362 (M+H)+; 306 (M+H-tBU)+.1H NMR (300 MHz, d6-DMSO) of 1.56 (s, 9H), 2,68 (dd, J=6,1, 6,1 Hz, 1H), 2,90 (dd, J= 6,1, 6,1 Hz, 1H), 3,14 (dd, J=6,8, 6,8 Hz, 1H), 3,74 (s, 3H), 5,14 (m, 1H), of 7.70 (d, J=8,4 Hz, 2H), of 7.90 (d, J=8,4 Hz, 2H).13C NMR (60 MHz, d6-DMSO): 28,46; 39,31; 39,58; 51,98; 77,89; 78,35; 126,91; 128,51; 132,79; 136,24; 156

To a solution of 18,95 g (a 52.4 mmol) of methyl 3-(4-N - BOC-lidinopril)isoxazolin-5-ilaclama (obtained according to example 434, part D) in 500 ml of methanol was added to 2.42 g (57,7 mmol) of lithium hydroxide (monohydrate) in 75 ml of water at 22oC. the Mixture was stirred 16 h at 22oC and then filtered: the filtrate is evaporated under reduced pressure to remove methanol. The remaining aqueous phase was cooled in an ice bath and sekilala 6 N and 1 N HCl to pH 4. Formed white solid residue, which was left over night at -4oC. the Precipitate was filtered and dried on the filter under nitrogen atmosphere, getting 17,74 g (97,4%) of the compounds in the form of not-quite-white powder. MS (ESI): m/e 348 (M+H)+; 292 (M+H-tBU)+.1H NMR (300 MHz, d6-DMSO) of 1.50 (s, 9H), 2,68 (d, J=7,0 Hz, 2H), up 3.22 (dd, J=7,2, 7.2 Hz, 1H), 3,62 (dd, J=6,8, 7.2 Hz, 1H), 5,04 (t, 1H), 7,78 (d, J=8,4 Hz, 2H), 7,94 (d, J=8,4 Hz, 2H).13C NMR (60 MHz, d6-DMSO): 28,27; 39,30; 40,44; 78,39; 81,55; 126,87; 129,43; 132,78; 133,87; 156,76; 158,61; 165,58; 171,91.

Part of the railway Receipt (S)-N-[3-(4-N-Boc-lidinopril) isoxazolin-5-(R,S) -ylacetic]-(O-t-butyl) - aspartate-N-(2-phenylethyl)amide.

To a suspension of (S)--(O-t-butyl) - aspartate-N-(2-phenylethyl)amide (0,30 g, 1.0 mmol), 3-(4-N-BOC-amidinophenoxy)-isoxazolin-5-yl-acetic acid (0.35 g, 1.0 mmol) and TBTU (0.32 g, 1.0 mmol) in EtOAc (20 ml) EXT is diluted with EtOAc (20 ml), washed with buffer with pH 4, water, 5% NaHCO3and saturated NaCl, dried over anhydrous MgS04, filtered and concentrated under vacuum obtaining of 0.58 g of the solid residue. The crude product was purified flash chromatography (100% EtOAc) to give 0.51 g (81%);1H NMR (300 MHz, CDCl3) 7,89 (t, J=8,1 Hz, 2H), 7,69 (m, 2H), 7,25 of 7.3 (m, 3H), 7,15-7,25 (m, 4H),? 7.04 baby mortality (d, J=8,4 Hz, 1H), 6,65-to 6.80 (dt, 1H), 5,10 (bm, 1H), 4,71 (bm, 1H), 3,4-3,7 (bm, 3H), 3,1-3,3 (Octet, 1H), 2,75-2,95 (m, ZN), a 2.5 to 2.65 (m, 3H), and 1.56 (s, 9H), of 1.44 (d, 9H); mass spectrum (ESI, e/z, relative abundance) 622, (M+H)+, 100%.

Example 435

Obtain (S)-N-[3-(4-amidinophenoxy) isoxazolin-5(R, S)-ylacetic] --aspartate-N- (2-phenylethyl)amide, salt triperoxonane acid

A solution of (S)-N-[3-(4-N-Vos-lidinopril)isoxazolin-5-ylacetic] --(O-t-butyl) - aspartate-N-(2-phenylethyl)amide (160 mg, 0.26 mmol) in triperoxonane acid (10 ml) and DCM (10 ml) was stirred for three days at room temperature. The solution was concentrated under vacuum, receiving 150 mg of the product;1H NMR (300 MHz, CDCl3) 9,40 (bs, 2H), 9,26 (bs, 2H), 8,33 (t, J=8.6 Hz, 1H), 7,85 to 8.0 (m, 1H), 7,88 (s, 4H), and 7.3 (m, 1H), 7,28 (d, J=7,1 Hz, 2H), 7,20 (d, J=7,1 Hz, 2H), 5,07 (bm, 1H), 4,56 (bm, 1H), 3,5-3,6 (octet, 1H), 3,26 (bt, J=7,0, 2H), 3,2 (m, 1H), 2,70 (bt, J=7,0, 2H), 2,6-2,65 (bm, 2H), 2,4-2,5 (m, 2H); mass spectrum (ESI, e/z, relative abundance) 466, (M+H)+, 100%.

Examples A and B

Razil]-S-2,3-diaminopropionic and salts of hydrochloric acid methyl N2- 3-methylphenylsulfonyl-N3-[3-(4-amidinophenoxy)-5S-ylacetic] -R-2,3 - diaminopropionic

Initially, the mixture was purified on column Pirkle DNBPG, using as eluent 10% HOAc/ 20% EtOH/ 70% hexane. The column temperature was maintained at 45oC, rate of 1.5 ml/min and the detector was set at 280 nm. The diastereomers were then separated on h cm column Chiralcel OD-25, using as eluent 0,l% TFA/ 20% MeOH/ 80% CO2. The column temperature was 30oC, the flow rate of 13 ml/min, pressure 175 bar and the detector was set at 280 nm. The application was installed on 23 mg of sample. Two columns in common was applied 300 mg of the sample obtained 59 mg of the R isomer, example A (MS BP calculated for C23H27N5O6S: 502,176031; found: 502,175508), and 85 mg of the S isomer, example B (MS BP calculated for C23H27N5O6S: 502,176031; found: 502,176358).

Example V

N2-methylphenylsulfonyl-N3-[3-(4-amidinophenoxy)-5S - ylacetic]-S-2,3-diaminopropionic acid

Part A. Methyl-N2-3-methylphenylsulfonyl-N3-[3-(4 - cyanophenyl)-5S-ylacetic]-S-2,3-diaminopropionic

To a solution of 3-(4-cyanophenyl)isoxazolin-5-S-luxusni acid (1,82 g of 7.90 mmol, obtained as described in example 314A, part E) in DMF (5 is), TBTU (2,53 g of 7.90 mmol) and the base of Hongsa (2,75 ml, 15.8 mmol). After stirring at room temperature for 16 h the reaction mixture was diluted with EtOAc (500 ml) and washed once with water (200 ml), once with saturated NaHCO3(200 ml), once with 0.1 N HCl (200 ml), dried (MgS04), filtered and concentrated, and column chromatography on silica gel with 10% EtOAc/hexane as eluent gave 1,99 g (52%) of the desired substance in the form of not-quite-white foam.1H NMR (CDCl3) 7,81 for 7.78 (d, 2H, J=8,4 Hz), 7,16-to 7.67 (d, 2H, J=8,8 Hz), to 7.61-7,58 (m, 2H), 7,39-7,37 (d, 2H, J=5,1 Hz), 6,35-6,30 (m, 1H), 5,54-5,52 (d, 1H, J=7,7 Hz), 5,18-5,17 (m, 1H), 4,00-of 3.96 (m, 1H), 3,62-to 3.50 (m, 3H), of 3.57 (s, 3H), 3.27 to 3,19 (dd, 1H, J= 7,7, of 17.0 Hz), 2,78-2,70 (dd, 1H, J=5,9, 14,8 Hz), 2,64-to 2.57 (dd, 1H, J=6,6,, 14.6 Hz), 2,42 (s, 3H).

Part B. Hydrochloric methyl-N2-3-methylphenylsulfonyl-N3-[3-(4 - amidinophenoxy)-5S-ylacetic] -S-2,3-diaminopropionic.

Methyl-N2-3-methylphenylsulfonyl-N3- [3-(4-cyanophenyl)-5S-ylacetic]-S-2,3 - diaminopropionic was dissolved in 100 ml of absolute ethanol at 0oC and let in a stream of gaseous HCl for 2 hours the Reaction vessel was sealed and after stirring at room temperature for 16 h volatile componenet was removed in vacuo. The residue was diluted with 100 ml of absolute ethanol, were added ammonium carbonate (9,6 Na chromatography on silica gel by gradient elution with 5% MeOH/CH2Cl2-20% MeOH/CH2Cl2gave 0,726 g (37%) of the desired amidine in the form of a white solid residue.1H NMR (CDCl3) 8,23-to 8.20 (m, 1H), to $ 7.91-a 7.85 (m, 4H), EUR 7.57-rate of 7.54 (m, 2H), 7,49 - 7,46 (m, 2H), 5,00-4,94 (m, 1H), 4,08-3,86 (m, 1H), 3,59-to 3.49 (m, 1H), 3,39 (s, 3H), 3,38-3,29 (m, 3H), 2.49 USD (s, 3H), 2,50 at 2.45 (m, 2H). MC BP calculated for C23H27N5O6S: 502,176031; found: 502,175992. []D=+48,88oC (c= 0,180, MeOH).

Part of the Century. N2-3-methylphenylsulfonyl-N3-[3-(4 - amidinophenoxy)-5(S)-yl]acetyl-S-2,3-diaminopropionic acid.

Connection example V, part B (0,077 g, 0.14 mmol) was dissolved in MeOH (4 ml). To the resulting solution was added a solution of lithium hydroxide (0,0066 g, 0,158 mmol) in water (4 ml) and the mixture was stirred overnight at room temperature. The methanol was removed by evaporation under vacuum and the product from the aqueous phase precipitated in the form of a white solid residue (0,026 g, 35%). MC BP calculated for C22H25N5O6S: 488,160381; found: 488,160827.

Example G

Hydrochloric methyl-N2-methylphenylsulfonyl-N3-[3- (4-amidinophenoxy)-5R-ylacetic]-S-2,3-diaminopropionic

Part A. Methyl-N2-methylphenylsulfonyl-N3-[3-(4-cyanophenyl)-5R - ylacetic] -S-2,3-diaminopropionic.

This compound was synthesized from 3-(4-cyanophenyl)isoxazolin-5-(R)-Ile in example V, part A. the Output is 41%. Calculated: C 57,02; H 4,99; N To 11.56. Found: C 56,83; H To 4.87; N Of 11.45.

The part b Methyl-N2-methylphenylsulfonyl-N3-[3-(4-cyanophenyl)-5R-ylacetic]- S-2,3-diaminopropionic.

This compound was synthesized from methyl-N2-methylphenylsulfonyl-N3-[3-(4-cyanophenyl)-5R-ylacetic] -S - 2,3-diaminopropionic in the same way as in example V, part B. the Output is 49%. MC BP calculated for C23H27N5O6S: 502,176031; found: 502,174103.

Example 496

Methyl-N2-(2,2-diphenyl-1-atenolol)-N3-[3-(4 - amidinophenoxy)isoxazolin-5-(R,S)-ylacetic]-(S)-2,3 - diaminopropionic, salt triperoxonane acid

Part A. Methyl-N2-(2,2-diphenyl-1-atenolol)-N3-Boc-(S)- 2,3-diaminopropionic.

To a mixture of methyl N3-Boc-(S)-2,3-diaminopropionic (255 mg, 1,17 mmol) and 2,2-diphenylethylenediamine chloride (Hasegawa and Hirooka, J. Chem.Soc.Japan 48, 1513-1518 (1975); 391 mg, of 1.40 mmol) in methylene chloride (10 ml), cooled in an ice bath, was added triethylamine (0.25 ml, of 1.76 mmol). After 22 h the mixture was concentrated and held flash chromatography (6:4 toluene/ethylacetat) to give 240 mg (46%) of the final product. NMR (CDCl3) 7,42-7,20 (10H), for 6.81 (s, 1H), 5,24 (bd, 1H), 4,87 (bs, 1H), 3,95 (q, 1H), and 3.72 (s, 3H), 3,50-3,42 (2H), the 1.44 (s, 9H); mass spectrum (NH3-CI) m/z 466,54 (M+l TFA.

The product of part a (210 mg, 0,468 mmol) was dissolved in 5 ml of methylene chloride and 3 ml TFA. After 1 h, the solution was concentrated, obtaining an oily product (222 mg, 100%). NMR (CDCl3) 8,02 (bs, 3H), 7,40 (m, 5H), 7.23 percent (m, 4H), 7,00 (s, 1H), 4.26 deaths (m, 1H), 3,71 (s, 3H), 3,20 (m, 1H), 2,98 (m, 1H); mass spectrum (NH3-CI) m/z.

Part of the Century Methyl-N2-(2,2-diphenyl-1-atenolol)-N3- [3-(4 - N-Boc-lidinopril)isoxazolin-5-(R,S)-ylacetic]-(S)-2,3 - diaminopropionic.

The product of part B (220 mg, 0.46 mmol) interacted with 3-(4-N-Boc-lidinopril)isoxazolin-5-luxusni acid (from example 434, part E; 0.46 mmol) according to the procedure of example DGB-1, part a, receiving the specified product (215 mg, 68%). NMR (CDCl3) to 7.84 (m, 2H), to 7.64 (m, 2H), 7,40-to 7.18 (10H), 6.75 in (s, 1H), 6.30-in (m, 4H), and 5.30 (m, 1H), 5,04 (m, 1H), 4,00 (1H), of 3.78 (s, 3H), 3,62 is 3.40 (4H), 3,10 (m, 1H), 2,70-of 2.50 (2H), 2,04 (s, 1H), 1,58 (s, 9H); mass spectrum (ESI) m/z 690,2 (M+H+, 100%).

Part, Methyl-N2-(2,2-diphenyl-1-atenolol)-N3-[3-(4 - amidinophenoxy)isoxazolin-5-(R, S)-ylacetic]-(S)-2,3-diaminopropionic, salt triperoxonane acid.

The product of part b (210 mg, 0.30 mmol) was dissolved in methylene chloride (3 ml) was added triperoxonane acid (1 ml) according to example DGB-1, part B, receiving the specified product (150 mg, 80%). NMR (CDCl3) 9,39 (bs, 2H), 9,05 (bs, 2H), by 8.22 (m, 1H), 8,00 (m, 1H), a 7.85 (s, 4H), 7,40 (m, 6H), 7,20 (m, is l (N2-(N,N-dimethylsulphamoyl)-N3-[3-(4 - amidinophenoxy)isoxazolin-5-(R,S)-ylacetic]-(S)-2,3 - diaminopropionic, salt triperoxonane acid

Part A. Methyl N2-(N,N-dimethylsulphamoyl)-N3-Boc-(S)-2,3 - diaminopropionic.

To a mixture of methyl N3-BOC-(S)-2,3-diaminopropionic (400 mg, of 1.80 mmol) and dimethylsulfoxide (0,24 ml of 2.20 mmol) in methylene chloride (10 ml), cooled in an ice bath, was added triethylamine (0,38 ml of 2.20 mmol). After 18 h the mixture was concentrated and put flash chromatography (6:4 toluene/ethyl acetate) to give 283 mg (49%) of product. NMR (CDCl3) 5,23 (bd, 1H), 4,90 (m, 1H), 4,06 (m, 1H), 3,80 (s, 3H), 3,52 (bt, 2H), 2,80 (s, 6H), of 1.42 (s, 9H); mass spectrum (NH3-CI) m/z 343,0 (M+NH4+, 100%).

The part b Methyl-N2-(N,N-dimethylsulphamoyl)-(S)-2,3 - diaminopropionic, TFA salt.

The product of part a was dissolved in 5 ml of methylene chloride and 3 ml TFA. After 1 h, the solution was concentrated to obtain an oily product (294 mg, 100%). NMR (DMSO-d6) of 6.52 (bs, 2H), 4,4-3,9 (2H), and 3.8 (bs, 3H), of 2.93 (bs, 6H).

Part C. Methyl N2-(N, N-dimethylsulphamoyl)-N3-(4-N-BOC - lidinopril)isoxazolin-5-(R,S)-ylacetic]-L-2,3-diaminopropionic.

The product of part B (200 mg, 0.61 mmol) interacted with 3-(4-N-Boc-lidinopril)isoxazolin-5-luxusni of kislotnost (203 mg, 61%). NMR (CDCl3) for 7.78 (m, 2H), 7,42 (bt, 2H), 7,00 (m, 1H), of 5.92 (m, 1H), 5,04 (m, 1H), 3,80 (2s, 3H), of 3.64 (m, 2H), 3,40 (m, 1H), 3,05 (m, 1H), 2,80 (2s, 6H), is 2.74 (m, 1H), 3,60 (m, 1H), 2,02 (s, 3H), 1,60 (s, 9H); mass spectrum (ESI) m/z 555,1 (M+H+100%).

Part G of Methyl N2-(N, N-(dimethylsulphamoyl)-N3-[3-(4 - amidinophenoxy)isoxazolin-5-(R, S)-ylacetic] -L-2,3-diaminopropionic, salt triperoxonane acid.

The product of part b (183 mg, 0,329 mmol) was dissolved in methylene chloride (3 ml) and treated triperoxonane acid (1 ml) according to the procedure of example DGB-1, part a, receiving the specified product (159 mg, 85%). NMR (DMSO-d6) 9,40 (bs, 2H), 9,00 (bs, 2H), by 8.22 (m, 1H), 7,82 (s, 4H), to 5.00 (m, 1H), 3,95 (m, 1H), 3,68 (2s, 3H), of 3.60 (m, 2H), 3,20 (m, 4H), 2,80 (s, 6H); mass spectrum (ESI) m/z 455,1 (M+H+, 100%).

Example 512

Methyl N2-(m-toluensulfonyl)-N3- [3-(4-amidino-2-forfinal)isoxazolin - 5-ylacetic]-S-2,3-diaminopropionic, salt of hydrochloric acid

Part A. 3-fluoro-4-methylbenzamide.

3-fluoro-4-methylbenzoic acid (10 g, 65 mmol) was heated in thionyl chloride (100 ml) with shitennou tube of 2.5 hours the Excess SOCl2was removed by distillation. The oily acid chloride was diluted in CH2Cl2(100 ml) and cooled in an ice bath. Was added dropwise concentrated aqueous solution of NH3(20 ml) and continued stirring at 02CO3(2), H2O and brine, dried (MgSO4) and concentrated to obtain 9,9 g light yellow solid residue; tPL161-163oC; IR spectrum (KBr) 3382, 1654 cm-1. Analytically calculated for C8H8FNO: C 62,74; H 5,27; N 9,15; F 12,40. Found: C 62,66; H 5,17; N 9,12; F To 12.28.

Part B. 3-fluoro-4-methylbenzonitrile.

The solution trichloroacetamide (7.3 ml, 65 mmol) in CH2Cl2(20 ml) dropwise over 0.5 h was added to a solution/suspension of the amide of part a (9.0 g, 59 mmol) and Et3N (17 ml, 120 mmol) in CH2Cl2(80 ml) at 0oC. After 40 min the mixture was concentrated in vacuo, then diluted with Et2O. the Solution was extracted with 1 M HCl, saturated aqueous NaHCO3H2O and brine, then dried (MgSO4) and concentrated to obtain 7.8 g of the reddish-brown solid residue; tPL45-47oC; IR spectrum (KBr) 2232 cm-1; MCBP, e/z calculated for (M+H)+: 135,0484; found: 135,0482.

Part C. 2-fluoro-4-cyanobenzeneboronic.

N-bromosuccinimide (9.6 g, 54 mmol) and the substance of part B (7,3 g, 54 mmol) was heated under reflux in CCl4(100 ml) under nitrogen atmosphere, irradiating for 2 h fluorescent light with high intensity. After cooling to the temperature of wallisville from hot cyclohexane (4) with the release of 4.5 g not quite white needle-like solid residue; tPL75-55oC; IR spectrum (KBr) 2236 cm-1; MCBP, e/z calculated for (M+H)+: 213,9668; found: 213,9660.

Part, 2-fluoro-4-cyanobenzaldehyde.

Benzylbromide part In (3,68 g, 17 mmol), trimethylamine-N-oxide dihydrate (7.6 g, 68 mmol), CH2Cl2(15 ml) and DMSO (30 ml) was stirred for several hours at 0oC, then slowly warmed overnight to ambient temperature. The mixture was diluted with water (30 ml) and brine (30 ml) and was extracted with Et2O (4). The combined organic phases were washed with brine, dried (MgSO4) and concentrated to yield 1.1 g of a yellow solid residue; IR-spectrum (KBr) 2238, 1706 cm-1; MCBP, e/z calculated for (M+H)+: 150,0355; found: 150,0341.

Part D. 2-fluoro-4-cyanobenzylidene.

The aldehyde part G (1.1 g, 7.4 mmol), hydrochloric acid hydroxylamine (1.0 g, 15 mmol), K2CO3(1.0 g, 7.4 mmol), water (1 ml) and MeOH (10 ml) was heated under reflux with 2.25 hours After rapid cooling, the mixture was diluted with water and the insoluble product was collected by filtration, then washed with water. Drying under high vacuum gave 0,94 g light yellow amorphous solid residue; tPL179-182oC; IR spectrum (KBr) 3256, 2236, 1556 cm-1; MCBP, e/z calculated for (M+H) The oxime part D gave to interact with Chlorox and methylvinylether the usual way of obtaining isoxazoline in the form of a yellow solid residue to yield 32%; tPL92-94oC; IR spectrum (KBr) 2240, 1746 cm-1: MCBP, e/z calculated for (M+H)+: 263,0832; found: 263,0818. Analytically calculated for C13H11FN2O3: C 59,54; H TO 4.23; N IS 10.68; F 7,24. Found: C 59,84; H Or 4.31; N 10,53; F 7,26.

Part G. of Methyl N2-(m-toluensulfonyl) -N3-[3-(4-amidino - 2-forfinal)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic, salt of hydrochloric acid.

The intermediate connection part E was converted in the specified connection through the usual sequence of steps: synthesis of amidine of Pinner, Boc protection of amidine, saponification of the ester, the condensation of 2,3-diaminodiphenylsulfone and Boc cleavage with formation of a yellow resin; MCBP, e/z calculated for (M+H)+: 520,1666; found: 520,1675.

Example 513

Methyl N2-(n-butyloxycarbonyl)-N3-[3-(3 - lidinopril-6-yl)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid

Obtaining described in example 514 methods gave a powder of light yellow color; tPL90-110oC (decomposition); MCBP, e/z calculated for (M+H)+: 449,2149; found: 449,2140.

Example 514

Methyl N2-(m-toluensulfonyl)-N3-[3-(3-lidinopril-6-yl)isoxazolin-5 - ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid

Part of the nick in DMSO (200 ml) 1 tsp After cooling to room temperature, hydrochloric acid was added hydroxylamine (16 g, 0.23 mol), potassium carbonate (29 g, 0.21 mol) and water (21 ml). The resulting mixture was heated up to 80oC 2.5 h, cooled, diluted with water (100 ml) and a large amount of acetone and deposited on the silica gel. Chromatography on silica gel with elution of 0-50% EtOAc in hexane gave 12.2 g of reddish-brown solid residue; tPL204-207oC (decomposition); MCBP, e/z calculated for (M+H)+: 148,0511; found: 148,0516.

The part b Methyl 3-(3-canopied-6-yl)isoxazolin-5-ylacetic.

The oxime of example 514, part a was converted into isoxazolin as described in example 516, part B, exit 76% yellow solid residue; tPL97-98oC; MCBP, e/z calculated for (M+H)+: 246,0879; found: 246,0881. Analytically calculated for C12H11N3O3: C 58,77; H TO 4.52; N 17,13. Found: C 58,74; H 4,51; N 17.11 Per Bbl.

Part C. Methyl 3-(3-t-butyloxycarbonyl-6 - yl)isoxazolin-5-ylacetic.

The nitrile of example 514, part B, was converted into amidin as described in example 516, parts D and e (except what was required of 0.6 EQ. NaOMe) and was carried out by attaching the Vos standard method, receiving a yellow solid after purification the product; tPL143oC (videv>N4O5: C 56,35; H 6,12; N 15,46. Found: C 56,35; H 6,10; N 15,39.

Part, Lithium 3-(3-t-butyloxycarbonyl-6 - yl)isoxazolin-5-ylacetic.

The ester of example 514, part b, omilami and liofilizirovanny as described in the method of example 516, part E, receiving quantitatively colorless amorphous solid residue; tPL> 230oC; MCBP, e/z calculated for conjugate acid (M+H)+: 349,1512; found: 349,1527.

Part D. Methyl N2-(m-toluensulfonyl-N3-[3-(3 - lidinopril-6-yl)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid.

The lithium carboxylate part of the Town was turned into the connection specified by the treatment with HCl in MeOH to obtain a yellow solid residue; tPL90oC (decomposition); MCBP, e/z calculated for (M+H)+: 503,1713; found: 507,1718.

Example 515

Methyl N2-(n-butyloxycarbonyl)-N3-[3-(2 - lidinopril-5-yl)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid

In the same way as described in example 516, the compound of example 514, part D, connected with hydrochloric acid methyl N2-(n - butyloxycarbonyl)-2,3-diaminopropionic in the above-described conditions, followed by removal of Boc 4 M HCl/dioxane with the formation of a light yellow powder; MCBP, IS)-N3-[3-(2-lidinopril - 5-yl)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid

Part A. 2-chloro-5-pyridyloxy.

2-chloro-5-formylpyridine (2.1 g, 15 mmol) are condensed with hydrochloric acid by hydroxyamino the usual way to obtain the oxime, 1.5 g, in the form of yellow crystals; tPL171-175oC (decomposition); MCBP, e/z calculated for (M+H)+: 157,0169; found: 157,0175.

The part b Methyl 3-(2-chloropyrid-5-yl)isoxazolin-5-ylacetic.

Chlorox (20 ml) was added dropwise over 1.75 h to a mixture of oxime part a (1.13 g, 7.2 mmol), methylvinylketone (70% purity, 3.0 g, 21 mmol), CH2Cl2(40 ml) and DMF (4 ml), stirring at ambient temperature. Delete CH2Cl2evaporation and diluted with a mixture of EtOAc, was extracted with water (5x) and brine, then dried (MgSO4), filtered and concentrated. Chromatography on silica gel, elution of 0-70% EtOAc in hexane, gave 1.4 g of a solid residue; tPL94-96oC; MCBP, e/z calculated for (M+H)+: 255,0536; found: 255,0531.

Part C. Methyl 3-(2-canopied-5-yl)isoxazolin-5-ylacetic.

Chloropyridin part B (0.51 g, 2.0 mmol), cyanide zinc (0,23 g, 2.0 mmol), Pd(PPh3)4(0.12 g, 0.10 mmol) and DMF (2 ml) was heated at 80oC virue of CHCl3. Chromatography on silica gel with elution 0-90% EtOAc/hexane gave 0.28 g of the solid residue light yellow color; tPL115 - 116oC; MCBP, e/z calculated for (M+H)+: 246,0879; found: 246,0880. Analytically calculated for C12H11N3O3: C 58,77; H TO 4.52; N 17,13. Found: C 58,68; H 4,48; N 16,90.

Part G of Methyl 3-(2-lidinopril-5-yl)isoxazolin-5-ylacetic, salt of formic acid.

Cyano part (of 0.47 g, 1.9 mmol) and sodium methylate (obtained in situ from the metal Na, 4 mg, 0.2 mmol) was stirred in anhydrous MeOH (6 ml) for 16 h at ambient temperature, after which1H NMR analysis of an aliquot of the reaction mixture showed the complete formation of meteomedia [a 9.25 (s, 1H) and to 3.92 (s, 3H)] . To the reaction mixture was added ammonium formate (0,60 g, 9.5 mmol) and continued stirring for another 7 hours the Mixture was absorbed on silica gel concentration in vacuo. Chromatography on silica gel by elution 0-20% MeOH in CHCl3and concentration gave 0,61 g amidine as not quite white solid residue; tPL180-182oC (decomposition); MCBP, e/z calculated for (M+H)+: 263,1144; found: 263,1148.

Part D. Methyl 3-(2-t-butyloxycarbonyl-5 - yl)isoxazolin-5-ylacetic.

To amidino part D was added Boc stands for (M+H)+: 363,1668; found: 363,1682.

Part of that is, Lithium 3-(2-t-butyloxycarbonyl-5 - yl)isoxazolin-5-ylacetic.

Methyl ester of part D (of 0.37 g, 1.0 mmol) omilami, stirring with 0.5 M LiOH in MeOH at room temperature. MeOH was removed in vacuo, and then the aqueous solution was frozen and liofilizirovanny, receiving quantitatively light yellow solid residue; MCBP, e/z calculated for (M+H)+: 349,1512; found: 349,1531.

Part G. of Methyl N2-(m-toluensulfonyl)-N3-[3-(2-lidinopril-5 - yl)isoxazolin-5-ylacetic]-S-2,3-diaminopropionic bis salt of hydrochloric acid.

The lithium carboxylate part E are condensed with hydrochloric acid methyl N2-(m-toluensulfonyl)-2,3-diaminopropionic in the above-described conditions, followed by standard Boc cleavage with 4 M HCl/dioxane, receiving an amorphous solid residue yellow; MCBP, e/z calculated for (M+H)+: 503,1713; found: 503,1707.

Example 548

Obtaining 3-bromothiophene-2-sulphonylchloride

A solution of chlorosulfonic acid (14.3 g, 0.12 mol) in 35 ml of 1,2-dichloroethane was cooled to -10oC and protected from moisture absorption. Added small portions pentachloride phosphorus (from 20.8 g, 0.1 mol), keeping the temperature between -5 and -10oC. the resulting suspension per temperature between -5 and -10oC. adding 3-bromothiophene was the highlight of hydrogen chloride; the reaction mixture became thick and pasty and hardly stirred. After complete addition of 3-bromothiophene the temperature of the reaction mixture maintained 0oC 2 h Then the mixture was heated up to 80oC and left at this temperature for 1 h, during which occurred the dissolution of the solid residue and release hydrogen chloride. The reaction mixture was cooled in an ice bath, pouring on 250 g of crushed ice and stirred for one hour to dissolve the ice. The obtained two-phase system was separated and the aqueous layer was washed three times with 125 ml of chloroform. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, receiving and 24.1 g (92%) of the crude product in the form of butter dark yellow;1H NMR (300 MHz, CDCl3) 7,22 (d, J=5,3, 1H), 7,73 (d, J= 5,3, 1H); mass spectrum (CH4-DCI/GC-MS, e/z, relative abundance) 262,8, (M+H)+, 100%; 226,9, (M+H-HCl)+, 89,7%.

Example 587A

N2-3-methylphenylsulfonyl-N3-[3-(4-amidinophenoxy)-5S-ylacetic] - S-2,3-diaminopropionic acid

Connection example V, part B (0,077 g, 0.14 mmol) was dissolved in MeOH (4 ml), LiOH (0,0066 g, 0,158 mmol) was added in the aqueous phase (or 0.027 g, yield 35%). MCBP calculated for C22H25N5O6S: 488,160381; found: 488,160827.

Example 602

Methyl N2-n-butyloxycarbonyl-N3-[3-(4-guanidinate)isoxazolin-5- (R, S)-ylacetic]-(S)-2,3-diaminopropionic, salt triperoxonane acid

Part A. [3-[(4-t-butyloxycarbonyl)phenyl] isoxazolin - 5-yl]acetic acid.

This compound was obtained with the yield of 49% of 4-t-butyloxycarbonyl and t-butylbenzylamine according to the method described in example 275, part A.1H NMR (CDCl3) 0,99 (t, 3H), of 1.35 (m, 2H), 1,50 (s, 9H), to 1.61 (m, 2H), 2,60 (dd, J=7,7 and 16.5 Hz, 1H), 2,84 (dd, J=5.9 and 16 Hz, 1H), 3,06 (dd, J= 7,4 & 16,9 Hz, 1H), 3,48 (dd, J= 10,3 & a 16.5 Hz, 1H), 4,10 (t, 2H), to 5.03 (m, 1H), 6,60 (broad s, 1H), 7,38 (d, J=8,3 Hz, 2H), 7,58 (J=8,3 Hz, 2H); IR (Kbr): 2966, 1734, 1740, 1610, 1578, 1528, 1508, 1458, 1442, 1412, 1392, 1368, 1234, 1160, 1058, 916, 878, 828, 772, 612 cm-1; MCBP calculated for C20H28N2O5: 377,207647; found: 377,207278. LiOH saponification under standard conditions gave the corresponding carboxylic acid in the form of colourless crystals with a yield of 88%. tPL178-180oC;1H NMR (CDCl3) of 1.52 (s, 9H), to 2.67 (dd, J=7.8 and 16 Hz, 1H), 2,89 (dd, J=8,3 & 16 Hz, 1H), 3,06 (dd, J=9.5 to & to 16.9 Hz, 1H), 3,48 (dd, J=10,3 & a 16.5 Hz, 1H), to 5.03 (m, 1H).

The part b Methyl N2-n-butyloxycarbonyl-N3-[3-[(4-t - butyloxycarbonyl with methyl N2-tBoc-(S)-2,3-diaminopropionic the method described in example 275, part C receives the desired product, tPL80-82oC; 1H NMR (CDCl3) a 1.88 (t, 3H), of 1.30 (m, 2H), 1,47 (sm, 20H), 2,50 (dd, 1H), 2,61 (dd, 1H), of 3.07 (dd, 1H), 3,40 (dd, 1H), 3,63 (t, 2H), 3,74 (s, 3H), 4.00 points (m, 2H), to 4.38 (m, 1H), 5,00 (m, 1H), 5,88 (dd, 1H), 6,77 (t, 1H), 7,58 (d, 2H), to 7.84 (d, 2H), 10,4 (s, 1H); IR (KBr): 3286, 2964, 1722, 1646, 1546, 1414, 1368, 1340, 1312, 1294, 1240, 1156, 1122, 1100, 1058, 1030, 844, 776 cm-1; MCBP (CI/NH4) 663 (M+H, 20), 563 (7), 549 (78), 506 (81), 463 (100).

Part C. Methyl N2-n-butyloxycarbonyl-N3-[3-(4 - guanidinate) isoxazolin-5-ylacetic]-(S)-2,3-diaminopropionic.

Connection example 602, part B, was treated with TFA in dichloromethane, receiving the appropriate aniline in the form of the TFA salt. This intermediate compound was converted into the corresponding bis-BOC-protected guanidinoacetate with the release of 59% in accordance with the method of Kim et al. (Tet. Lett. 1993, 48, 7677). The Boc cleavage under standard conditions (TFA/CH2Cl2) given a specified compound as TFA salt (90%).1H NMR (DMSO-d6) 1,89 (t, 3H), of 1.34 (m, 2H), 1.57 in (m, 2H), 2,44 (dd, 1H), 2,58 (t, 2H), 2,64 (m, 1H), 3,17 (m, 1H), 3,40 (m, 2H), 3,65 (m, 1H), 3,70 (s, 3H), 4.00 points (t, 2H), or 4.31 (m, 1H), 5,02 (m, 1H), 6,80 (m, 1H), 7,28 (d, 2H), to 7.64 (broad s, 2H), 7,68 (d, 2H), to 7.84 (broad, 1H); mass spectrum (ES) m/z 463 (M+H, 100).

Example 651

The N2-benzyloxycarbonyl-N3N-methyl-N32-benzyloxycarbonyl-N3-methyl-[3- (4-N-Boc-lidinopril)isoxazolin-5-(R,S)-ylacetic]-(S)-2,3-diaminopropionic.

To a mixture of 3-(4-N-Boc-lidinopril)isoxazolin-5-yl-acetic acid (obtained in accordance with the method of example 434, part E; 189 mg, 0.54 mmol), methyl N3N-methyl-N2-Cbz-L-2,3-diaminopropionic (obtained according to Sakai and Ohfune, J. Am. Chem. Soc. 114, 998 (1992); 145 mg, 0.54 mmol) and TBTU (175 mg, 0.54 mmol) in ethyl acetate (10 ml) was added triethylamine (0.15 ml, of 1.09 mmol). After stirring for 26 h, the mixture was diluted with ethyl acetate, washed with buffer with pH 4, then a saturated aqueous solution of bicarbonate, then saturated brine. Was the organic phase is dried (MgSO4) and concentrated. The residue flash was chromatographically (ethyl acetate) to give the product as a colourless glass (279 mg, 86%); NMR (CDCl3) 7,88 (m, 2H), 7,69 (m, 2H), 5,79 (bd, 1H), 5,09 (m, 3H), 4,58 (m, 1H), 3,86 (m, 1H), of 3.77 (2s, 3H), 3,63 (m, 2H), 3,14 (dd, 1H), 3,01 (2s, 3H), 2,9 (m, 1H), 2,53 (m, 1H), 1,66 (b, 2H), and 1.56 (s, 9H); mass spectrum (ESI) m/z 596,2 (M+H+100%).

Part B. Obtain methyl N2-benzyloxycarbonyl-N3N-methyl - N3-[3-(4-amidinophenoxy)isoxazolin-5-(R, S)-ylacetic] -(S)-2,3 - diaminopropionic, salt triperoxonane acid

The product of part a (226 mg, 0.38 mmol) Rast and room temperature the mixture was diluted with ether and stirred. The resulting white precipitate was collected by filtration, receiving the specified product in the form of a white solid residue (201 mg, 87%); NMR (DMSO-d6) 9,39 (bs, 2H), 9,19 (bs, 2H), 7,87 (s, 4H), 7,79 (t, 1H), 7,32 (m, 5H), to 5.03 (3H), and 4.40 (m, 2H), 3,90 (m, 1H), 3,65 (2s, 3H), 2.95 and and 2.82 (4s, 3H), 3,6-2,8-(4H); mass spectrum (ESI) m/z 496,3 (M+H+, 100%).

Example 701

Methyl N2-n-butyloxycarbonyl-N3-[3-(4 - amidinophenoxy)isoxazolin-5-ylacetic]-L-2,3-diaminopropionic, TFA salt

Part A. Obtain methyl 3-(4-cyanophenyl)isoxazolin-5 - ylacetic.

To a suspension of methyl 3-(4-cyanophenyl)-5(R,S)-isoxazolin-5-ilaclama (5,28 g, 21,62 mmol) in chloroform (150 ml) was added N-bromosuccinimide (to 4.23 g, 23,78 mmol) and AIBN (100 mg) and the mixture is boiled under reflux. A small amount of AIBN (100-200 mg) were added at intervals of 1 h before until TLC showed full completion of the reaction. Was added potassium acetate (17.3 g) and acetic acid (6.5 ml) and heated the reaction mixture under reflux for 1 h, cooled, then poured into 1 N NaOH (325 ml). Separated the organic layer, the aqueous layer was extracted with EtOAc (g ml). The organic layers were combined and washed the feast upon. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographically on silica gel (15-35% EtOAc in hexane), s, 1H), 3,92 (s, 2H), and 3.8 (s, 3H).

Part B. Obtain methyl 3-(4-methoxyaminomethyl)isoxazol-5 - racette, salts of hydrochloric acid.

A suspension of methyl 3-(4-cyanophenyl)isoxazol-5-ilaclama (2,19 g, 9,04 mmol) in 100 ml of anhydrous methanol was cooled in an ice bath and propulsively through the reaction mixture with gaseous HCl to form a solution. Add - 2 hours the Reaction vessel was closed and the reaction mixture was allowed to warm to room temperature with stirring for 24 hours At this point in time, the methanol solution was poured into 500 ml of anhydrous ether, precipitating the product, and the resulting suspension was cooled 3 h at -25oC. the Precipitate was filtered off, washed with two portions of 100 ml of cold ether, and dried in nitrogen atmosphere under vacuum, obtaining 2.3 g (82%) salt of hydrochloric acid;1H NMR (300 MHz, suspension in CDCl3) charged 8.52 (d, J=of 8.06 Hz, 2H), 8,03 (d, J=8,4 Hz, 2H), to 6.67 (s, 1H), 4,6 (s, 3H), 3,93 (s, 2H), and 3.8 (s, 3H).

Part C. Obtain methyl 3-(4-amidinophenoxy)isoxazol - racette, HCl salt.

A solution of methyl 3-(4-methoxyaminomethyl)isoxazol - 5-racette, HCl salt (2.3 g, 7.4 mmol) in 50 ml of anhydrous methanol was cooled in an ice bath was added 2 M ammonia in methanol (18.5 ml, 37 mmol). The reaction flask was closed and the reaction is ovale in vacuo, obtaining 2.2 g (quantitative yield) of a yellow foam;1H NMR (300 MHz, d6-DMSO) 9,6-9,2 (b) to 8.12 (d, J=8,4 Hz, 2H), of 7.97 (d, J=8,4 Hz, 2H), 7,14 (s, 1H), 4,15 (s, 2H), and 3.7 (s, 3H).

Part, Obtain methyl 3-(4-N-Boc-lidinopril)isoxazol - 5-racette.

To a solution of methyl 3-(4-amidinophenoxy)isoxazol-5-ylacetic, HCl salt (2.2 g, 7.4 mmol) in 30 ml DMF, cooled in an ice bath, was added triethylamine (of 2.06 ml of 14.8 mmol) and di-tert-BUTYLCARBAMATE (1.78 g, 8,14 mmol). The reaction mixture was warmed to room temperature and stirred for 64 hours and Then the reaction mixture was separated between EtOAc and water. The aqueous layer was washed with EtOAc. The organic layers were combined and washed with water, feast upon. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographically on silica gel (15%-25% EtOAc in hexane) to give 1.45 g (54% of the product);1H NMR (300 MHz, CDCl3) of 7.96 (d, J=8,4 Hz, 2H), 7,87 (d, J=8,4 Hz, 2H), 6,65 (s, 1H), 3,91 (s, 2H), and 3.8 (s, 3H), and 1.56 (s, 9H).

Part D. Obtain 3-(4-N-BOC-lidinopril)isoxazol-5-luxusni acid/

To a solution of methyl 3-(4-N-BOC-lidinopril)isoxazol-5-ilaclama (1.45 g, a 4.03 mmol) in 30 ml of methanol solution was added lithium hydroxide, monohydrate, (of € 0.195 g, with 4.64 mmol) in water (5 ml). The mixture was stirred 16 h at room temperature. Then the reaction dobavlyali 1 N HCl to pH 3-4 and the resulting acidic aqueous mixture was re-extracted with EtOAc. The organic layers were combined and washed with saturated NaCl, dried over Na2SO4, filtered and concentrated un vacuo, getting 0.97 g (70%) of product as not quite white powdery solid residue;1H NMR (300 MHz, d6- DMSO) 8,07 (d, J=8,79 Hz, 2H), of 7.97 (d, J=8,4 Hz, 2H), 7,03 (s, 1H), 3,99 (s, 2H), 1,45 (s, 9H).

Part E. Obtain methyl N2-n-butyloxycarbonyl-N3-[3-(4-N - BOC-lidinopril)isoxazol-5-ylacetic]-L-2,3-diaminopropionic.

To a solution of 3-(4-N-BOC-lidinopril)isoxazol-5-luxusni acid (0,262 g, from 0.76 mmol), methyl N2-carboxy-n-butyl-L-2,3 - diaminopropionic, HCl salt (0,193 g, from 0.76 mmol) and TBTU (0,256 g, 0.8 mmol) in DMF (15 ml) was added triethylamine (0.45 ml, of 3.23 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours the Reaction mixture was separated between EtOAc and water. The aqueous layer was twice washed with EtOAc. The organic layers were combined and washed with water, a buffer with a pH of 4.5% NaHCO3and saturated NaCl, dried on Na2SO4, filtered and evaporated in vacuo. The residue was chromatographically on silica gel (100% EtOAc) to yield 0,315 g (76%) light amber foam;1H NMR (300 MHz, CDCl3) to 7.93 (d, J= 8,42 Hz, 2H), 7,83 (d, J=8,42 Hz, 2H), and 6.6 (s, 1H), 6,57 (bm, 1H), 5,66 (bm, 1H), 4,45 (bm, 1H), of 4.05 (m, 2H), of 3.77 (s, 5H), and 3.7 (m, 2H), 1.57 in (s, 9H), and 1.56 (m, 2H), enil)isoxazol-5-ylacetic]-L-2,3-diaminopropionic, the TFA salt.

A solution of methyl N2-carboxy-n-butyl-N3-[3-(4-N-BOC - lidinopril)isoxazol-5-ylacetic]-L-2,3-diaminopropionic (0,215 g 0,39 mmol) in 1:1 methylene chloride/triperoxonane acid (total volume 20 ml) was stirred 16 h at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was chromatographically on silica gel (10-30% methanol in chloroform) to yield 0.11 g (50%) of a white solid residue;1H NMR (300 MHz, d6-DMSO) to 9.4 (bs, 2H), to 9.15 (bs, 2H), 8,45 (t, 1H), 8,11 (d, J=8,42 Hz, 2H), 7,94 (d, J= 8,42 Hz, 2H), 7,53 (d, J=of 8.06 Hz, 1H), 7,01 (s, 1H), 4,21 (m, 1H), 3,95 (t, 2H), 3,81 (s, 2H), 3,62 (s, 3H), 3,55 (m, 1H), 3,34 (m, 1H), 1,5 (m, 2H), 1,3 (m, 2H), 0,87 (t, J=to 7.32 Hz, 3H); mass spectrum (ESI, e/z, relative abundance) 446,5, (M+H)+, 100%.

Example 829

Methyl N2-n-butyloxycarbonyl-N3-[5-(4 - formamidine)isoxazolin-3-ylacetic]-(2S)-2,3-diaminopropionic

Part A. t-butyl{5-(4-cyanophenyl)isoxazolin-3-yl]acetate.

Cycloaddition of 4-cyanobenzylidene (MP&D chemical Co.) and tert-butylferrocene conducted according to the method Gree et al. (Bioorganic&Medicinal Chemistry letters 1994, 253), obtaining the desired isoxazoline with the release of 72%.

1H NMR (CDCl3) of 1.40 (s, 9H), of 3.00 (dd, J=8,3 and 17 Hz, 1H), 3,35 (dd (AB) J=18 and 8.3 Hz, 2H), 3,48 (m, 1H), ceiling of 5.60 (dd, J=9 and 4.5 Hz, 1H), 7,47 (d, J= 8 Hz, 2H), 7,65 (d, J= 8 Hz, 2H); if 2235, 1718, 1610 C2">

Hydrolysis of the compound of example 829, part a, with excess TFA in dichloromethane gave the acid with a yield of 90%.1H NMR (CDCl3) to 3.00 (dd, J=8 and 17.2 Hz, 1H), 3,55 (s, 2H) and 3.59 (m, 1H), to 5.66 (dd, J=8 and 11 Hz, 1H), 7,45 (d, J= 8,4 Hz, 2H), 7,66 (d, J= 8.0 Hz, 2H); IR 3325, 2235, 1718, 1605 cm-1. Mass spectrum m/z 231 (M+H, 100).

Part C. Methyl [5-(4-BOC-lidinopril)isoxazolin-3-yl]acetate.

Connection example 829, part B, was subjected to standard Pinner reaction conditions described in example 275, part G, to obtain amidinopropane, which, without purification, was treated with di-tert-BUTYLCARBAMATE in dioxane/water (9:1) and excess triethylamine, getting the desired compound with a yield of 28%.1H NMR (CDCl3) and 1.54 (s, 9H), 2,98 (dd, J=8 and 17 Hz, 1H), 3,49 (s, 2H), 3,53 (m, 1H), 3,71 (s, 3H), 5,63 (dd, J=8 & 11,4 Hz, 1H), 7,38 (d, 8.2 Hz, 2H), 7,82 (d, 8.2 Hz, 2H); mass spectrum m/z 362 (M+H, 8), 306(18), 262 (M+H-Boc, 100).

Part, [5-(4-BOC-lidinopril)isoxazolin-3-yl]acetic acid.

Hydrolysis of the ester LiOH under standard conditions gave the desired acid with a yield of 5%.1H NMR (CDCl3) and 1.54 (s, 9H), of 3.00 (dd, J=8 and 17 Hz, 1H), 3,51 (s, 2H), 3,53 (m, 1H), 5,63 (dd, J=8 & 11,4 Hz, 1H), 7,38 (d, 8.2 Hz, 2H), 7,82 (d, 8.2 Hz, 2H); mass spectrum m/z 348 (M+H, 12), 348 (M+H-Boc, 100).

Part D. Methyl N2-n-butyloxycarbonyl-N3- [5-(4 - formamidine) isoxazolin-3-ylacetic] boil-2,3-diaminopropionic way described in example 275, part b, receiving Boc-protected intermediate compound with a yield of 80%.1H NMR (CDCl3) to 0.89 (t, 3H), 1,32 (m, 2H), 1,53 (s, 9H), 1,17 (m, 2H), 2,95 (dd, J= 8 and 17 Hz, 1H), 3.33 and (s, 2H), 3.46 in (m, 1H), 3,60 (m, 2H), of 3.73 (s, 3H), 4.00 points (m, 2H), or 4.31 (m, 1H), ceiling of 5.60 (dd, J=8 and 11.4 Hz, 1H), 5,70 (bd, 1H), 6,70 (broad, 1H), 7,33 (d, 8.2 Hz, 2H), 7,89 (d, 8.2 Hz, 2H). Mass spectrum m/z 534 (M+H, 30), 434 (M+H-Boc, 100). Remove protection was carried out by treatment of the above Boc-amidino excess TFA in dichloromethane, receiving the specified compound as TFA salt.

1H NMR (CDCl3/DMSO-d6) a 1.88 (t, 3H), of 1.30 (m, 2H), 1,53 (m, 2H), 3,00 (dd, J= 8 and 17 Hz, 1H), 3,32 (s, 2H), 3,40-3,63 (m, 3H), 3,63 (d, 3H), 3,98 (t, 2H), 4,29 (m, 1H), ceiling of 5.60 (dd, J=8 & 11 Hz, 1H), 6,80 (d, 1H), 7,50 (d, J= 8 Hz, 2H), 7,80 (d, J=8,2 Hz, 2H) 8,03 (broad s, 1H), 9,05 (broad s, 2H); IR (KBr): 3388, 1718, 1664, 1620, 1528, 1456, 1436, 1384, 1366, 1280, 1254, 1168, 1144, 1074, 980, 882, 778 cm-1; mass spectrum (ES) m/z 448 (M+H, 100).

Using the above methods and their variations, known to experts in the field of organic synthesis, you can get more examples of tables 1 to 15.

Application

The compounds of this invention possess antiplatelet efficacy, as evidenced by their activity in the standard methods for determining platelet aggregation or binding of fibrinogen platelet described below. Believe that compounds the determination of platelet aggregation and binding to fibrinogen, which can be used to demonstrate the antiplatelet activity of the compounds of the invention.

Method for the determination of platelet aggregation. Venous blood was received from the hand of a healthy donor, which for at least two weeks prior to blood collection did not take drugs and aspirin. Blood was collected in 10 ml Vacuteiner tubes with citrate. Centrifuged blood 15 min at 1500g at room temperature and was collected platelet-rich plasma (SWEAT). The remaining blood was centrifuged for 15 min at 1500g at room temperature and selected does not contain platelets plasma (PBT). Samples primeraly on aggregometer (PAP-4 Platelet Aggregation Profiler), using as control PBT (100% transparency). In each microprobing for testing was added 200 μl of the POT and set to 0% transparency. To each tube was added 20 µl of various agonists (ADP, collagen, arachidonate, epinephrine, thrombin) and built the curves of aggregation (% transparency with respect to time). The results are expressed as % suppression caused by the agonist of platelet aggregation. To determine the IC50test compounds were added in various concentrations to activate platelets.

The esters of the prodrugs pre/SUP>C. Aliquots diluted with 0.1 M Tris, pH 7.4 to the required concentrations. Aliquots (20 μl) treated with esterase prodrugs added to 200 μl of platelet-rich plasma. The samples were placed in aggregometer for 8 min at 37oC, was then added 100 μl of ADP (Sigma Chemical Co., St. Louis, MO, # A - 6521) to induce platelet aggregation. The aggregation process was allowed to develop for 5 minutes, the Percentage of suppression is calculated as the percent aggregation in the presence of the test compound divided by the percentage of agreesee in control, multiplied by 100. This value is subtracted from 100, receiving a percentage of suppression. The calculation of the IC50held at Texas Instruments T program IC50.

Enzyme-linked immunosorbent assay (ELISA) binding of purified IIb/IIIa with fibrinogen

In ELISA binding IIb/IIIa-fibrinogen using the following reagents:

- cleaned IIb/IIIa (148, 8 persons μg/ml);

- biotinylated fibrinogen (approximately 1 mg/ml or 3000 nm);

- conjugate with alkaline phosphatase to Biotin (Sigma no. A);

- flat-bottomed, 96-well tablets with high binding (Costar Cat. no. 3590);

the substrate for the phosphatase (Sigma 104) (40 mg capsules);

- bovine serum albumin (BSA) (Sigma no. A);

buffer d: 20 mm Tris-HCl, 150 mm NaCl, 1 mm CaCl22H2O, 0.02% of NaN3, pH 7.0;

buffer A 50 mm Tris-HCl, 100 mm NaCl, 2 mm CaCl22H2O, 0.02% of NaN3, pH 7,4;

buffer A + 3,5% BSA (buffer for driving);

buffer A +0.1% BSA (dilution buffer);

- 2 N NaOH.

In ELISA binding IIb/IIIa with fibrinogen, use the following procedure.

Tablets saturate IIb/IIIa in the buffer for the binding of (125 ng/100 μl per well) overnight at 4oC (leave the first row of unsaturated to determine nonspecific binding). The tablet cover and freeze at -70oC before use. Defrost the tablet 1 h at room temperature or overnight at 4oC. Pour the saturating solution and washed 1 time with 200 ál/well of buffer for binding. Clogging the tablets produced by the buffer And + 3.5% BSA (buffer for driving) (200 XL/well) for 2 h at room temperature with shaking. Remove the buffer for driving and washed once with buffer A + 0.1% BSA (dilution buffer) (200 μl/well). Contribute to 11 μl of the test compounds (10x concentration from the one that should be tested in dilution buffer) per well (two parallel). Contribute to 11 ál of dilution buffer in the wells with non-specific and total binding.th concentration = 20 mm). Incubated tablets 3 h at room temperature on the shaker for the tablet. Remove the designated solution and wash each well twice with 300 ál of buffer for binding. Add to each well 100 ál conjugate with alkaline phosphatase to Biotin (1/1500 in dilution buffer). Incubated tablets 1 h at room temperature on the shaker for the tablet. Remove conjugate and wash each well with 300 ál of buffer for binding. Add 100 ál/well of substrate phosphatase (1.5 mg/ml in buffer for alkaline phosphatase). Incubate the plate at room temperature on the shaker until color development. Stop the color development by adding 25 μl of 2 N NaOH/well. Proberaum the plate at 405 nm. Control - well nonspecific binding (HCC). % suppression is calculated as

100-(absorption with the test compound/total absorption)X100.

The method of determining the binding of fibrinogen to platelets. Binding 125I-fibrinogen to platelets was performed as described (Bennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, with some modifications described below. Human SWEAT (h-POT) was applied on the column with separate to clean the fraction of platelets. Aliquots of platelets (5 x 108 cells) together with 1 mm the STES) person. Activation of purified on a gel of human platelets was performed using ADP, collagen, arachidonate, epinephrine and/or thrombin in the presence of ligand,125I-fibrinogen. Associated with125I-fibrinogen activated platelets were separated from free platelets by centrifugation and then counted on a gamma counter. To determine the IC50before activating the platelets were added to test compounds in different concentrations.

The compounds of formula I of the present invention may also possess thrombolytic efficacy, i.e. they are able to cause lysis of already formed platelet-rich blood clots, fibrin and therefore suitable for the treatment of blood clots, as evidenced by their activity in the following tests. Preferred compounds of the present invention for use in thrombolysis include those compounds in which the values of the IC50(i.e., the molar concentration at which achieved 50% lysis of clots) less than 1 μm, more preferably the value of the IC50less than 0.1 microns.

Determination of ability to thrombolysis. Venous blood was taken from the hands of a healthy donor, which for at least two weeks prior to blood collection is l500xg at room temperature and was collected platelet-rich plasma (SWEAT). Then the POT was added 110-3M agonist, namely ADP, epinephrine, collagen, arachidonate, serotonin or thrombin, or a mixture thereof, and incubated SWEAT 30 minutes the Supernatant was decanted, the remaining in vitro platelet resuspendable in not containing the platelet plasma (PBT), which served as a source of fibrinogen. The suspension was investigated by Coulter Counter (Coulter Electronics, Inc., Hialeah, FL) to determine the number of platelets at time 0. After receiving zero added test compound in various concentrations. Selected test samples at different points of time and thought platelets on the Coulter Counter. To determine the % lysis account of platelets in the time after addition of test compounds subtracted from the account of platelets at time 0. Multiply this result by 100 gave the percentage of clot lysis test data connection. To determine the IC50added test compound in various concentrations and expected % lysis caused by under test connected.

The compounds of formula I of the present invention are also suitable for administration in combination with anticoagulant drugs such as warfarin or heparin, or antiplatelet preprotein or argatroban, or thrombolytic drugs such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.

The compounds of formula I of the present invention can also be useful as antagonists of other integrins, such as, for example, or the vitronectin receptor, or both, in essence, can also be useful in the treatment and diagnosis of osteoporosis and metastasis in cancer, diabetic retinopathy, rheumatoid arthritis, inflammation and autoimmune diseases. The compounds of formula I of the present invention can be used in the treatment or prevention of other diseases, which include the processes of cell adhesion, including, but not limited to, inflammation, bone breakdown, rheumatoid arthritis, asthma, allergies, adult respiratory distress, the reaction of "graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.

Table 16 presents antiplatelet activity characteristic siedentop (using platelet-rich plasma (SWEAT)), values shown IC50(the concentration of antagonist, in which platelet aggregation is inhibited by 50% relative to control without antagonist). Table 16 values IC50marked as follows:

+++ = IC50< 10 μm, ++ = IC5010-50 μm + = IC5050-100 microns.

Dose and technology preparation of dosage forms

Compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes a form with a continuous or time-limited release of the active ingredient), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They also may be injected intravenously (ball or infusion), intraperitoneal, subcutaneous or intramuscular injection, using dosage forms well known to specialists in the field of pharmacology. An effective but non-toxic amount of the desired compounds can be used as protivoerozionnye drug.

The compounds of this invention can be administered by any means that creates the contact of the active substance from the place of action glycoprotein IIb/IIIa (IIb/IIIa), in the body of mammals. They can contain any traditional medicines, or in combination with drugs such as a second antiplatelet drug, namely aspirin or ticlopidine, which is agonist-specific. They can be entered in themselves, but mainly introduced together with a pharmaceutical carrier selected on the basis of the chosen route of administration and generally accepted pharmaceutical practice.

Regimen compounds of the present invention will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular drug and its form and route of administration; the species, age, gender, health status, medical conditions and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; the route of administration, the kidneys and the liver of the patient and the desired effect. Usually skilled physician or veterinarian can readily determine and prescribe the effective amount required to prevent, counter or stop disease progression.

As General guidance, the daily oral dosage of each active component in the application to achieve these effects will vary from 0.001 to 1000 mg/kg body weight, FAV is the preferred intravenous dose will be in the range of from about 1 to about 10 mg/kg/min constant rate infusion. It would be better if the connection of the present invention was administered as a single daily dose or the total daily dose was administered in the form of several separate doses of two, three or four times a day.

Compounds of the present invention can be introduced through the nose by means of respective intranasal carriers or transdermal routes, using the well-known specialists forms of transdermal skin patches. With the introduction in the form of a transdermal system introduction will be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention described compounds can form the active ingredient, and are typically introduced in a mixture with the corresponding pharmaceutical solvents, fillers or carriers, shown here under the General name substance-fillers, accordingly selected depending on the intended form of administration, i.e. oral tablets, capsules, elixirs, syrups, etc. and according to accepted pharmaceutical practice.

For example, in oral introduction in the form of tablets or capsules, the active ingredient can be combined with non-toxic oral, pharmaceutically tion, phosphate of potassium, calcium sulfate, mannitol, sorbitol, etc.,; in oral introduction in the form of a liquid dosage form, the oral drug components can be combined with any non-toxic oral, pharmaceutically acceptable, inert filler, such as ethanol, glycerol, water, etc. moreover, if desired or if necessary, the mixture can also be included appropriate binder, lubricant, dispersant compounds and dyes. To suitable binding agents include starch, gelatin, natural sugars, namely glucose or beta-lactose, corn fragrances, natural or synthetic gums such as acacia, tragant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc., lubricants used in these dosage forms include OMAT sodium, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc., Dispersing compounds include, without limitation, starch, methylcellulose, agar, bentonite, xanthene resin, etc.

Compounds of the present invention can also be administered in the form of liposomes, namely a small single-layer vesicles, large single-layer vesicles and Mamin or phosphatidylcholine.

Compounds of the present invention can also be associated with soluble polymers, acting as carriers of drugs, delivers it to the scene. Such polymers include polyvinylpyrrolidine, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethyleneoxide-polylysine, substituted residues of Palmitoyl. Moreover, the compounds of the present invention may be associated with polymers, degradable by bacteria, which is important when providing a controlled release of drugs, for example, polaktinova acid, polyarteritis, polyacetylene, policyidreference, polycyanoacrylate or sewn or amphipatic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 100 mg of the active ingredient per unit dose. The active ingredient in these pharmaceutical compositions will generally be present in an amount of about 0.5 to 95% by weight of the total weight of the composition.

The active ingredient can be administered orally in solid dosage form such as capsules, tablets and powders, or in jidlizolley liquid dosage form. Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and others. Such diluents can be used in the manufacture of tablets. Tablets and capsules can be manufactured in such a way as to support the release of products that provide drug release in a certain period of time. Tablets can be sugar coated or film that eliminates unpleasant taste and protect the tablet from the weather, or enteric coated for selective degradation in the gastrointestinal tract. Liquid dosage forms for oral administration can contain color or flavor additives, improving their patient. For parenteral solutions of suitable carriers are water, suitable oil, salt, aqueous dextrose (glucose), which are suitable sugar solutions and glycols such as propylene glycol or polyethylene glycols.

Solutions for parenteral administration preferably contain a water-salt solution of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Protiva in combination, are suitable stabilizing agents. Citric acid or its salts, and sodium ethylenediaminetetraacetate can also be used. In addition, parenteral solutions can contain stabilizers, such as benzalkonium, methyl - or propylparaben or chlorbutanol. Suitable farmatsevticheskii media described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference in this field.

Characteristic suitable for use dosage forms for the administration of compounds of this invention can be illustrated by the following examples.

Capsules

Capsules produced by filling a standard hard gelatin capsules consisting of two parts, each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

Prepare a mixture of the active ingredient in the edible oil such as soybean oil, cottonseed oil or olive oil and injected her with the help of a piston pump into gelatin to the formation of soft gelatin capsules containing 100 mg of the active component. The capsules are washed and dried.

Tablets

Tablets are prepared by traditional methods such about 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. To improve taste or delay suction can be applied to the appropriate shell.

Injection

A parenteral composition suitable for administration in the form of injections, is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. Solution make isotonic with sodium chloride and sterilized.

Suspension

Aqueous suspension is prepared for oral administration so that each 5 ml contains 100 mg of finely ground active ingredient, 200 mg of carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of a solution of sorbitol, U. S. P. and 0.025 ml of vanillin.

Compounds of the present invention can be administered in combination with a second drug selected from: anticoagulation tools, such as warfarin or heparin; protivotromboznoe medication, such as aspirin, piroxicam or ticlopidine; thrombin inhibitor, such as biopeptide thrombin inhibitor or hirudin, or thrombolytic drug, such as plasminogen activators, namely, tissue plasminogen activator, anistreplase, urokinase, or streptokinase. Soed one unit dose, in any dosage forms and by various routes of administration described above.

The compound of formula I together with a second drug may be included in the unit of a single dose (i.e., combined together in one capsule, tablet, powder or liquid, and so on). In this case, if the compound of formula I and the second drug are not part of the unit dose, the compound of formula I and the second drug (anticoagulant agent, protivotrematodoznye drug, an inhibitor of thrombin and/or thrombolytic drug) can be administered simultaneously or in any order; for example, the compound of formula I may be administered first followed by the introduction of a second drug (blood-money, protivotromboznoe drug, thrombin inhibitor, and/or thrombolytic drug). If the drugs are not at the same time, it is preferable that the introduction of the compounds of formula I and the second drug was carried out with an interval of less than 1 h

Preferred oral administration of the compounds of formula I. Although preferably the introduction of the compounds of formula I and a second drug (anticoagulant sredstva (so that is, for example, both drugs are introduced orally), if desired, they can be entered in different ways and in different dosage forms (i.e., for example, one component of the combination product may be administered orally, and the second component may be administered intravenously).

The dose of a compound of formula I with the introduction alone or in combination with a second drug may vary depending on various factors, namely the pharmacodynamic characteristics of the individual drug and the form and method of administration, age, health and weight of the recipient, the nature and extent of symptoms, kind of concurrent treatment, frequency of treatment and the desired effect, as described above.

Despite the fact that an appropriate dose of a compound of formula I in the case, if it is injected in combination with a second drug, is easily installed by experts, taking into account the present opening, as a General guide in cases where compounds of this invention can be combined with anticoagulant drugs, for example, the daily dose may be from about 0.1 to 100 mg of the compounds of formula I and about 1-7,5 mg anticoagul in the amount of from about 1 to 10 mg per unit dose and the anticoagulant in an amount of about 1-5 mg per unit dose.

In the case where the compounds of formula I are introduced into the mix in the second protivotromboznoe drug, as a General guidance, typically a daily dosage may be about 0.01 to 25 mg of the compounds of formula I and about 50-150 mg additional protivotromboznoe drug, preferably about 0.1-1 mg of the compounds of formula I and about 1-3 mg protivodiabeticakih drugs per 1 kg of body weight of the patient.

Further, as a General guideline, if the compounds of formula I are introduced in combination with a thrombolytic, a daily dose can typically be about 0.1-1 mg of the compounds of formula I per 1 kg of body weight of the patient and to thrombolytic usual dose thrombolytic drug, administered alone may be reduced to about 70-80% in the case when it is administered together with a compound of formula I.

In that case, if two or more of the above additional drug is introduced together with the compound of the formula I, generally, the amount of each component in the usual daily dose and conventional dosage form may be reduced relative to conventional doses, administered separately, taking into account the additive or synergistic effect of the drug is a mini interaction between the combined active ingredients. For this reason, if the compound of formula I and the second drug are combined in a single unit dose, they are prepared so that, despite their presence in a single unit dose, physical contact between the active components was minimized. For example, one of the active components may be covered intersolubility shell. Intersolubility shell of one of the active components allows not only to reduce the contact between the combined active ingredients, but also gives you the ability to control the release of one of the components in the gastrointestinal tract in such a way that one of these components will not be released in the stomach, and will be released in the small intestine. One of the active components may also be covered by a substance that controls the continuous secretion in the gastrointestinal tract, thus it serves to minimize physical contact between the active components. Moreover, continuously released component can be additionally covered intersolubility shell so that its release was only in the intestine. Additional accomplishments may include the preparation of a combination of the and release in the gut, and the second component is coated with such a polymer, as hypromellose with low viscosity or other suitable material known in the art, for further separation of active components. The polymer coating serves as an additional barrier to interaction with another component.

These, and other ways to reduce contact between the components of the combined product of the present invention, administered either in a single unit dose, or as separate dosage forms, but at the same time in the same way, will be obvious to those having a real discovery.

The present invention also includes pharmaceutical kits, for example, to inhibit platelet aggregation, treatment of blood clots and/or treatment of thromboembolic complications, which include one or more container containing a pharmaceutical composition comprising a therapeutically effective amount of compounds of formula I. Such kits can also include, if desired (one or more) of the various conventional components of pharmaceutical kits, namely, for example, containers with one or more pharmaceutically acceptable excipient, additional to the ISA, or labels indicating the number of components that must be entered, instructions for use and/or instructions for mixing the components.

In the present invention means that these materials and conditions are important for the implementation of the invention, but which are not excluded unspecified substances and conditions in order not to prevent the use of the invention from its implementation.

1. The isoxazolines of the formula I

< / BR>
or their pharmaceutically acceptable salt,

where b is a single bond;

R1represents a radical of the formula

< / BR>
Z represents O;

R2is selected from H and C2- C10alkoxycarbonyl;

U represents a single bond (i.e., U is not present);

V is phenyl;

W represents a single bond (i.e., W is not present)

X represents -(C1- C7alkyl) - substituted with 0 to 3 groups of R4;

Y is chosen from hydroxy, or C1- C10alkoxy;

R4selected from H or-N(R12R13;

R12and R13independently are H, C1- C10alkylcarboxylic, C1- C10alkylsulfonyl, phenyl(C1- C10alkyl)sulfonium or phenyl(C1- C10ALCO is to place H;

n = 0 - 4;

r = 0 - 3.

2. Connection on p. 1 of formula II

< / BR>
where R1represents a radical of the formula

< / BR>
R2is selected from H and C2- C10alkoxycarbonyl;

values of R14, X, V, Y, n and r are specified in paragraph 1.

3. Connection on p. 1, where R1represents a radical of the formula

< / BR>
n = 1 or 2; X is (C1- C2)-alkyl-, substituted 0 - 2 R4; R4is-NR12R13; R12is H, C1- C4alkylcarboxylic, C1- C4alkylsulfonyl, phenyl(C1- C10)alkylsulfonyl or phenyl(C1- C10alkoxy)carbonyl; R13is H.

4. Connection on p. 1 or its pharmaceutically acceptable salt, representing the connection, the following connections:

5(R,S)-3-[[4-(2-piperidine-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid;

5(R, S)-N-(butanesulfonyl)-L-{ 3-[4-(2-piperidine-4-yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R,S)-N-(-toluensulfonyl)-L-{3-[4-(2-piperidine-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;

5(R, S)-N-[(benzyloxy)carbonyl)-L-{ 3-[4-(2-piperidine-4-yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R, S)-N-(pentanoyl)-L-{ 3-[4-(2-piperidine-4-yl)ethoxyphenyl] isoxazolin-5-yl}glycine;

5(R,S)-[4-uridin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R,S)-5(R,S)-N-(-toluensulfonyl)amino{3-[4-(piperidine-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R, S)-5(R, S)-N-[(benzyloxy)carbonyl] amino-{ 3-[4-(piperidine-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;

2(R, S)-5(R, S)-N-(pentanoyl)amino-{ 3-[4-(piperidine-4-yl)methoxyphenyl] isoxazolin-5-yl}propanoic acid;

5. The isoxazolines or isoxazoles of the formula I

< / BR>
or its pharmaceutically acceptable salt,

where b is a single or double bond;

R1is R2(R3)N(R2N=)C-, R2a(R3)N(CH2)qZ-, R2(R3)N(R2N=)CN(R2or

< / BR>
Z is selected from O or S;

R2and R3independently selected from H, C1- C10of alkyl, C3- C11cycloalkyl, C7- C11arylalkyl, C1- C10alkoxycarbonyl or aryl(C1- C10alkoxy)carbonyl;

R2ais selected from R2or R2(R3)N(R2N=C;

U is selected from a single bond and phenyl;

V is selected from a single bond; C1- C7of alkyl, phenyl and (phenyl)-Q specified phenyl substituted by 0 to 2 groups independently selected from R6or R7; or -(pyridyl)-Q;

Q is selected from a single CT-C(R4)(R8)-CHR4a-;

R4represents hydrogen;

R4arepresents hydrogen or-N(R16R17;

Y is selected from hydroxy or C1- C10alkyloxy;

R8is selected from R6C1- C10of alkyl, substituted 0 - 3 R6C2- C10the quinil, substituted with 0 to 3 R6, phenyl or pyridyl;

R6is selected from hydrogen, C1- C10of alkyl, halogen, -N(R12R13C1- C10alkoxy, CO2R5C(= O)R5a, CONR5R5a, NR5aSO2NR5R5a, NR5aSO2R5, SR5a, SiMe3, phenyl, pyrrolidinyl or pyridyl;

R7is selected from H, C1- C4of alkyl, C1- C10alkoxy and halogen;

R5is selected from H, C1- C8of alkyl, C3- C11cycloalkyl, phenyl, phenylethyl;

R5ais selected from hydrogen, hydroxy, C1- C8of alkyl, phenyl, phenylethyl, adamantylamine or C1- C10of alkyl, substituted 0 - 2 R4b;

or R5and R5aboth as substituents on the same nitrogen atom may join together with the nitrogen atom to which they are attached, form a 3-Isabelline or 1-piperazinil, possibly replaced by vinylmation;

R4brepresents methoxy, NMe2, NH2or COOH;

R12and R13independently are H, C1- C10the alkyl or C1- C10alkylcarboxylic;

R14is selected from H or CO2R5where R5represents C1- C8alkyl;

R15is selected from H or OH;

R16is selected from-C(= O)-O-R18a, -C(= O)-R18b, -C(=O)-N(R18b)2, -SO2-R18a, -SO2-N(R18b)2;

R17is selected from H and C1- C10of alkyl;

R18ais selected from C1- C8of alkyl, substituted 0 - 2 R19; C2- C8alkenyl, substituted 0 - 2 R19; C3- C8cycloalkyl, substituted 0 - 2 R19; aryl substituted with 0 4 R19; aryl(C1- C6the alkyl), substituted 0 - 4 R19; 5 - to 10-membered heterocyclic system containing 1 to 3 heteroatoms, selected independently from O, S or N, specified heterocyclic ring, substituted 0 - 4 R19;

R18bis selected from R18aor H;

R19is selected from H, halogen, CF3, CN, NR12R13C1- C8of alkyl, C3- C11cycloalkyl, phenyl, ethoxalyl, pyrazolyl, p is= 0 - 3;

provided that n, q and r are chosen so that the number of atoms linking R1and Y is in the range of 8 - 18.

6. Connection on p. 5, formula Ia

< / BR>
where b represents a single bond;

R1is selected from R2(R3)N(R2N=C;

Z is selected from O or S;

R2and R3independently selected from H or C1- C10alkoxycarbonyl;

W represents -(CH2)nC(=O)NH-;

X represents C(R4)(R8)-CH2-;

Y is hydroxyl or C1- C10alkyloxy;

R8is selected from R6; C1- C10of alkyl, substituted 0 - 3 R6; C2- C10the quinil, substituted with 0 to 3 R6; phenyl or pyridyl;

R6is selected from C1- C10of alkyl, N(R12R13, CO2R5C(=O)R5a, CONR5R5a, NR5aSO2NR5R5a, NR5aSO2R5, SR5a, SiMe3, phenyl, pyrrolidinyl or pyridyl;

R5is selected from H, C1- C8of alkyl, phenyl or Venetia;

R5ais selected from hydrogen, hydroxyl, phenyl, Venetia, adamantylamine or C1- C10of alkyl, substituted 0 - 1 Rin-NR5R5a), can be taken together with the nitrogen atom to which they are attached to form a 3-azabicycloalkanes, 1,2,3,4-tetrahydro-1-chinoline, 1,2,3,4-tetrahydro-2-izochinolina, 1-pyrrolidinyl, thiomorpholine, thiazolidine or 1-piperazinil, optionally substituted vinylmation;

R4bis selected from methoxy, NMe2, NH2, imidazole or COOH;

R12and R13each independently selected from H, C1- C10of alkyl, C1- C10alkylcarboxylic.

7. Connection on p. 6, where Z is selected from the connection, O.

8. Connection on p. 6, where X is-CHR8CH2-; Y is hydroxy; R6is selected from C1- C4of alkyl, -N(R12R13, CO2R5; R8is selected from C1- C10of alkyl, substituted 0 - 3 R6C2- C10the quinil, substituted with 0 to 3 R6, phenyl; R12is selected from H, C1- C6of alkyl, C1- C6alkylcarboxylic; R13is H.

9. Connection on p. 5 or its pharmaceutically acceptable salt, representing a compound selected from:

3(R,S)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-yl-acetyl]amino}-3-phenylpropane acid;

3(R,S)-{5(R,S)-N-[3-(4-amidine]amino}-heptane acid;

3(R, S)-{ 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-yl-acetyl]amino}-4-(phenylthio)butane acid;

3(R, S)-{ 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-yl-acetyl]amino}-4-(phenylsulfonyl)butane acid;

3(R, S)-{ 5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-yl-acetyl]amino}-4-(n-butylsulfonyl)butane acid;

3(S)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3-(adamantanecarbonyl)propanoic acid;

3(S)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3-(1-azabicyclo[3.2.2]noninterbank)propanoic acid;

3(S)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3-(penicillinaseand)propanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3-(3-pyridylethyl)propanoic acid;

3(R)-{5(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]amino}-3-(2-pyridylethyl)propanoic acid;

3(R)-{ 5(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic] amino} -3-(phenylpropyl)propanoic acid.

10. Connection on p. 5 formula Ic:

< / BR>
where b represents a single or double bond;

R1is selected from R2(R3)N(R2N=)C-, R2(R3)N(R2N=)C(CH2)qZ-, R2(R3)N(R2N= )CN(R2)- or

< / BR>
Z UB>3- C11cycloalkyl, C7- C11arylalkyl, aryl(C1- C10alkoxy)carbonyl or C1- C10alkoxycarbonyl;

R2ais an R2or R2(R3)N(R2N=C;

U represents a single bond;

V is selected from: a single bond, -C1- C7the alkyl-, -(phenyl)-Q-, with the specified phenyl substituted by 0 to 2 groups independently selected from R6or R7or (pyridyl)-Q-;

Q is selected from a single bond, -CH2-, -OCH2-;

W represents (C(R4)2-C(=O)-N(R5a)-;

X represents-C(R4)(R8)-CHR4a-;

R4is selected from H;

R4arepresents-N(R16R17;

R5ais selected from hydrogen or C1to C8of alkyl;

Y is selected from hydroxy, C1to C10alkyloxy;

R6and R7each independently selected from H, halogen, methyl or methoxyl;

R12or R13each is selected from H, C1- C10the alkyl or C1- C10alkylcarboxylic;

R15is selected from H or OH;

R16is selected from: -C(=O)-O-R18a, -C(=O)-R18b, -C(=O)N(R18b)2, -SO2-R18athe 1 - C8of alkyl, substituted 0 - 2 R19C2- C8alkenyl, substituted 0 - 2 R19C3- C8cycloalkyl, phenyl or naphthyl, substituted with 0 4 R19, phenyl(C1- C6alkyl)-, substituted 0 - 4 R19system of heterocyclic rings selected from pyridinyl, thiazolyl, teinila, pyrazolyl, imidazolyl, chinoline, isoxazolyl, benzimidazolyl, benzothiazolyl and diimidazole, and specified heterocyclic ring is substituted by 0 to 4, R19;

R18bselected from R18aor hydrogen;

R19is selected from H, halogen, CF3, CN, NR12R13C1- C8of alkyl, C1- C6alkoxyl, C3- C11cycloalkyl, phenyl, ethoxalyl, pyrazolyl, pyridinyl or C1- C4alkoxycarbonyl;

n = 0 - 4;

q = 1 to 7;

r = 0 - 3;

provided that n, q and r are chosen so that the number of atoms in the chain between R1and Y was in the range of 8 to 17.

11. Connection on p. 10 formula Ib

< / BR>
where R1is selected from R2NH(R2N=)C-, R2NH(R2N=)CNH or

< / BR>
n = 0 - 1;

Z is selected from O;

V is a single bond, -(phenyl)- or -(pyridyl)-;

R16is selected from-C(= O)-O is .10, where R1is R2NH(R2N=)C -, or R2HN(R2N)CNH-; and V is phenylene or peridinin; or R1is

< / BR>
V is a single bond;

n = 1 or 2;

R18ais selected from C1- C4of alkyl, substituted 0 - 2 R19C2- C4alkenyl, substituted 0 - 2 R19C3- C7cycloalkyl, substituted 0 - 2 R19, phenyl or naphthyl, substituted with 0 4 R19, phenyl(C1- C6alkyl)-, substituted 0 - 4 R19system of heterocyclic rings selected from pyridinyl, thiazolyl, teinila, pyrazolyl, imidazolyl, chinoline, benzimidazole, and the specified heterocyclic ring is substituted by 0 to 4, R19.

13. Connection on p. 5 or its pharmaceutically acceptable salt, representing a compound selected from:

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(phenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(4-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(butanesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} and the 5(R, S)-yl} acetyl] -N2-(econsultancy)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(ethoxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl]-N2-(1-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl]-N2-(2-propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(S)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(S)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazole isoxazolin-5(R, S)-yl} acetyl]-N2-(1-(2-methyl)propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl]-N2-(2-(2-methyl)propylenecarbonate)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R)-yl}acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(S)-yl}acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-methoxybenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-chlorobenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-bromobenzyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-forantimicrobial)-2,3-(S)-diaminopropanol acid;

The N acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(2-(methoxyethyl)oxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-pyridylcarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(3-pyridylcarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-pyridylcarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-(2-pyridinyl)acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-(3-pyridinyl)acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-(4-pyridinyl)acetyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(3-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(4-pyridyl-methyloxycarbonyl)-2,3-what anysurfer)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl]-N2-(2-thienylmethyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(S)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(S)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-iodinesulphur)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(3-triftormetilfullerenov)-2,3-(S)-who were radioactive)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(3-2-methoxycarbonylaminophenyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-triftormetilfullerenov)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-triftormetilfullerenov)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-perpenicular)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-perpenicular)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-methoxybenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(2,3,5,6-tetramethylbutylphenol)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}azeti the 5(R,S)-yl}acetyl]-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-propylpentanoic)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-phenylethylamine)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(4-isopropylbenzenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(3-phenylpropionyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(phenylenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(dimethylaminomethyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(2-fluoro-4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)isoxazolin-5(R, S)-yl}acetyl]-N2-(n-Butylochka]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)isoxazolin-5(R, S)-yl}acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)isoxazolin-5(R, S)-yl}acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(phenylenecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(4-ftorpolimernoj)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl]-N2-(1-naphthalenesulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(3-bromo-2-thienylmethyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(3-methyl-2-benzothiazolone)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R, S)-yl} acetyl] -N2-(isobutylketone)-2,3-(S)-diaminopropanol acid;

N3-[2-{3-(4-formamidine)isoxazolin-5(R)-yl}acetyl]-N2-(isobut the]-N2-(isobutylketone)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R,S)-yl}acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(R)-yl} acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-formamidine)isoxazolin-5(S)-yl} acetyl]-N2-(2-cyclopropanecarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinate)isoxazolin-5(R, S)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinate)isoxazolin-5(R)-yl} acetyl] -N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 3-(4-guanidinate)isoxazolin-5(R)-yl} acetyl] -N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanol acid;

N3-[2-{ 5-(4-formamidine)isoxazolin-5(R, S)-yl}acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanol acid.

14. Connection on p. 5 or enantiomerically or diastereomeric forms or a mixture of enantiomers or diastereomers or pharmaceutically acceptable salt, characterized in that it is a compound selected from:

N3-[2-{3-(4-formamidine)isoxazolin-5-yl}acetyl]-N2-(phenylsulfonyl)-2,3-dieulivol)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(butanesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(propanesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(econsultancy)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2(methyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2(ethoxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(1-propylenecarbonate)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-propylenecarbonate)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(n-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(1-(2-methyl)-propylenecarbonate)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-(2-methyl)profilaktika unselectable)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-methylbenzyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-methoxybenzenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-chlorobenzenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-bromobenzyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-forantimicrobial)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-phenoxybenzenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-(methoxyethyl)-oxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-pyridylcarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(3-pyridylcarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine the-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-(2-pyridinyl)-acetyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-(3-pyridinyl)-acetyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-(4-pyridinyl)-acetyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-pyridylmethylene)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(3-pyridylmethylene)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-pyridylmethylene)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-thienylmethyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-iodinesulphur)-2,3-diaminopropane Kislova acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(3-chlorophenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(3-2-methoxycarbonylaminophenyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-chlorophenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-triftormetilfullerenov)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-triftormetilfullerenov)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-perpenicular)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-perpenicular)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-methoxybenzenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine 3
-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(4-cyanobenzylidene)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-chlorophenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-propylpentanoic)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-phenylethylamine)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-isopropylbenzenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(3-phenylpropionyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(3-pyridylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(phenylenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(benzylaminocarbonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(dimethyl]-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)-isoxazolin-5-yl} -acetyl]-N2-(n-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)-isoxazolin-5-yl} -acetyl] -N2-(methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)-isoxazolin-5-yl} -acetyl]-N2-(n-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)-isoxazolin-5-yl} -acetyl]-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2(phenylenecarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(4-ftorpolimernoj)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(1-naphthalenesulfonyl)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2(benzylaminocarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(3-bromo-2-thienylmethyl)-2,3-diaminopropane is of IMT-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2(isobutylketone)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-cyclopropanecarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-guanidinium)-isoxazolin-5-yl} -acetyl] -N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-guanidinium)-isoxazolin-5-yl} -acetyl]-N2-(n-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(n-butyloxycarbonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl] -N2-(2-brompheniramine)-2,3-diaminopropionic acid;

N3-[2-{ 3-(4-formamidine)-isoxazolin-5-yl} -acetyl]-N2-(2-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(3-formamido-6-pyridinyl)-isoxazolin-5-yl} -acetyl]-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(2-formamido-5-pyridinyl)-isoxazolin-5-yl} -acetyl]-N2-(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;

N3-[2-{ 3-(2-fluoro-4-formamidine)-isoxazolin-5-yl)-isoxazolin-5-yl} -acetyl] -N2-(3-brompheniramine)-2,3-diaminopropionic acid;

N3-[2-{3-(4-formamidine)-isoxazolin-5-yl}-acetyl]-N2-(4-brompheniramine)-2,3-diaminopropionic acid;

these enantio and diastereoisomers, selected from: (R,S), (R,S); (R), (R, S); (S), (R,S); (R) (R); (S), (R); (R), (S); (S) (S).

15. Connection on p. 14 or its enantiomers or diastereoisomers or of a mixture enantiomerically or diastereomeric forms or its pharmaceutically acceptable salt, characterized in that the said enantiomerically and diastereomeric form is: (R) (S).

16. The ester compounds on p. 14, selected from the group comprising methyl, ethyl propyl.

17. The isoxazolines of the formula Id

< / BR>
and its pharmaceutically acceptable salt,

where R1is an R2(R3)N(R2N=)C -, or

< / BR>
R3represents H or C1- C10alkyl;

Z represents a single bond;

R2is H or C1- C10by alkyl;

U represents a single bond;

V represents a single bond or phenyl;

Y represents hydroxy or C1to C10alkoxy;

R14and W are attached to the same gulley N;

p = 1 or 2;

n = 0-4.

18. The isoxazolines of the formula I:

< / BR>
or its pharmaceutically acceptable salt,

where b is a single bond;

R1is R2(R3)N(R2N=C;

R2and R3independently selected from N or C1-C10of alkyl;

U represents a single bond;

V is phenylene;

X represents -(C(R4)2)n-C(R4) (R4A)-;

R4is hydrogen;

R4Ais hydrogen;

W is selected from:

< / BR>
< / BR>
< / BR>
Y represents hydroxy or C1to C10alkoxy;

Z1is-S - or-NR22-;

Z2is-NR22-; R14and R15- N.;

R22represents hydrogen or connection with X;

m = 0-2;

p = 1-2;

n = 0-2.

19. Connection on p. 18 formula IC

< / BR>
where R2and R3hydrogen;

X is CHR4awhere R4arepresents hydrogen.

20. Connection on p. 18 formula Ib

< / BR>
where R1is R2NH(R2N=C;

R2is N or C1-C5alkyl;

V - -(phenyl)-;

X represents-CH2-;

Y is selected from hydroxy, C1-C10alkoxy, C1-C10alkoxy;

R22- H.

22. Connection on p. 18 or its pharmaceutically acceptable salt is a:

2-(R, S)-2-carboxymethyl-1-(5-(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]piperidine;

2-(R, S)-2-carboxymethyl-1-(5-(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]azepin;

2-(R, S)-2-carboxymethyl-1-(5-(R,S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]pyrrolidin;

3-(R, S)-carboxymethyl-1-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]piperazine-2-he;

6-(R, S)-carboxymethyl-1-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]piperidine-2-he;

5-(R, S)-carboxymethyl-1-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]pyrrolidin-2-he;

7-(R, S)-carboxymethyl-1-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]azetidin-2-he;

2-(R, S)-carboxymethyl-1-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]pyrazolidine;

3-(R, S)-carboxymethyl-4-(5-(R, S)-N-[3-(4-amidinophenoxy)isoxazolin-5-ylacetic]morpholine.

23. Pharmaceutical composition that inhibits platelet aggregation, characterized in that it contains a therapeutically effective amount of the compounds on p. 1, 5, 10, 17 and 18 and a pharmaceutically acceptable filler.

24. The method of suppressing platelet aggregation, otlichayushiesya connection PP.1, 5, 17 or 18.

Priority points and features:

24.11.93 on PP.1 - 24, where b represents a single bond;

22.04.94 on PP.6, 10 - 13, 18 - 22, where b is a single bond;

10.11.94 on PP.1 - 24, where b is a double bond.

 

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